Use of xanthine oxidase inhibitor febuxostat inhibits renal interstitial inflammation and fibrosis in unilateral ureteral obstructive nephropathy.

BACKGROUND: Renal interstitial fibrosis is the common pathway in progressive renal diseases, where oxidative stress promotes inflammation and macrophage infiltration. Febuxostat is a novel nonpurine xanthine oxidase (XO)-specific inhibitor for treating hyperuricemia. While some reports suggest a relationship between hyperuricemia and chronic kidney disease (CKD), the renoprotective mechanism of an XO inhibitor in CKD remains unknown. Recent reports have focused on XO as a source of oxidative stress. METHODS: Here, we investigate the potential of febuxostat to reduce fibrogenic and inflammatory responses in an established interstitial fibrosis model-unilateral ureteric obstruction (UUO). Male Sprague-Dawley rats were divided into three groups: sham-operated group, vehicle-treated UUO group, and febuxostat-treated UUO group. RESULTS: Treatment with febuxostat diminished XO activity in obstructed kidneys, and suppressed nitrotyrosine, a marker of oxidative stress. Consequently, febuxostat inhibited early proinflammatory cytokine expression, followed by a reduction of interstitial macrophage infiltration. In addition, febuxostat suppressed transforming growth factor-ß messenger RNA expression, thereby ameliorating smooth muscle alpha actin and type I collagen expression. CONCLUSION: Our results provide evidence for the renoprotective action of febuxostat against the formation of interstitial fibrosis. A decrease in macrophage infiltration and interstitial fibrosis, along with a decrease of the oxidative stress marker, strongly suggests the existence of a causal relationship between them. Febuxostat may have therapeutic value in slowing or preventing interstitial fibrosis in patients with CKD.

Performance of the Japanese GFR equation in potential kidney donors.

BACKGROUND: Japanese GFR equation was developed from mainly chronic kidney disease (CKD) subjects. Only a small number of healthy subjects were included in the development and validation of the GFR equation. We assessed the performance of the equation in potential kidney donors. METHODS: A total of 113 potential kidney donors was included. The data of CKD subjects that were previously reported were also included for comparison. GFR (mGFR) was measured by inulin clearance. The estimated GFR (eGFR) was calculated by the Japanese GFR equation. Bias of the equation (eGFR - mGFR) and urinary creatinine excretion were evaluated. RESULTS: There was no significant difference between eGFR and mGFR in 340 CKD subjects (54.2 ± 31.6 and 55.7 ± 33.2 ml/min/1.73 m(2), respectively). Contrarily, the eGFR was significantly lower than mGFR in 113 potential kidney donors (78.9 ± 16.2 and 93.6 ± 19.2 ml/min/1.73 m(2), respectively). The biases in potential kidney donors with eGFR 30-59 and 60-89 ml/min/1.73 m(2) were significantly greater than those in CKD subjects (-19.2 ± 12.2 and -18.3 ± 16.4 ml/min/1.73 m(2) in potential kidney donors and -3.8 ± 15.6 and -3.4 ± 17.6 ml/min/1.73 m(2) in CKD subjects, respectively). Creatinine excretion per body weight of potential kidney donors was significantly higher than that of CKD subjects, suggesting higher creatinine generation in potential kidney donors. CONCLUSION: The Japanese GFR equation underestimated GFR in potential kidney donors. Higher creatinine generation compared with CKD subjects may contribute to the underestimation of GFR by the Japanese GFR equation in potential kidney donors.

A nonerythropoietic derivative of erythropoietin inhibits tubulointerstitial fibrosis in remnant kidney.

BACKGROUND: The tissue-protective effects of erythropoietin (EPO) have been extensively investigated, and EPO administration can raise the hemoglobin (Hb) concentration. Recently, we reported that carbamylated erythropoietin (CEPO) protected kidneys from ischemia-reperfusion injury as well as EPO. METHODS: To investigate the clinical applications of CEPO, we next evaluated the long-term therapeutic effect of CEPO using a tubulointerstitial model rat. We randomized remnant kidney model rats to receive saline, EPO, or CEPO for 8 weeks. RESULTS: CEPO- and EPO-treated rats had improved serum creatinine levels compared with saline-treated remnant kidney model rats, although the Hb level was significantly increased in EPO-treated rats. Two-photon microscopy revealed that EPO/CEPO significantly ameliorated tubular epithelial cell damage assessed by endocytosis. In addition, CEPO or EPO protected endothelial cells with a sustained blood flow rate. EPO or CEPO suppressed the number of TUNEL-positive apoptotic cells with weak αSMA staining. Furthermore, PCR analysis demonstrated that TGF-ß and type I collagen expression was attenuated in EPO- or CEPO-treated rats, accompanied by a significant decrease in interstitial fibrosis. CONCLUSION: We established a long-term therapeutic approach to protect tubulointerstitial injury with CEPO, and thus, the therapeutic value of this approach warrants further attention and preclinical studies.