Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, but whether it is effective for human diabetic nephropathy is unknown. We conducted a randomized, double-blind, placebocontrolled study in 77 subjects with diabetic nephropathy who had elevated albuminuria and reduced estimated GFR (eGFR) (20 to 75 ml/min per 1.73 m 2 ). The prespecified primary outcome was a change in eGFR after 1 year of therapy. We randomly assigned 26 subjects to placebo, 26 to pirfenidone at 1200 mg/d, and 25 to pirfenidone at 2400 mg/d. Among the 52 subjects who completed the study, the mean eGFR increased in the pirfenidone 1200-mg/d group (ϩ3.3 Ϯ 8.5 ml/min per 1.73 m 2 ) whereas the mean eGFR decreased in the placebo group (Ϫ2.2 Ϯ 4.8 ml/min per 1.73 m 2 ; P ϭ 0.026 versus pirfenidone at 1200 mg/d). The dropout rate was high (11 of 25) in the pirfenidone 2400-mg/d group, and the change in eGFR was not significantly different from placebo (Ϫ1.9 Ϯ 6.7 ml/min per 1.73 m 2 ). Of the 77 subjects, 4 initiated hemodialysis in the placebo group, 1 in the pirfenidone 2400-mg/d group, and none in the pirfenidone 1200-mg/d group during the study (P ϭ 0.25). Baseline levels of plasma biomarkers of inflammation and fibrosis significantly correlated with baseline eGFR but did not predict response to therapy. In conclusion, these results suggest that pirfenidone is a promising agent for individuals with overt diabetic nephropathy.

II induces vasoconstriction, at least in part, by stimulating NADPH oxidase and generating reactive oxygen species. ANG II also induces heme oxygenase activity, and bilirubin, a product of such activity, possesses antioxidant properties. We hypothesized that bilirubin, because of its antioxidant properties, may reduce the pressor and prooxidant effects of ANG II. Our in vivo studies used the hyperbilirubinemic Gunn rat which is deficient in the enzyme uridine diphosphate glucuronosyl transferase, the latter enabling the excretion of bilirubin into bile. ANG II (0.5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) or saline vehicle was administered by osmotic minipump to control and Gunn rats for 4 wk. The rise in systolic blood pressure induced by ANG II, as observed in control rats, was markedly reduced in Gunn rats, the latter ϳ50% less at 3 and 4 wk after the initiation of ANG II infusion. The chronic administration of ANG II also impaired endothelium-dependent relaxation responses in control rats but not in Gunn rats. As assessed by the tetrahydrobiopterin/dihydrobiopterin ratio, ANG II induced oxidative stress in the aorta in control rats but not in Gunn rats. Heightened generation of superoxide anion in aortic rings in ANG II-infused rats and by vascular smooth muscle cells exposed to ANG II was normalized by bilirubin in vitro. We conclude that the pressor and prooxidant effects of ANG II are attenuated in the hyperbilirubinemic Gunn rat, an effect which, we speculate, may reflect, at least in part, the scavenging of superoxide anion by bilirubin. NADPH oxidase; heme oxygenase; nitric oxide; endothelial function ANG II ACTIVATES THE NADPH oxidase enzyme system and promotes the generation of superoxide anion and other reactive oxygen species (15,25,36,40,43). Such stimulation of superoxide anion contributes significantly to the vasoconstrictive and pressor effects of ANG II, as demonstrated by studies that use antioxidants including those that scavenge the superoxide anion (25,36,40,43). Indeed, it is generally accepted that systemic hypertension induced by the chronic administration of ANG II in rodents arises, at least in part, from the generation of superoxide anion as NADPH oxidase is activated by ANG II (25,36,40,43).Our prior studies as well as the studies of others demonstrate that systemic administration of ANG II leads to marked upregulation of heme oxygenase-1 (HO-1) (4, 15, 49). HO is the rate-limiting enzyme in the degradation of heme, enabling the conversion of heme to biliverdin, in the course of which carbon monoxide evolves and iron is liberated from the heme ring; subsequently, biliverdin is converted to bilirubin (2,3,31,32,39). The HO-1 isoform is rapidly induced by diverse stimuli and often confers a cytoprotective, anti-inflammatory, and vasorelaxant effect (2,3,31,32,39). The induction of HO-1 following the administration of ANG II likely exerts a countervailing, vasorelaxant effect: prior upregulation of HO-1 reduces the rise in systemic blood pressure induced by ANG II, whereas inhibition of HO activity exace...

Contrast-induced acute kidney injury (CIAKI) is a leading cause of iatrogenic renal failure. Multiple studies have shown that patients with diabetic nephropathy are at high risk of CIAKI. This Review presents an overview of the pathogenesis of CIAKI in patients with diabetic nephropathy and discusses the currently available and potential future strategies for CIAKI prevention.

Increased release of renal adenosine and stimulation of renal adenosine receptors have been proposed to be major mechanisms in the development of contrast media-induced acute renal failure (CM-ARF). Patients with diabetes mellitus or preexisting renal disease who have reduced renal function have a markedly increased risk to develop CM-ARF. This increased risk to develop CM-ARF in patients with diabetes mellitus is linked to a higher sensitivity of the renal vasculature to adenosine, since experimental studies have shown increased adenosine-induced vasoconstriction in the kidneys of diabetic animals. Furthermore, recent evidence suggests that administration of adenosine receptor antagonists reduces the risk of development of CM-ARF in both diabetic and nondiabetic patients. The purpose of this review is to discuss the role of adenosine in the development of CM-ARF, particularly in the kidneys of diabetic patients, and to evaluate the therapeutic potential of adenosine receptor antagonists in the prevention of CM-ARF. Selective adenosine A1 receptor antagonists may provide a therapeutic tool to prevent CM-ARF in patients with diabetes mellitus and reduced renal function.

Results: A total of 11,516 contrast exposures in 7977 patients had creatinine values available for review before and after contrast exposure. More than 90% of exposures to agents prophylactic for contrast nephropathy were available for analysis. Sodium bicarbonate was used in 268 cases, N-acetylcysteine was used in 616 cases, and both agents were used in combination in 221 cases of contrast exposure. After adjustment for total volume of hydration, medications, age, gender, prior creatinine, contrast iodine load, prior exposure to contrast material, type of imaging study, heart failure, hypertension, renal failure, multiple myeloma, and diabetes mellitus, use of sodium bicarbonate alone was associated with an increased risk of contrast nephropathy compared with no treatment (odds ratio 3.10, 95% confidence interval 2.28 to 4.18; P < 0.001). N-acetylcysteine alone and in combination with sodium bicarbonate was not associated with any significant difference in the incidence of contrast nephropathy.Conclusions: The use of intravenous sodium bicarbonate was associated with increased incidence of contrast nephropathy. Use of sodium bicarbonate to prevent contrast nephropathy should be evaluated further rather than adopted into clinical practice.

Various forms of renal replacement therapies (RRT) are available to treat acute kidney injury (AKI) after cardiac surgery. The objective of this review is to assess the incidence of postoperative AKI that necessitates the application of haemofiltration in adult patients undergoing cardiac operations with cardiopulmonary bypass (CPB), to determine the factors that influence the outcome in these patients. In addition, the review aims to assess the outcomes of postoperative early haemofiltration as compared to late intensive haemofiltration. Different forms of RRT such as intermittent haemodialysis, continuous haemofiltration, or hybrid forms which combine advantages of both are now available for application in cardiac surgery patients, and will be discussed in this article. The underlying disease, its severity and stage, the aetiology of AKI, clinical and haemodynamic status of the patient, the resources available, and different costs of therapy may all influence the choice of the RRT strategy. AKI, with its risk of uraemic complications, represents an independent risk factor for adverse outcomes in critically ill patients after cardiac surgery. Whether early initiation of RRT is associated with improved survival is unknown, and also clear guidelines on RRT durations are still lacking. In particular, it remains unclear whether haemodynamically unstable patients who develop septic shock pre- and postoperatively can benefit from early RRT initiation. In addition, it is not known whether in AKI patients undergoing cardiac surgery RRT modalities can eliminate significant amounts of clinically relevant inflammatory mediators. This review gives an update of information available in the literature on possible mechanisms underlying AKI and the recent developments in continuous renal replacement treatment modalities.

In rats with streptozotocin (STZ)-induced diabetes, the renal vasoconstrictor effect of adenosine is enhanced. We investigated the role of nitric oxide (NO) in the renal vascular response to exogenous and endogenous adenosine in control and STZ diabetic rats. Exogenous adenosine (0.01–100 nmol) injected into the abdominal aorta decreased renal blood flow (RBF) in a dose-dependent manner to a much greater extent in STZ rats than in control rats ( P < 0.001). Inhibition of NO synthesis with N ω-nitro-l-arginine (l-NNA, 30 μmol/kg iv) and with renal perfusion pressure controlled potentiated the adenosine-induced renal vasoconstriction to a significantly greater extent in control rats than in STZ rats. In control rats,l-NNA shifted the dose-response curve of exogenous adenosine-induced RBF reductions to the left by a factor of 32 [half-maximal effective dose (ED50), from 5.5 to 0.17 nmol adenosine, n = 6] and in STZ rats only by a factor of 4.6 (ED50, from 0.32 to 0.07 nmol adenosine, n = 6). The renal response to endogenous adenosine was assessed by the magnitude of the postocclusive reduction of RBF (POR) after a 30-s renal artery occlusion. POR was markedly enhanced in STZ rats (−67.8 ± 3.8%, P < 0.001) compared with control rats (−38.8 ± 4.3%).l-NNA markedly enhanced POR in control rats but did not increase POR in STZ rats. These findings demonstrate a greater potentiation of the adenosine-induced renal vasoconstriction in the presence ofl-NNA infusion in control rats compared with STZ rats. We conclude that the increased vasoconstrictor sensitivity of the diabetic renal vasculature to adenosine is caused by a defective NO-dependent renal vasodilation of the afferent arteriole in diabetic rats.

Adenosine (ADO) has been implicated as a pathophysiological factor in contrast media (CM)-induced acute renal failure, which has been encountered more often in patients with diabetes and impaired renal function. Therefore, we studied the renal vascular response to exogenous and endogenous ADO in streptozotocin-induced diabetic rats. We found that exogenous ADO (0.01-100 nmol), injected into the abdominal aorta, decreased renal blood flow (RBF) in a dose-dependent manner. The dose-response curve was shifted to the left by factor 30 in diabetic, compared with nondiabetic rats rats. Renal vascular response to endogenous ADO, assessed by postocclusive reduction of RBF after a 30-s renal artery occlusion, was significantly enhanced (P < 0.001) in diabetic rats (75.6 +/- 3.9%) compared with nondiabetic rats (36.5 +/- 2%). ADO A1-receptor blockade with 8-cyclopentyl-1,3-dipropylxanthine attenuated exogenous and endogenous ADO-induced renal vasoconstriction in both groups. We conclude that the ADO A1-receptor signal-transduction chain is altered in diabetic animals and that the enhanced vasoconstrictive action of ADO could be involved in the kidney pathophysiology of diabetes mellitus.