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Background: Growth factors, cytokines, and the renin-angiotensin system (RAS) are involved in chronic allograft dysfunction. However, it is unclear whether clinical evaluations of TGFBeta1 and the RAS in longterm stable transplant patients can predict the development of chronic allograft dysfunction., Methods: Urinary TGFBeta1 excretion and the response of plasma renin activity (PRA) to angiotensin I converting-enzyme inhibition (ACE-I) were prospectively examined in transplant patients who had had stable graft function (n = 16) for at least 1 year after renal transplantation. Four-year follow-up studies were undertaken to evaluate the impact of these parameters on the development of chronic allograft dysfunction., Results: Urinary TGFBeta1 excretion and PRA response to ACE-I in renal transplant patients who developed chronic allograft nephropathy 4 years after the evaluations (n = 7) were significantly higher and greater, respectively, than these values in those who did not ( n = 9; P < 0.01). If the cutoff level for urinary TGFBeta1 excretion was 250 pg/min, the 4-year positive predictive value (PPV) with respect to the development of chronic allograft nephropathy was 83% and the negative predictive value (NPV) was 78% (sensitivity [sen.], 71%; specificity [sp.], 88%). If the cutoff level for PRA at 60 min after ACE-I was 4.0 ng/ml per h, the 4-year PPV was 71% and NPV was 75% (sen., 70%; sp., 75%). The stable transplant patients with high TGFBeta1 excretion and exaggerated PRA response showed significantly higher rates of chronic allograft dysfunction than those with low TGFBeta1 excretion and weak PRA response., Conclusions: This study demonstrates that some transplant patients with longterm stable graft function show increases in the activities of the TGFBeta system and the RAS. Evaluations of urinary TGFBeta1 excretion and PRA response to ACE-I present a possibility for predicting the development of chronic allograft dysfunction, with significant 4-year predictive values.

Background. Insufficiency of renal function and high blood pressure influence each other and eventually result in life-threatening endstage renal disease. It has been proposed that proteinuria per se is a determinant of the progression of chronic kidney disease (CKD). The therapeutic strategy for patients with proteinuric CKD and hypertension should therefore be targeted with a view not merely toward blood pressure reduction but also toward renoprotection. Methods. We examined the effect of the angiotensin (AT)1 receptor antagonist losartan and the calcium channel blocker amlodipine, throughout a period of 12 months, on reduction of blood pressure and renoprotection. This was done by assessing amounts of urinary protein excretion, serum creatinine (SCr), and creatinine clearance (CCr) in patients with hypertension (systolic blood pressure [SBP] ≧ 140 mmHg or diastolic blood pressure [DBP] ≧ 90 mmHg) and CKD (male, body weight [BW] ≧ 60 kg: 1.5 ≦ SCr < 3.0 mg/dl; female or male BW < 60 kg: 1.3 ≦ SCr < 3.0 mg/dl), manifesting proteinuria of 0.5 g or more/day. Losartan was administered once daily at doses of 25 to 100 mg/day, and amlodipine was given once daily at 2.5 to 5 mg/day. No antihypertensive combination therapy was allowed during the first 3-month period. Results. A 3-month interim analysis revealed that, despite there being no difference in blood pressure between the two groups, there was a significant reduction in 24-h urinary protein excretion in the losartan group (n = 43), but there was no change in the amlodipine group (n = 43). Analysis of stratified subgroups with proteinuria of 2 g or more/day and less than 2 g/day showed that losartan lowered proteinuria by approximately 24% in both subgroups, while amlodipine lowered proteinuria by 10%, but only in the subgroup of less than 2 g/day (NS). SCr and CCr did not change throughout the period of 3 months in either group. No severe or fatal adverse event was experienced in either group during the study period. Conclusions. Losartan appeared to be efficacious for renoprotection in patients with proteinuric CKD and hypertension, with the mechanism being independent of its antihypertensive action. [ABSTRACT FROM AUTHOR]

Abstract: CXC chemokines are particularly significant for leukocyte infiltration in inflammatory diseases. Recent reports have shown that inflammation is one of potential pathogenic mechanisms for diabetic nephropathy. However, information on inflammation related with CXC chemokines in human Type 2 diabetic nephropathy still remains scarce. We measured urinary and serum levels of three CXC chemokines, CXCL5, CXCL8 and CXCL9, in 45 Type 2 diabetic patients (DM), 42 primary renal disease (PRD) patients and 22 healthy controls by enzyme-linked immunosorbent assay. Urinary levels of CXCL5, CXCL8 and CXCL9 in DM were significantly elevated compared to those in controls (P<.0001, P<.01, P<.001; respectively). They increased consistent with urinary albumin excretion rate (UAER) and correlated with UAER in partial correlation analyses (r=0.41, P<.01; r=0.40, P<.01; r=0.45, P<.01; respectively). Urinary levels of CXCL5 in DM were significantly interrelated to HbA1c (r=0.42, P<.01). On the other hand, PRD showed significant increased levels of urinary CXCL8 and CXCL9 compared to controls (P<.001, P<.01; respectively), and so did PRD as UAER increased. However, there were no significant elevations of urinary levels of CXCL5 in PRD in spite of the increased UAER. We found significant associations of UAER in DM with diabetes duration, 1/serum creatinine, urinary CXCL5 (adjusted R 2=0.67, P<.0001) or CXCL9 (adjusted R 2=0.69, P<.0001) in a stepwise multiple regression analysis. These results suggest that these three CXC chemokines may be involved in the progression of human Type 2 diabetic nephropathy and that CXCL5 may be of use for telling diabetic nephropathy from primary renal diseases. [Copyright &y& Elsevier]

Oxidative stress is enhanced in correlation with renal dysfunction: Examination with the redox state of albumin.Background.Cardiovascular disease is known to be the most important complication among patients with renal failure, and oxidative stress has been proposed to play a major role as the source of such complications. Human serum albumin (HSA) is composed of human mercaptoalbumin (HMA) with cysteine residues having reducing powers, of reversibly oxidized human non-mercaptoalbumin-1 (HNA-1), and strongly oxidized human non-mercaptoalbumin-2 (HNA-2).Methods.We used the“redox state of HSA” as a marker to investigate the current status of oxidative stress in predialysis patients with renal failure. The subjects were 55 nondialysis patients (31 males and 24 females) with chronic renal diseases, and having various degrees of renal function. The subjects' redox state of HSA was determined by a high-performance liquid chromatographic (HPLC) procedure, and the results presented in terms of the ratios between HNA-total(HNA-1+ HNA-2) and HNA-2.Results.The values for each fraction of HNA-total (f(HNA-total)) and f(HNA-2) were increased with a decrease of renal functions, and a significant positive correlation with serum creatinine (R= 0.529,P<0.0001 andR= 0.618,P<0.0001) was detected. Multiple (forward stepwise) regression analysis using f(HNA-total) and f(HNA-2) as the criterion variables was performed, and creatinine was adopted as significant explanatory variable in both equations.Conclusion.We found that even before dialysis, oxidative stress was enhanced in correlation with the level of renal dysfunction among patients with chronic renal failure. In the future, antioxidant strategies should become part of treatment for predialysis renal failure. [ABSTRACT FROM AUTHOR]