Chronic allograft nephropathy represents cumulative and incremental damage to nephrons from time-dependent immunologic and nonimmunologic causes.

Nonalcoholic steatohepatitis (NASH) is often linked with disorders that are clearly associated with insulin resistance (IR): obesity, type 2 diabetes mellitus, and hypertriglyceridemia. We tested the hypotheses that (1) IR is an essential requirement for the development of NASH and (2) a high association between IR and liver disease is relatively specific for NASH. We measured body mass index (BMI), waist/hip ratio, and fasting serum lipid, insulin, C-peptide, and glucose levels in 66 patients with NASH (21 with advanced fibrosis and 45 with mild fibrosis). IR was determined by the homeostasis model assessment (HOMA). We also determined the strength of the association of NASH with insulin resistance syndrome (IRS) as defined by World Health Organization criteria. To assess whether the finding of IR was relatively specific to NASH rather than simply to obesity or liver disease, we compared the results of a subset of 36 patients with less-severe NASH with 36 age-and sex-matched patients with chronic hepatitis C virus (HCV) of comparable fibrotic severity. IR was confirmed in 65 patients (98%) with NASH, and 55 (87%) fulfilled minimum criteria for IRS. IR was found in lean as well as in overweight and obese patients. The IR values and the prevalence of IRS (75% vs. 8.3%) were significantly higher in those with NASH than in comparable cases of HCV. Hyperinsulinemia was attributable to increased insulin secretion rather than decreased hepatic extraction. N onalcoholic steatohepatitis (NASH) is characterized by morphological features indistinguishable from alcoholic liver disease in individuals who do not consume excess alcohol. 1 NASH can progress to cirrhosis, and death from liver failure is now the second-leading cause of death in these patients. 2 Although the prevalence of NASH appears to be increasing, the etiopathogenesis remains poorly understood.Associations with drug toxicity, weight-reducing operations, lipodystrophy, and other uncommon inherited syndromes are well documented but are rarely present in most patients with NASH. [1][2][3][4][5][6][7][8] Rather, attention has been drawn to the increased prevalence of common metabolic disorders in the "typical" patient with NASH. [1][2][3][4][5][6][7] Autopsy data indicate that NASH is at least 6 times more prevalent in obese individuals compared with lean subjects. 7 Type 2 diabetes mellitus or abnormalities of glucose tolerance are present in up to one third of patients with NASH, 8 often with hypertriglyceridemia and/or hypercholesterolemia. 9,10 The above metabolic disorders are also cardiovascular risk factors and often cluster together as syndrome X, which includes impaired glucose tolerance, dyslipidemia, and hypertension. 11 This disease cluster is also referred to as the metabolic or insulin resistance syndrome (IRS); the latter highlights a central role for insulin resistance (IR) in this disorder. 12,13 The expanded formulation of IRS includes central (visceral or truncal) adiposity, lipid abnormalities, hyperuricemia, polycystic ovarian syndrome, and...

Pathologic changes of CsA nephrotoxicity were virtually universal by 10 years and exacerbated chronic allograft nephropathy. CsA is unsuitable as a universal, long-term immunosuppressive agent for kidney transplantation. Strategies to ameliorate or avoid nephrotoxicity are thus urgently needed.

On the basis of cross-sectional studies, it has been proposed that hepatic steatosis is a cytopathic effect of hepatitis C virus (HCV) genotype 3 but not genotype 1 infections. We tested this hypothesis by examining whether antiviral treatment altered hepatic steatosis in chronic hepatitis C. In 28 patients with genotype 1 and 34 with genotype 3 HCV, we determined the severity of steatosis in pre-and posttreatment liver biopsies using computerassisted morphometric image analysis as well as conventional semiquantitative scoring. Before treatment, hepatic steatosis was present in 16 (57%) patients infected with HCV genotype 1 and 21 (62%) of those with genotype 3. Sustained viral response (SVR) was achieved in 9 (32%) patients with genotype 1 and 22 (65%) with genotype 3. In neither group were there significant changes in body weight or alcohol consumption between preand posttreatment biopsies. In patients with HCV genotype 1, there was no change in hepatic steatosis after treatment, irrespective of the treatment response. Among those infected with genotype 3, SVR significantly reduced steatosis (P < .001), but there was no change in steatosis among those without a SVR. By logistic regression analysis, SVR was the only variable predictive of improvement in hepatic steatosis (OR ‫؍‬ 36, 95% CI ‫؍‬ 2.7-481, P ‫؍‬ .007). In conclusion, these data provide strong support for a direct causal association between HCV genotype 3 infection and hepatic steatosis. H epatic steatosis is a common feature on liver biopsy specimens from patients with chronic hepatitis C, and its presence is associated with fibrotic progression. 1,2 The pathogenesis is complex; host factors including alcohol consumption, exposure to other hepatotoxins, obesity, insulin resistance, type 2 diabetes, and hypertriglyceridemia have been identified as determinants. 3 We and others have recently found that viral factors, particularly hepatitis C virus (HCV) genotype, may be a critical determinant of steatosis in chronic hepatitis C. 2,4,5 Thus, patients with HCV genotype 3 infection and chronic hepatitis C are more likely to have steatosis and more likely to have extensive hepatic steatosis than those infected with HCV genotype 1. Furthermore, hepatic steatosis in genotype 3 chronic hepatitis C correlates directly with serum and intrahepatic titers of HCV RNA and inversely with apolipoprotein B levels. 2,5,6 In contrast, steatosis in HCV genotype 1 infection appears independent of virus levels but correlates with measures of obesity, including body mass index and visceral fat distribution. 2,4 We hypothesized that, if the genotype-specific associations between HCV and hepatic steatosis are real, then a sustained response to antiviral therapy should be accompanied by improvement in steatosis in those infected with genotype 3 but not in those with genotype 1 HCV infection.The effect of viral eradication on hepatic steatosis in relation to HCV genotype has not been evaluated. Published data on steatosis after antiviral treatment of hepatitis C are limited b...