Elevated hepatic 11ß-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia.

Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the pathogenesis has yet to be fully elucidated. 11ß-Hydroxysteroid dehydrogenase type 1 (11ßHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11ßHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11ßHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11ßHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11ßHSD1(-/-) mice and rats treated with a specific 11ßHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11ßHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11ßHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD.

Proteinuria and hypoalbuminemia are risk factors for thromboembolic events in patients with idiopathic membranous nephropathy: an observational study.

BACKGROUND: Patients with nephrotic syndrome are at an increased risk of thromboembolic events (TEs). However, this association has not been thoroughly investigated in adult patients with idiopathic membranous nephropathy (IMN). METHODS: A retrospective analysis of all 101 consecutive adult patients with MN diagnosed at our centre during 1995 to 2008 was performed. Pertinent data including thromboembolic events and the risk factors for TEs were recorded. RESULTS: The cohort was followed for 7.2 ± 3 years. Out of 78 patients with IMN, 15 (19.2%) had at least one TE. No TEs occurred six months after diagnosis. The incidence of TEs in the first 6 months of diagnosis was 7.69% (95%CI, 2.5-17.0) and all patients except one had venous TEs. At the time of diagnosis of MN, the patients with TEs had lower serum albumin (1.9 ± 0.5 vs. 2.4 ± 0.4 g/dl, TE vs. no TE; p < 0.01) and greater serum cholesterol (414 ± 124 vs. 317 ± 108 mg/dl, TE vs. no TE; p = 0.01) and 24-h proteinuria (10.7 ± 3 vs. 7.1 ± 4 g, TE vs. no TE; p < 0.01). Multivariate logistic regression adjusted for age, sex, cholesterol and creatinine revealed, an odds ratio of 0.8 (95% CI 0.7 - 0.96; p = 0.01) for every one g/dl increase in baseline serum albumin and, an odds ratio of 1.3 (95% CI 1.05-1.58; p = 0.01) for one gram increase in 24-h proteinuria, for TEs. CONCLUSIONS: Our study finding confirms IMN as a prothrombotic state particularly in the first six months of diagnosis. Proteinuria, in addition to hypoalbuminemia, is a risk factor for TEs. These results have important implications for clinical care of patients with IMN, particularly with regards to initiation and duration of prophylactic anticoagulation.

Presentation, diagnosis, and treatment outcome of tuberculous-mediated tubulointerstitial nephritis.

Insidious Mycobacterium tuberculosis infection causing tubulointerstitial nephritis is a rare disorder. Here we report on a single-center case series of patients with tubulointerstitial nephritis due to tuberculosis, addressing clinicopathologic features and treatment outcome. Twenty-five adult patients with clinical evidence of tuberculosis and significant renal disease were assessed, 17 of whom had a kidney biopsy and were subsequently diagnosed with chronic granulomatous tubulointerstitial nephritis as the primary lesion. All patients were given standard antitubercular treatment, with some receiving corticosteroids, and showed a good response in clinical symptoms and inflammatory markers. Nine of the 25 patients, however, started renal replacement therapy within 6 months of presentation. Of the remaining 16, renal function improved for up to a year after presentation but subsequently declined through a median follow-up of 36 months. This case series supports that chronic tubulointerstitial nephritis is the most frequent kidney biopsy finding in patients with renal involvement from tuberculosis. Thus, a kidney biopsy should be considered in the clinical evaluation of kidney dysfunction with tuberculosis since tubulointerstitial nephritis presents late with advanced disease. A low threshold of suspicion in high-risk populations might lead to earlier diagnosis and treatment, preserving renal function and delaying initiation of renal replacement therapy.

Tuberculosis in the 21st century: A narrative review.

Sadly, despite the discovery of the tuberculosis bacillus over a century ago by Robert Koch, tuberculosis remains a major killer and modern day plague. Progress in the eradication of tuberculosis has been very slow and will require determined efforts on multiple fronts to make substantial inroads to lower the currently stagnant incidence of around 2% globally.