Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat.

Tubuloglomerular feedback (TGF) stabilizes nephron function from minute to minute and adapts to different steady-state inputs to maintain this capability. Such adaptation inherently renders TGF less efficient at buffering long-term disturbances, but the magnitude of loss is unknown. We undertook the present study to measure the compromise between TGF and TGF adaptation in transition from acute to chronic decline in proximal reabsorption (Jprox). As a tool, we blocked proximal tubule sodium-glucose cotransport with the SGLT2 blocker dapagliflozin in hyperglycemic rats with early streptozotocin diabetes, a condition in which a large fraction of proximal fluid reabsorption owes to SGLT2. Dapagliflozin acutely reduced proximal reabsorption leading to a 70% increase in early distal chloride, a saturated TGF response, and a major reduction in single nephron glomerular filtration rate (SNGFR). Acute and chronic effects on Jprox were indistinguishable. Adaptations to 10-12 days of dapagiflozin included increased reabsorption by Henle's loop, which caused a partial relaxation in the increased tone exerted by TGF that could be explained without desensitization of TGF. In summary, TGF contributes to long-term fluid and salt balance by mediating a persistent decline in SNGFR as the kidney adapts to a sustained decrease in Jprox.

Transition of kidney tubule cells to a senescent phenotype in early experimental diabetes.

Diabetic nephropathy is the commonest cause of end-stage renal disease. Inordinate kidney growth and glomerular hyperfiltration at the very early stages of diabetes are putative antecedents to this disease. The kidney is the only organ that grows larger with the onset of diabetes mellitus, yet there remains confusion about the mechanism and significance of this growth. Here we show that kidney proximal tubule cells in culture transition to senescence in response to oxidative stress. We further determine the temporal expression of G(1) phase cell cycle components in rat kidney cortex at days 4 and 10 of streptozotocin diabetes to evaluate changes in this growth response. In diabetic rats we observe increases in kidney weight-to-body weight ratios correlating with increases in expression of the growth-related proteins in the kidney at day 4 after induction of diabetes. However, at day 10 we find a decrease in this profile in diabetic animals coincident with increased cyclin-dependent kinase inhibitor expressions. We observe no change in caspase-3 expression in the diabetic kidneys at these early time points; however, diabetic animals demonstrate reduced kidney connexin 43 and increased plasminogen activator inhibitor-1 expressions and increased senescence-associated beta-galactosidase activity in cortical tubules. In summary, diabetic kidneys exhibit an early temporal induction of growth phase components followed by their suppression concurrent with the induction of cyclin-dependent kinase inhibitors and markers of senescence. These data delineate a phenotypic change in cortical tubules early in the pathogenesis of diabetes that may contribute to further downstream complications of the disease.

Ornithine decarboxylase inhibitor eliminates hyperresponsiveness of the early diabetic proximal tubule to dietary salt.

Heightened sensitivity of the diabetic proximal tubule to dietary salt leads to a paradoxical effect of salt on glomerular filtration rate (GFR) via tubuloglomerular feedback. Diabetic hyperfiltration is a feedback response to growth and hyperreabsorption by the proximal tubule. The present studies were performed to determine whether growth and hyperfunction of the proximal tubule are essential for its hyperresponsiveness to dietary salt and, hence, to the paradoxical effect of dietary salt on GFR. Micropuncture was performed in four groups of inactin-anesthetized Wistar rats after 10 days of streptozotocin diabetes drinking tap water or 1% NaCl. Kidney growth was suppressed with ornithine decarboxylase (ODC) inhibitor, DFMO (200 mg.kg(-1).day(-1)), or placebo. Single nephron GFR (SNGFR) was manipulated by perfusing Henle's loop so that proximal reabsorption (Jprox) could be expressed as a function of SNGFR in each nephron, dissociating primary effects on the tubule from the effects of glomerulotubular balance. Alone, DFMO or high salt reduced SNGFR and suppressed Jprox independent of SNGFR. Suppression of Jprox was eliminated and SNGFR increased when high salt was given to rats receiving DFMO. ODC is necessary for hyperresponsiveness of the proximal tubule to dietary salt and for the paradoxical effect of dietary salt on GFR in early diabetes. This coupling of effects adds to the body of evidence that feedback from the proximal tubule is the principal governor of glomerular filtration in early diabetes.

Hepatitis B vaccination in human immunodeficiency virus-infected adults receiving hemodialysis.

BACKGROUND: The Centers for Disease Control and Prevention (CDC) recommends hepatitis B virus (HBV) immunization for all hemodialysis (HD) patients because they are at high risk of infection. Several studies have shown that the development of protective antibody titers after HBV vaccination is much lower in HD patients. We hypothesized that human immunodeficiency virus (HIV) infection in patients with end-stage renal disease (ESRD) would further impair the immune response to hepatitis B vaccination. METHODS: We performed a retrospective cohort study of patients undergoing long-term hemodialysis from 1990 to 2002 at the United States-based dialysis facilities of Gambro Corporation, North America. The response rate defined as an increase in anti-HBs levels >/=10 mIU/L after a month of the third dose of HBV vaccination was determined in HIV-infected and a randomly selected group of ESRD patients. The demographic information, laboratory data, and hepatitis B surface antibody (anti-HBs) titers were recorded from the Gambro Corporation database on these patients. RESULTS: Of the 347 adult HIV ESRD patients, 116 received three doses of recombinant hepatitis B vaccination. Seventy percent were male, and the majority (86%) were black. Of the 116 patients who received three doses of HBV vaccination, 62 (53.4%) developed protective antibody titers. This was comparable to the response rate of 50.4% in the randomly selected 220 non-HIV hemodialysis patients. Among HIV ESRD patients, the mean hemoglobin (Hgb) was higher in patients who developed protective antibody titers (Hgb 11.61 +/- 2 vs. 10.55 +/- 1.86, P value <0.01). On multivariate logistic regression analysis, higher Hgb was associated with protective antibody titers (odds ratio: 1.34, 95% CI 0.99-1.72). Seventy percent of the HIV-infected responders maintained protective antibody titers 6 months after vaccination. CONCLUSION: Hepatitis B vaccination should be offered to all HIV-infected ESRD patients because over half of the patients with HIV and ESRD can develop protective antibodies.