Cynthia M. Miracle

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 Henles 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.

Linking clinic and home: a randomized, controlled clinical effectiveness trial of real-time, wireless blood pressure monitoring for older patients with kidney disease and hypertension

ObjectiveOlder adults with chronic kidney disease have a high rate of uncontrolled hypertension. Home monitoring of blood pressure (BP) is an integral part of management, but requires that patients bring records to clinic visits. Telemonitoring interventions, however, have not targeted older, less technologically-skilled populations. MethodsVeterans with stage 3 or greater chronic kidney disease and uncontrolled hypertension were randomized to a novel telemonitoring device pairing a Bluetooth-enabled BP cuff with an Internet-enabled hub, which wirelessly transmitted readings (n=28), or usual care (n=15). Home recordings were reviewed weekly and telemonitoring participants were contacted if BP was above goal. The prespecified primary endpoints were improved data exchange and device acceptability. Secondary endpoint was BP change. ResultsForty-three participants (average age 68 years, 75% white) completed the 6-month study. Average start-of-study BP was 147/78 mmHg. Those in the intervention arm had a median of 29 (IQR 22, 53) transmitted BP readings per month, with 78% continuing to use the device regularly, whereas only 20% of those in the usual care group brought readings to in-person visits. The median number of telephone contacts triggered by the wireless monitoring was 2 (IQR 1, 4) per patient. Both groups had a significant improvement in systolic BP (P<0.05, for both changes); systolic BP fell a median of 13 mmHg in monitored participants compared with 8.5 mmHg in usual care participants (P for comparison 0.31). ConclusionThis low-cost wireless monitoring strategy led to greater sharing of data between patients and clinic and produced a trend toward improvements in BP control over usual care at 6 months.

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 Henles 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.

Combined Effects of Carbonic Anhydrase Inhibitor and Adenosine A1 Receptor Antagonist on Hemodynamic and Tubular Function in the Kidney

Background: Carbonic anhydrase inhibitors (CAI) reduce proximal reabsorption, activating tubuloglomerular feedback (TGF) and reducing glomerular filtration rate (GFR). Adenosine A1 receptors (A1R) mediate the TGF response and stimulate proximal reabsorption. Methods: Clearance and micropuncture studies were performed in Wistar rats to determine whether blockade of A1R (KW3902 0.3 mg/kg i.v.) would prevent CAI (benzolamide 5 mg/kg i.v.) from lowering GFR, whether CAI and KW3902 exert additive effects on sodium excretion, and to what extent such interactions depend on events in the glomerulus, proximal tubule, or distal nephron. Results: KW3902 raised GFR and prevented CAI from lowering GFR. KW3902 and CAI caused additive diuresis and natriuresis. KW3902 and CAI increased lithium clearance, but their effects were redundant. CAI increased the dependence of proximal reabsorption on active chloride transport. KW3902, alone, did likewise, but to a lesser extent than CAI. Adding KW3902 to CAI lessened the shift toward active chloride transport. Conclusions: The data reveal that A1R mediate glomerular vascular resistance whether or not TGF is activated, that additive effects of CAI and KW3902 on salt excretion occur, in part, because KW3902 inhibits reabsorption downstream from the macula densa, and that KW3902 likely inhibits proximal reabsorption by interfering with apical sodium-hydrogen exchange.

The Association between Depression, Perceived Health Status, and Quality of Life among Individuals with Chronic Kidney Disease: An Analysis of the National Health and Nutrition Examination Survey 2011-2012

Background: Depression is the most common mental health disorder among those with end-stage renal disease (ESRD), with prevalence of 15-40%. However, the association between chronic kidney disease (CKD) and depression is more variable. We examined the associations of CKD with depression, perceived health status, and quality of life in the National Health and Nutrition Examination Survey (NHANES) 2011-2012. Methods: This study included 4,075 adults. Depression was defined as a condition when a Patient Health Questionnaire score was ≥10, or when there was reported antidepressant use. Reduced quality of life was defined by the number of days having poor mental and physical health, or feeling anxious. We calculated ORs for associations between CKD and depression and self-perceived health status, and used linear regression to examine associations between CKD and the number of days of poor health or anxiety. Results: The prevalence of CKD was 7.0% and that of depression was 19.1%. Those with CKD were not more likely to be depressed versus those without CKD after multivariate adjustment. Although they were 2.2 times more likely to have fair/poor health status after adjusting for demographic characteristics, this was attenuated by adjustment for confounders. Those with CKD reported one more day of being inactive due to poor health in the past month (p < 0.05), after multivariate adjustment. No differences were found for self-reported anxiety. Conclusion: Our findings suggest that NHANES participants with CKD have more days of poor health but are not more likely to be depressed or anxious. This may reflect differences between clinical CKD populations and community-based samples.