To define the luminal agent(s) responsible for the reduction of nephron filtration rate following increases of loop of Henle flow rate early proximal flow rate (EPFR) during loop perfusion with 17 different salt solutions were compared to the non-perfused tubules. During orthograde microperfusions a reduction of EPFR as indication of a feedback response was noted with a number of monovalent Cl- and Br- salts (LiCl, KCl, NaCl, RbCl, CsCl, NH4Cl, choline Cl, NaBr, KBr), with Na+ salts except Na acetate (NaHCO3, NaNO3, NaF, NaI, NaSCN), and with CaCl2 and MgCl2. These latter 2 solutions where used in a concentration of 70 mM while all other solutions had a concentration of 140 mM. During retrograde perfusion from the distal to the proximal end of the loop of Henle EPFR fell significantly with Cl- and Br- salts with percentage changes of EPFR ranging from -8.0 to -44.3%. In contrast, Cl- free salts and Cl- salts of divalent cations were associated with percentage changes of EPFR ranging from +7.1 to -6.2%, significance being reached only during perfusion with NaSCN. When furosemide (5 x 10(-4) M) was added to NaBr or KBr a feedback response was not observed. During orthograde perfusion with NaNO3 distal Cl- concentrations were 44.2 +/- 5.08, mM (mean +/- S.E.) at a perfusion rate of 10 nl/min and 59.1 +/- 3.93 mM at a rate of 40 nl/min. CaCl2 perfusion induced a marked elevation of distal Cl- concentrations to levels higher than 140 mM. Loop chloride handling was normal during RbCl perfusion. The magnitude of the feedback response during retrograde perfusion was not changed by lowering NaCl concentration from 140 to 60 mM, but fell when NaCl concentration was further reduced. In contrast to orthograde perfusions it was insensitive to changes in flow rate. Our results are compatible with the thesis that feedback responses depend critically upon the rate of Cl- transport probably across the macula densa cells. Br- ions can replace Cl- because they appear to share a common transport pathway which can be inhibited with furosemide. Unspecificity of feedback responses during orthograde microperfusions is due to presence of Cl- ions in the macula densa region even when solutions are initially Cl- free. Cl- salts of divalent cations do not elicit a feedback response because Cl- transport is severely curtailed.

Our understanding of the physiology of the renin-angiotensin system has advanced remarkably in the last decade as a result of the development of several pharmacologic agents that effectively block components of this humoral cascade. The use of these antagonists has also advanced our understanding of the contribution of the renin-angiotensin system to the development and maintenance of two-kidney, one-clip renal vascular hypertension. These antagonists have contributed greatly to the characterization of the systemic hemodynamic changes that occur in this model and, particularly, to the delineation of the behavior of the nonclipped kidney, a previously normal kidney that is subjected acutely to an environment of elevated systemic blood pressure and the input of a variety of other extrinsic influences. This kidney not only allows the blood pressure to increase and persist at elevated levels but appears to actively participate in the development and propagation of the hypertension. Although a variety of mechanisms impinge on the function of the nonclipped kidney in this model, the goal of this review is to analyze the behavior of this kidney and how its functional state is perturbed, primarily by the influence of angiotensin, which is believed to be delivered to it by the systemic circulation.

The optimal BP target for patients receiving hemodialysis is unknown. We randomized 126 hypertensive patients on hemodialysis to a standardized predialysis systolic BP of 110-140 mmHg (intensive arm) or 155-165 mmHg (standard arm). The primary objectives were to assess feasibility and safety and inform the design of a full-scale trial. A secondary objective was to assess changes in left ventricular mass. Median follow-up was 365 days. In the standard arm, the 2-week moving average systolic BP did not change significantly during the intervention period, but in the intensive arm, systolic BP decreased from 160 mmHg at baseline to 143 mmHg at 4.5 months. From months 4-12, the mean separation in systolic BP between arms was 12.9 mmHg. Four deaths occurred in the intensive arm and one death occurred in the standard arm. The incidence rate ratios for the intensive compared with the standard arm (95% confidence intervals) were 1.18 (0.40 to 3.33), 1.61 (0.87 to 2.97), and 3.09 (0.96 to 8.78) for major adverse cardiovascular events, hospitalizations, and vascular access thrombosis, respectively. The intensive and standard arms had similar median changes (95% confidence intervals) in left ventricular mass of -0.84 (-17.1 to 10.0) g and 1.4 (-11.6 to 10.4) g, respectively. Although we identified a possible safety signal, the small size and short duration of the trial prevent definitive conclusions. Considering the high risk for major adverse cardiovascular events in patients receiving hemodialysis, a full-scale trial is needed to assess potential benefits of intensive hypertension control in this population.

We recently showed an association between strict BP control and lower mortality risk during two decades of follow-up of prior participants in the Modification of Diet in Renal Disease (MDRD) trial. Here, we determined the risk of ESRD and mortality during extended follow-up of the African American Study of Kidney Disease and Hypertension (AASK) trial. We linked 1067 former AASK participants with CKD previously randomized to strict or usual BP control (mean arterial pressure ≤92 mmHg or 102-107 mmHg, respectively) to the US Renal Data System and Social Security Death Index; 397 patients had ESRD and 475 deaths occurred during a median follow-up of 14.4 years from 1995 to 2012. Compared with the usual BP arm, the strict BP arm had unadjusted and adjusted relative risks of ESRD of 0.92 (95% confidence interval [95% CI], 0.75 to 1.12) and 0.95 (95% CI, 0.78 to 1.16; P=0.64), respectively, and unadjusted and adjusted relative risks of death of 0.92 (95% CI, 0.77 to 1.10) and 0.81 (95% CI, 0.68 to 0.98; P=0.03), respectively. In meta-analyses of individual-level data from the MDRD and the AASK trials, unadjusted relative risk of ESRD was 0.88 (95% CI, 0.78 to 1.00) and unadjusted relative risk of death was 0.87 (95% CI, 0.76 to 0.99) for strict versus usual BP arms. Our findings suggest that, during long-term follow-up, strict BP control does not delay the onset of ESRD but may reduce the relative risk of death in CKD.

SUMMARYThe influence of the renln-angiotensin system on individual kidney function of two-kidney, one clip Goldblatt hypertensive (GH) rats was evaluated by determining renal functional responses during intravenous infusion of converting enzyme inhibitor (CEI) (SQ 20,881, 0 J rag/100 g-hr) for 3.5 bourn. Rats were made hypertensive by placing a 0.25 mm silver clip on the right renal artery 3-4 weeks prior to study. Normal rats and GH rats were prepared to allow urine collections from each kidney. Mean arterial pressure of GH rats fell significantly from preinfusion levels of 153 ± 7 to 126 ± 4 mm Hg during CEI infusion. Despite this decrease in arterial pressure, the nondipped kidneys with reduced renal renin activity (14 ± 5 vs 293 ± 40 ng Al/mg-hr in the clipped kidney) exhibited dramatic increases in gtomerular filtration rate (GFR) (from 1.45 ± 0.06 to 2.56 ± 0.35 ml/mln), urine flow (4.82 ± 0.71 to 9.11 ± 1.19 ^il/mln), sodium excretion (0.10 ± 0.02 to 1.15 ± 0.39 M Eq/mln), fractional sodium excretion (0.05% ± 0.02% to 0.43% ± 0.18%), and potassium excretion (0.94 ± 0.08 to 2.50 ± 0.55 /