Leptin, the gene product of the ob gene, is important in the control of appetite in rodents and may have an important role in humans. The clearance of leptin from the circulation is unknown. As the leptin receptor is present in the kidney, we evaluated the role of the kidney in removing circulating leptin in humans. We measured leptin in aortic and renal vein plasma in 8 patients with intact renal function and 6 patients with impaired renal function who were undergoing elective cardiac catheterization. Renal blood flow was measured in all patients to calculate net mass balance across the kidney. In patients with intact renal function there is net renal uptake of 12% of circulating leptin, whereas in patients with renal insufficiency there is no renal uptake of leptin. In a separate cohort of 36 patients with end-stage renal failure on hemodialysis, peripheral leptin levels factored for body mass index was increased by > fourfold as compared to a group of healthy controls (N = 338). In addition, plasma leptin is not cleared by hemodialysis with a modified cellulose membrane. Additional studies are required to evaluate the role of leptin in mediating the anorexia of uremia.

The present study was designed to test whether altered renovascular reactivity is associated with the increased risk of radio-contrast nephropathy (RCN) in diabetics. We studied 50 patients (24 diabetics, 26 nondiabetics) with chronic renal insufficiency undergoing cardiac catheterization. Patients were randomized to receive either saline, or one of three renal vasodilator/diuretic drugs--dopamine, atrial natriuretic peptide (ANP), or mannitol--by intravenous infusion during cardiac catheterization. Renal blood flow (RBF) was measured by thermodilution at various time points during cardiac catheterization. RCN was defined as an increase in PCr of at least 25% over baseline within 48 hours of cardiac catheterization. Baseline PCr and creatinine clearance were similar in diabetics and nondiabetics (2.6 +/- 0.2 mg/dl vs. 2.4 +/- 0.1 mg/dl, and 32 +/- 3 ml/min vs. 34 +/- 3 ml/min, respectively), but baseline RBF was significantly lower in diabetics (154 +/- 21 ml/min/kidney vs. 277 +/- 36 ml/min/kidney, P < 0.05). Diabetic patients exposed to the three vasodilator/diuretic drugs had the greatest increase in RBF throughout cardiac catheterization. The incidence of RCN among the diabetics receiving those drugs was 83%, 83% and 75%, in the dopamine, ANP and mannitol groups, respectively. In contrast, among the nondiabetics in each of those groups the incidence of RCN was zero (all P < 0.05, diabetics vs. nondiabetics). In the saline control group the rates of RCN in the diabetics and nondiabetics were 43% and 38%, respectively (NS). In conclusion, the increased risk of RCN among diabetics was associated with exaggerated renovascular reactivity: baseline vasoconstriction and enhanced vasodilation with vasodilator/diuretic drugs. These same drugs, however, reduced the risk of RCN in nondiabetic patients.

Diabetic nephropathy is a common complication in patients with either type I or type II diabetes. The pathogenesis of diabetic nephropathy is thought to involve both metabolic and vascular factors leading to chronic accumulation of glomerular mesangial matrix. In this context, both transforming growth factor-beta (TGF-beta) and endothelin may contribute to these processes. To determine if diabetic patients demonstrate increased renal production of TGF-beta and endothelin, aortic, renal vein, and urinary levels of these factors were measured in 14 type II diabetic patients and 11 nondiabetic patients who were undergoing elective cardiac catheterization. Renal blood flow was measured in all patients to calculate net mass balance across the kidney. Diabetic patients demonstrated net renal production of immunoreactive TGF-beta1 (830 +/- 429 ng/min [mean +/- SE]), whereas nondiabetic patients demonstrated net renal extraction of circulating TGF-beta1 (-3479 +/- 1010 ng/min, P < 0.001). Urinary levels of bioassayable TGF-beta were also significantly increased in diabetic patients compared with nondiabetic patients (2.435 +/- 0.385 vs. 0.569 +/- 0.190 ng/mg creatinine, respectively; P < 0.001). Renal production of immunoreactive endothelin was not significantly increased in diabetic patients. In summary, type II diabetes is associated with enhanced net renal production of TGF-beta1, whereas nondiabetic patients exhibit net renal extraction of circulating TGF-beta1. Increased renal TGF-beta production may be an important manifestation of diabetic kidney disease.

There is a circadian variation in the ability of TPA to rapidly open coronary arteries, with highest efficacy between noon and midnight. This complements clinical and in vitro knowledge of increased morning thrombosis and is concordant with knowledge of increased morning thrombosis and is concordant with knowledge of a fibrinolytic profile that is more favorable for evening lysis. This finding has implications for understanding the circadian pathophysiology of myocardial infarction and for its chronotherapy.

Radiocontrast-induced nephropathy (RCIN) is a common cause of acute renal failure in hospitalized patients. Renal vasoconstriction figures prominently in the proposed pathogenesis of RCIN based on animal experiments. Prior human studies examining renal hemodynamic changes after contrast medium (CM) injection are inconclusive. No previous study of animals or humans has established a relationship between CM-associated renal hemodynamic changes and the subsequent development of RCIN. In the present study, we examined the renal hemodynamic effects of CM in patients at high risk of RCIN. In addition, we related those effects to the subsequent development of RCIN. Using renal vein thermodilution catheters, we measured renal blood flow (RBF) in 12 patients with chronic renal failure [serum creatinine (SCr) greater than or equal to 159 mumol/liter] during ionic CM injection for cardiac catheterization. We made measurements at the start of the procedure (t = 0), before the ventriculogram (t = 5), after the ventriculogram (t = 15), and after the coronary angiogram (t = 65). We measured SCr at t = 0 and again 24 and 48 hours later. Mean RBF for the group tended to increase after the ventriculogram, and increased significantly by t = 65 (P less than 0.005 vs. t = 0). When examined by individual patient, RBF fell below baseline in three patients (30%) at t = 15, but rose above baseline again by t = 65. Only one patient (8.3%) had a fall in RBF below baseline at t = 65. RCIN (defined as an increase in SCr greater than or equal to 25% above baseline) developed in six patients (50%) within 48 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

To clarify the mechanisms of afterload reduction on left ventricular diastolic function, the influence of nitroglycerin upon ventricular diastolic pressure-volume relations was studied in 22 patients during catheterization. After nitroglycerin, average ventricular systolic pressure declined by 25 mm Hg (18%) and end-diastolic pressure by 7 mm Hg (28%) (P less than 0.005). End-systolic and diastolic ventricular volumes decreased by 37% and 23% respectively (P less than 0.005). Although peak negative dP/dt fell by 22% (P less than 0.0005), "T", an index of the time course of isovolumic diastolic ventricular relaxation, was insignificantly changed. Diastolic pressure-volume curves were significantly displaced downward and leftward without significant change in slope, suggesting that a family of pressure-volume curves for each ventricle with similar slope but positions depend upon immediate loading conditions. Absence of change in slope or of "T" suggests that this displacement may be mediated indirectly, perhaps by relaxation of extracardiac constraints to ventricular distensibility. Accordingly, improvement in ventricular function by vasodilators may be partly due to downward displacement of the pressure-volume relation, with associated reduction of wall tension and myocardial oxygen consumption.

Previous studies suggest a role for renal vasoconstriction in the pathogenesis of radiocontrast-induced nephropathy (RCIN). A renal vasodilator such as dopamine may be protective. However, the effect of dopamine on renal blood flow (RBF) in patients with chronic renal failure (CRF) is controversial. Patients with CRF of diabetic (DM) or nondiabetic (NDM) origin were hydrated with 0.45% NaCl intravenously at 100 mL/h for 12 h and then randomized to either 0.45% NaCl IV at 100 mL/h (Group 1) or dopamine IV at 2 micrograms/kg/min in 0.45% NaCl at 100 mL/h for 2 h during and after cardiac catheterization. Mean arterial pressure (MAP), cardiac output (CO), and RBF were measured at baseline (t = 0), after 5 min of vehicle (Group 1) or dopamine (Group 2) but before ionic radiocontrast (t = 5 min), after ventriculogram (t = 15 min), and after coronary angiography (t = 65 min). Serum creatinine (SCr) was measured at baseline and 24 and 48 h after cardiac catheterization. RCIN was defined as a 25% increase of SCr above baseline 48 h after cardiac catheterization. Baseline characteristics demonstrated the groups to be equivalent in age, SCr, creatinine clearance, CO, MAP, RBF, and radiocontrast dose administered. The incidence of RCIN was not different between Group 1 and Group 2 (Group 1, 6 of 15 patients; Group 2, 5 of 15 patients). Dopamine infusion was associated with a significant increase in RBF at 5 min (Group 1, 110 +/- 13%; Group 2, 193 +/- 40% at t = 5, p < .05). RBF remained elevated throughout the catheterization in Group 2.(ABSTRACT TRUNCATED AT 250 WORDS)

110-116, 1985. TISSUE-TYPE plasminogen activator (t-PA) is a naturally occurring serum protein with high affinity for fibrin. It activates plasminogen and induces fibrinolysis physiologically or pharmacologically. Since the Km (Michaelis constant) of t-PA for free plasminogen is so much greater (65 gM) than the Km for plasminogen bound to fibrin (0.14 ,M), essentially no conversion of plasminogen to plasmin occurs in the circulation