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We compared the clinical outcomes of patients with (n = 71) and without (n = 185) diabetes mellitus enrolled into the placebo arm of a large, multicenter clinical trial of patients with acute tubular necrosis (ATN). Compared with the nondiabetic patients, diabetic patients were older (65.5 +/- 12.9 versus 60.7 +/- 18.0 years, P < 0. 05), had higher usual serum creatinine concentration (1.7 +/- 0.6 versus 1.4 +/- 0.5 mg/dL, P < 0.001), and had a higher prevalence of underlying hypertension, coronary artery disease, and congestive heart failure (all P < 0.007). By day 21 after enrollment, neither mortality nor dialysis-free survival was different between the groups. Length of stay for surviving patients, in both the intensive care unit and the hospital, were significantly shorter for the diabetics. Among acute comorbidities predicting mortality or the need for dialysis, sepsis was more prevalent among the nondiabetic patients (18% versus 35%, diabetics versus nondiabetics, P < 0.05). In conclusion, clinical outcomes for diabetic patients with ATN were no worse than for nondiabetic patients, despite their older age and worse underlying renal function. Patients with diabetes mellitus had more chronic cardiovascular disease but were less acutely ill. We speculate that cardiovascular disease is a risk factor for ATN in patients with diabetes mellitus. These results fail to implicate the increasing prevalence of diabetes mellitus in the persistently poor prognosis of patients with ATN.

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.

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.

Background: Atrial natriuretic peptide, a hormone synthesized by the cardiac atria, increases the glomerular filtration rate by dilating afferent arterioles while constricting efferent arterioles. It has been shown to improve glomerular filtration, urinary output, and renal histopathology in laboratory animals with acute renal dysfunction. Anaritide is a 25-amino-acid synthetic form of atrial natriuretic peptide., Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial of anaritide in 504 critically ill patients with acute tubular necrosis. The patients received a 24-hour intravenous infusion of either anaritide (0.2 microgram per kilogram of body weight per minute) or placebo. The primary end point was dialysis-free survival for 21 days after treatment. Other end points included the need for dialysis, changes in the serum creatinine concentration, and mortality., Results: The rate of dialysis-free survival was 47 percent in the placebo group and 43 percent in the anaritide group (P = 0.35). In the prospectively defined subgroup of 120 patients with oliguria (urinary output, < 400 ml per day), dialysis-free survival was 8 percent in the placebo group (5 of 60 patients) and 27 percent in the anaritide group (16 of 60 patients, P = 0.008). Anaritide-treated patients with oliguria who no longer had oliguria after treatment benefited the most. Conversely, among the 378 patients without oliguria, dialysis-free survival was 59 percent in the placebo group (116 of 195 patients) and 48 percent in the anaritide group (88 of 183 patients, P = 0.03)., Conclusions: The administration of anaritide did not improve the overall rate of dialysis-free survival in critically ill patients with acute tubular necrosis. However, anaritide may improve dialysis-free survival in patients with oliguria and may worsen it in patients without oliguria who have acute tubular necrosis.

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.

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)

Systemic and renal oxygen consumption and hemodynamics were studied in patients with normal renal function (NI; serum creatinine concentration (Screat), 1.0 +/- 0.04 mg/dL) and those with moderate chronic renal failure with diabetes mellitus Screat, 2.7 +/- 0.2 mg/dL) or without diabetes mellitus (Screat, 2.4 +/- 0.1 mg/dL). Patients with chronic renal failure were anemic and had normal systemic oxygen consumption (NI, 10,564 +/- 277; chronic renal failure, 9,669 +/- 362 mumol of O2/min) and elevated systemic oxygen extraction (NI, 22.9 +/- 1; chronic renal failure, 30.9 +/- 1.2%) (P less than 0.02). Cardiac output and index and arterial oxygen saturation were equivalent in normal patients and in patients with chronic renal failure. Patients with chronic renal failure had higher renal oxygen extraction (NI, 7.3 +/- 0.8; chronic renal failure, 13.9 +/- 1%), lower RBF (NI, 572 +/- 146; chronic renal failure, 197 +/- 20 mL/min/kidney), and lower renal oxygen consumption per kidney (NI, 391 +/- 101; chronic renal failure, 177 +/- 20 mumol of O2/min/kidney) than did normal patients (P less than 0.02). There was a linear relationship between hemoglobin and RBF (r = 0.47, P less than 0.02). Patients with chronic renal failure and diabetes had lower RBF (diabetes mellitus, 146 +/- 23; without diabetes, 242 +/- 28 mL/min/kidney) and renal oxygen consumption per kidney (diabetes mellitus, 131 +/- 21; without diabetes, 218 +/- 29 mumol of O2/min/kidney (P less than 0.03) but equivalent renal oxygen extraction when compared with patients without diabetes. Patients with chronic renal failure without diabetes mellitus had higher renal oxygen consumption when expressed per 100 mL of creatinine clearance (diabetes mellitus, 1,016 +/- 150; without diabetes mellitus, 1,453 +/- 175 mumol of O2/min/100 mL of creatinine clearance; P less than 0.03). There was a significant linear relationship (P less than 0.005, r = 0.38) between calculated creatinine clearance and renal oxygen consumption with a y intercept representing basal renal oxygen consumption (115 mumol of O2/min/kidney) and a slope of 2.3 mumol of O2/mL. Patients with moderate chronic renal failure have normal systemic oxygen consumption but reduced RBF and renal oxygen consumption. The latter parameters are even lower in patients with chronic renal failure and diabetes. Renal hypermetabolism is more likely to exist in nondiabetic than diabetic renal disease. Basic human renal physiology and pathophysiology are described by the relationships between renal oxygen consumption, blood flow, oxygen extraction, and creatinine clearance in patients with normal and abnormal renal function of varied cause.

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)

Acute renal failure is an infrequent adverse reaction following the administration of dextran-40. We report a case of anuric acute renal failure in a 59-year-old female following the administration of 90 gm of dextran-40 and radiocontrast. An increased risk secondary to radiocontrast-induced ischemia is discussed in relationship to the pathogenesis of the dextran-induced acute renal failure. In addition, plasmapheresis is demonstrated to be of potential therapeutic benefit.

The purpose of this study was to determine if mannitol stimulates atrial natriuretic peptide (ANP) release in humans and to examine potential mechanisms for this effect. Twenty patients requiring cardiac catheterization were randomized to receive either mannitol (15-g bolus followed by 15% infusion mixed in 75 mmol/L saline at 100 mL/h for 1 hour) or an equal volume of 75 mmol/L saline, intravenously (IV). All measurements were made at three time points: at baseline, at 10 minutes (after the bolus but before radiocontrast administration), and at 60 minutes (after completion of the study). Baseline plasma ANP (PANP) measurements (mean +/- SE) were similar in both groups (saline, 73 +/- 38 pg/mL; mannitol, 62 +/- 11 pg/mL). PANP increased significantly over time for the set of all patients (analysis of variance [ANOVA], P less than 0.05); however, at 10 minutes PANP increased significantly only in the group receiving mannitol (saline, 76 +/- 43 pg/mL; mannitol, 100 +/- 29 pg/mL) (P less than 0.04). Serum osmolality (SOSM), over time for the set of all patients (ANOVA, P less than 0.04). At 10 minutes there were significant increases only in the group receiving mannitol, and after radiocontrast, there were significant increases in both groups for all parameters. Regression analysis demonstrated a significant correlation between the change in PANP and the change in SOSM (P less than 0.04, r = 0.33). In conclusion, intravascular infusion of mannitol or radiocontrast increased PANP levels. The mechanism may be multifactorial, with a potential role for an increase in SOSM and/or PADH.

This study was performed to investigate the effects of atrial natriuretic peptide (ANP) and mannitol on renal blood flow (RBF) and radiocontrast-induced nephropathy (RCIN) in human subjects with chronic renal failure. ANP preserves glomerular filtration rate or RBF (or both) in severe animal models of acute renal failure. Radiocontrast is known to substantially decrease RBF and can induce acute renal failure. Twenty consecutive patients with chronic renal failure (60% with diabetes) were randomized in a prospective, double-blind fashion to receive either ANP (50 micrograms bolus, then 1 microgram/min infusion) or mannitol (15% at 100 ml/hr) for 2 hours before and during cardiac catheterization with diatrizoate. Baseline serum creatinine level (ANP 2.4 +/- 0.7 mg/dl, mannitol 2.5 +/- 0.8 mg/dl), medications, and quantity of radiocontrast were similar in both groups. Direct measurements of RBF were made with thermodilution catheters placed in the left renal vein. RBF rose significantly (p less than 0.05), to 198% of baseline at 15 minutes and 166% of baseline at 65 minutes in the group receiving ANP and remained stable in the group receiving mannitol. ANP levels rose significantly from baseline at 5, 15, 65 and 120 minutes in both groups (p less than 0.05). Acute renal failure defined as a 0.5 mg/dl rise of creatinine within 24 hours of cardiac catheterization, developed only in patients with diabetes mellitus and was similar in both experimental groups (ANP, 50%; mannitol, 30%). Only patients with diabetes mellitus responded with an increase in RBF after a 5-minute infusion of either ANP or mannitol (diabetes, 165% +/- 28% baseline; no diabetes, 96% +/- 8% baseline) (p less than 0.05). In conclusion, RBF was maintained or increased despite administration of radiocontrast, a documented renal vasoconstrictor. Patients with diabetes mellitus had a renal vasodilatory response to drug infusion. Acute renal failure occurred to a similar extent in both groups. Plasma ANP levels rose significantly in both groups. Mannitol may induce ANP release, thus contributing to mannitol's renal effects.

To clarify the role of vitamin D in renal phosphate transport, weanling rats were fed a vitamin D-deficient diet containing 1.8% calcium and 1.2% phosphorus. After 5-6 wk, the rats were normocalcemic, normophosphatemic, and had normal levels of PTH. Assays of vitamin D metabolites revealed undetectable plasma levels of 25(OH)D, and 1,25(OH)2D levels of 92 +/- 16 pg/ml in partially vitamin D-depleted (PVDD) rats and 169 +/- 58 pg/ml in normal rats. PVDD rats had increased phosphate excretion, both absolute and fractional, and a decrease in Na+ gradient-dependent Pi transport in proximal tubular brush border membrane vesicles (BBMV) prepared from their kidneys. Vitamin D repletion of PVDD rats with 1,25(OH)2D3, 15 pmol/100 g body wt, decreased fractional excretion of Pi from 22.6 +/- 1.9 to 13.5 +/- 1.3%; the latter values were similar to normal rats. Repletion with 1,25(OH)2D3 also increased Na+-dependent phosphate transport in BBMV from 322 +/- 24 pmol X mg protein-1 X 15 s-1 in BBMV from PVDD rats to 698 +/- 70 pmol X mg protein-1 X 15 s-1. Repletion with larger doses of 1,25(OH)2D3 produced hypercalcemia and hyperphosphatemia from intestinal absorption, an increase in phosphate excretion, and a blunted response of Pi transport to 1,25(OH)2D3. Prevention of hyperphosphatemia by dietary adjustments allowed full expression of the stimulatory effects of 1,25(OH)2D3 on Pi transport. These later data may partially explain the inhibitory effects reported in prior studies in which plasma Pi was not controlled and the larger doses of 1,25(OH)2D3 administered.(ABSTRACT TRUNCATED AT 250 WORDS)

The phosphatidylcholine content of both the intestinal and renal brush-border membranes and ion transport are affected by 1,25-dihydroxycholecalciferol (1,25(OH)2D3). To investigate the mechanism of this effect, liposomes were prepared containing self-quenching concentrations of fluorescent phospholipid derivatives. When these liposomes were incubated with rat renal brush-border membrane vesicles, an immediate increase in the relative fluorescence of N-4-nitrobenz-2-oxa-1,3-diazole phosphatidylcholine (NBD-PC) was detected, indicating transfer of NBD-PC into a non-quenched membrane. Addition of 1,25(OH)2D3 to the liposomes produced a dose-dependent stimulation of NBD-PC transfer to the acceptor brush-border membrane vesicles. Peripheral fluorescence was visible when the brush-border membrane vesicles were viewed with a fluorescent microscope. Using brush-border membrane vesicles from kidneys of vitamin D-deficient animals, quantitation of lipid transfer revealed a 1,25(OH)2D3 (10(-7) M) stimulation of NBD-PC transfer from 1.38 +/- 0.27 to 2.07 +/- 0.26 micrograms/h, and of PC transfer, assessed by vesicle phosphatidylcholine content, from 49.7 +/- 12 to 57.3 +/- 12 micrograms/mg protein per h (P less than 0.05). There was no significant transfer of N-(lissamine rhodamine B sulfonyl)dioleoylphosphatidylethanolamine (N-Rh-PE). In the absence of hormone, the amount of NBD-PC transferred to brush-border membrane vesicles prepared from normal rats was significantly greater than that transferred to brush-border membrane vesicles prepared from vitamin D-deficient animals (2.12 +/- 0.02 vs. 1.39 +/- 0.27 micrograms of NBD-PC/h, P less than 0.05). Both physiologic and pharmacologic concentrations of 1,25(OH)2D3 stimulated NBD-PC transfer with maximum response at 10(-14) M (2.98 +/- 0.15 micrograms/h). 24,25-Dihydroxycholecalciferol and 25-hydroxycholecalciferol (25(OH)D3) also stimulated transfer, although dose-response curves were less effective than for 1,25(OH)2D3. Cortisol and vitamin D-3 did not stimulate transfer. 1,25(OH)2D3 did not stimulate NBD-PC transfer between liposome populations.

Vitamin D has been shown to stimulate renal phosphate transport and to alter membrane phospholipid composition. The present studies examine the possibility that the effects of 1,25(OH)2D3 on phosphate transport are related to its effects on membrane lipids. Arrhenius plots, which relate maximum rates of sodium dependent phosphate uptake into brush-border membrane vesicles to temperature were constructed. Phosphate transport was studied using brush-border membrane vesicles from normal, vitamin D-deficient, and physiologically replete (15 pmol/100 g body weight per 24 h) rats. These plots were triphasic with characteristic, lipid-dependent, slopes (M1,M2,M3) representing activation energies and transition temperatures (T1,T2). Physiologic 1,25(OH)2D3 repletion normalized these plots by stimulating phosphate transport at all temperatures, increasing T2 from 18 +/- 0.7 to 23.5 +/- 0.9 degrees C and decreasing M2 and M3 from -5.8 +/- 0.2 and -10.2 +/- 0.4 to -4.5 +/- 0.4 and -7.7 +/- 0.3, respectively. Pharmacologic (1.2 nmol/100 g per 3 h) 1,25(OH)2D3 treatment resulted in a change in the Arrhenius plot of phosphate transport to a biphasic one with a transition temperature of 30 degrees C. This effect was not blocked by cycloheximide. The Arrhenius plots of glucose transport were triphasic and unchanged with vitamin D repletion. These data support a liponomic mechanism of action for 1,25(OH)2D3 on phosphate transport.

Controversy exists regarding the mechanisms by which 1,25-dihydroxycholecalciferol (1,25(OH2)D3) alters membrane lipid composition and ion transport. Recent studies have demonstrated stimulation of the transfer of 1-acyl-2-(N-4-nitrobenz-2-oxa-1,3-diazole)aminocaproylphosphatidylcholine (NBD-PC) by 1,25(OH)2D3. In the present studies, brush border membrane vesicle phosphatidylcholine content was increased after incubation with liposomes composed of dioleoylphosphatidylcholine or beta-linoleyl, gamma-palmitoyl phosphatidylcholine and 1,25(OH)2D3 (10(-7) M). Vesicular phosphatidylcholine content was increased from control levels of 49.5 micrograms/mg protein to 56.9 and 58.5, respectively, after treatment with the liposomes containing 1,25(OH)2D3, P less than 0.05. When the vesicles were incubated with liposomes composed of beta-linoleyl, gamma-palmitoyl phosphatidylcholine, phosphate transport was stimulated from 231 +/- 20 to 431 +/- 41 pmol/mg protein per 15 s in the presence of 1,25(OH)2D3 if the vesicles were derived from vitamin D deficient rats and from 443 +/- 33 to 601 +/- 42 pmol/mg protein per 15 s if the vesicles were prepared from normal rats. Despite phosphatidylcholine transfer, incubation with liposomes composed of dioleoylphosphatidylcholine and 1,25(OH)2D3 did not stimulate phosphate transport. Furthermore, incubation of vesicles with liposomes and 1,25(OH)2D3 did not alter glucose transport.

Magnesium is the fourth most abundant cation in the body and the second most plentiful intracellularly. Magnesium is crucial to mitochondrial integrity, oxidative phosphorylation, protein synthesis, nucleic acid stability, membrane permeability, and neuro-muscular excitability. In addition, magnesium deficiency induces other electrolyte disturbances including hypocalcemia, hypokalemia, and hypophosphatemia. Because it is not routinely measured, many physicians fail to remember the significance of this element. Reported here is a patient with bulimia who presented with a magnesium deficiency which resulted in her refractory and eventually fatal cardiomyopathy. The cardiac pathophysiology of hypomagnesemia, hypokalemia, hypocalcemia and hypophosphatemia is reviewed and correlated with the clinical and pathological findings.