Dominik E. Uehlinger

Blood levels and renal effects of atrial natriuretic peptide in normal man.

Since mammalian atria were recently found to contain vasoactive and natriuretic peptides, we investigated the following in normal humans: plasma human atrial natriuretic peptide concentrations, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), urinary water and electrolyte excretion, blood pressure (BP), and catecholamine, antidiuretic hormone (ADH), angiotensin II, and aldosterone levels before, during, and after intravenous administration of the newly synthetized alpha-human atrial natriuretic peptide (alpha hANP). In 10 subjects alpha hANP given as an initial bolus of 50 micrograms followed by a 45-min maintenance infusion at 6.25 micrograms/min increased plasma alpha hANP from 58 +/- 12 to 625 +/- 87 (mean +/- SEM) pg/ml; caused an acute fall in diastolic BP (-12%, P less than 0.001) and a hemoconcentration (hematocrit +7%, P less than 0.01) not fully explained by a negative body fluid balance; increased GFR (+15%, P less than 0.05) despite unchanged or decreased ERPF (filtration fraction +37%, P less than 0.001); augmented (P less than 0.05- less than 0.001) urinary chloride (+317%), sodium (+224%), calcium (+158%), magnesium (+110%), phosphate excretion (+88%), and free water clearance (from -0.76 to +2.23 ml/min, P less than 0.001) with only little change in potassium excretion; and increased plasma norepinephrine (P less than 0.001) while plasma and urinary epinephrine and dopamine, and plasma ADH, angiotensin II, and aldosterone levels were unchanged. The magnitude and pattern of electrolyte and water excretion during alpha hANP infusion could not be accounted for by increased GFR alone. Therefore, in normal man, endogenous alpha hANP seems to circulate in blood. alpha hANP can cause a BP reduction and hemoconcentration which occur, at least in part, independently of diuresis and are accompanied by sympathetic activation. An increase in GFR that occurs in the presence of unchanged or even decreased total renal blood flow is an important but not sole mechanism of natriuresis and diuresis induced by alpha hANP in man.

Prophylactic hemodialysis after radiocontrast media in patients with renal insufficiency is potentially harmful.

PURPOSE Acute renal failure induced by contrast media is an important cause of hospital-acquired renal insufficiency. Preexisting renal failure and the dose of contrast media are known risk factors for the development of radiocontrast nephropathy. We performed a randomized trial to test whether radiocontrast nephropathy can be avoided by prophylactic hemodialysis immediately after the administration of contrast media in patients with impaired renal function. SUBJECTS AND METHODS Renal function and other parameters, hemodialysis requirement, and relevant clinical events were recorded before and during the 6 days after administration of contrast media in 113 patients with a baseline serum creatinine level >200 microm/L (>2.3 mg/dL). Patients were randomly assigned to either hemodialysis (n = 55) or nonhemodialysis (n = 58) treatment after parenteral low-osmolality contrast media. RESULTS The characteristics of the patients in the two groups were similar. Compared with baseline levels, the mean [+/- SD] serum creatinine level decreased at day 1 (277 +/- 95 microm/L), peaked at day 4 (353 +/- 126 microm/L), and returned to baseline at day 6 (327 +/- 119 microm/L, P <0.05 by analysis of variance) after administration of contrast media in the hemodialysis group, whereas in the nonhemodialysis group, no significant changes in mean serum creatinine level were observed. Eleven patients required 1 or more hemodialyses (8 in the hemodialysis group and 3 in the nonhemodialysis group, P = 0.12), 6 of whom (4 vs. 2, P = 0.44) required 3 or more hemodialyses. Clinically relevant events included pulmonary edema (1 vs. 4 patients, P = 0.36), myocardial infarction (2 vs. 2), stroke (2 vs. 0, P = 0.24), and death (1 vs. 1). CONCLUSIONS The strategy of performing hemodialysis immediately after the administration of low-osmolality contrast media in all patients with a reduced renal function did not diminish the rate of complications, including radiocontrast nephropathy.

Medical futility: Predicting outcome of intensive care unit patients by nurses and doctors: A prospective comparative study

ObjectiveFirst, to assess the pattern of the prediction of intensive care unit patients’ outcome with regard to survival and quality of life by nurses and doctors and, second, to compare these predictions with the quality of life reported by the surviving patients. DesignProspective opinion survey of critical care providers; comparison with follow-up for survival, functional status, and quality of life. SettingSix-bed medical intensive care unit subunit of a 1,000-bed tertiary care, university hospital. PatientsAll patients older than 18 yrs, admitted to the medical intensive care unit for >24 hrs over a 1-yr period (December 1997 to November 1998). InterventionsDaily judgment of eventual futility of medical interventions by nurses and doctors with respect to survival and future quality of life. Telephone interviews with discharged patients for quality of life and functional status 6 months after intensive care unit admission. Measurements and Main ResultsData regarding 521 patients including 1,932 daily judgments by nurses and doctors were analyzed. Disagreement on at least one of the daily judgments by nurses and doctors was found in 21% of all patients and in 63% of the dying patients. The disagreements more frequently concerned quality of life than survival. The higher the Simplified Acute Physiology Score and the longer the intensive care unit stay, the more divergent judgments were observed (p < .001). In surviving and dying patients, nurses gave more pessimistic judgment and considered withdrawal more often than did doctors (p < .001). Patients only rarely indicated bad quality of life (6%) and severe physical disability (2%) 6 months after intensive care unit admission. Compared with patients’ own assessment, neither nurses nor doctors correctly predicted quality of life; false pessimistic and false optimistic appreciation was given. ConclusionsDisagreement between nurses and doctors was frequent with respect to their judgment of futility of medical interventions. Disagreements most often concerned the most severely ill patients. Nurses, being more pessimistic in general, were more often correct than doctors in the judgment of dying patients but proposed treatment withdrawal in some very sick patients who survived. Future quality of life cannot reliably be predicted either by doctors or by nurses.

Effects of posture and ageing on circulating atrial natriuretic peptide levels in man

Possible influences of posture or age on plasma immunoreactive atrial natriuretic peptide (irANP) levels and potential correlates were assessed in 12 young (age +/- s.e.m. 24 +/- 1 year) and 12 elderly (63 +/- 8 year) healthy subjects on a liberal sodium intake. The groups did not differ significantly in their basal 24-h urinary sodium excretion (210 +/- 23 versus 180 +/- 15 mmol/l). However, plasma irANP was five- to ninefold higher in the elderly (P less than 0.05-0.01). Plasma irANP averaged 167 +/- 31 and 24 +/- 3 pg/ml in the elderly and young, respectively, during recumbency, fell (P less than 0.05) to 101 +/- 21 and 11 +/- 1 pg/ml, respectively, with upright posture, and rose (P less than 0.01) to 250 +/- 51 and 50 +/- 9 pg/ml, respectively, after intravenous (i.v.) loading with 0.9% saline (2.14 l in 3 h). Supine blood pressure (BP) and plasma norepinephrine tended to be higher while renin and aldosterone levels were lower (P less than 0.01) in the elderly; the three latter variables rose (P less than 0.001) with upright posture. These findings demonstrate that in normal humans, circulating irANP levels vary with posture and ageing. These changes may have potential physiological relevance and should be considered when interpreting plasma irANP levels in pathological conditions.

Clinical outcome relative to the dose of dialysis is not what you think: the fallacy of the mean☆

Several recent retrospective studies of mortality relative to the dose of dialysis have been widely interpreted to indicate that adequate thrice-weekly hemodialysis requires a single pool Kt/V (spKt/V) of at least 1.4 to 1.6 and higher. In these studies, mortality rate has been correlated to the mean delivered spKt/V, (spKt/Vd)m, with coefficient of variation (CV) on the means ranging up to 45%. To evaluate these reported relationships, two large databases were analyzed using population constants to transform urea reduction ratio and spKt/Vd to equilibrated Kt/Vd (eKt/Vd), which expresses dose corrected for treatment time. The eKt/V dose (D) values were correlated to the reported relative risks (RR) of mortality to derive a RR/D function. The RR/D function, derived from these data with stepwise linear regression analysis, is nonlinear, with a steep linear increase in RR for eKt/Vd less than 1.05 and constant RR for eKt/Vd > or = 1.05. This RR/D function is mathematically expressed as RR = 1.96 - 1.03(eKt/Vd) (equation 1) when 0.50 < or = eKt/Vd < or = 1.05, and RR = 0.88 (equation 2) when eKt/V > or = 1.05. We show that regression of RR on (eKt/Vd)m with large CV results in overestimation of RR relative to eKt/Vd for individual patients because of extrapolation of the linear relationship beyond the threshold where the slope becomes zero (see equation 2 above). It is concluded that (1) current clinical data indicate that adequate dialysis is provided with eKt/Vd of 1.0 to 1.1 on a thrice-weekly schedule, (2) it is essential to assure that all patients achieve this level of therapy, which is best accomplished using urea kinetic modeling for both prescription and measurement of delivered eKt/Vd, and (3) the current HEMO study is well designed to determine whether higher levels of eKt/Vd will further improve clinical outcome.

Serum Lipoproteins During Treatment with Antihypertensive Drugs

SummaryHypertension and certain alterations in serum lipoproteins such as a decrease in high density lipoprotein-cholesterol (HDL-C), an increase in low density lipoprotein-cholesterol (LDL-C) and perhaps also elevated triglycerides (Tg), are complementary coronary risk factors. Moreover, it has become evident that several of the drugs used for standard anti-hypertensive therapy may also interact with lipoprotein metabolism. The following has been observed after 1 to 12 months of treatment.Various diuretics can significantly increase LDL- C and/or very LDL-C and total C/ HDL-C ratio, while HDL-C is often largely unchanged; Tg also are often elevated. LDL-C increased in diuretic-treated men and in chlorthalidone-treatedpostmenopausal women, but not in chlorthalidone-treated premenopausal women. The latter may be protected from this side effect. Drug dosages were usually high in these studies. Indapamide, given at a dose of 2.5 mg/day, seems to exert no relevant effect on the lipoproteins. It is not established whether this difference is related to the nature of the drugs or the doses used. There is little doubt that the dose of chlorthalidone used was greater than that required for a full antihypertensive effect of this drug.Several β-blockers given as monotherapy induce significant increases in Tg and a tendency for decreases in HDL-C. These changes are most prominent on non-selective β1+2− blockers without partial intrinsic sympathomimetic activity (ISA), less pronounced on highly selective β1blockers without ISA, and even more discrete or absent on β-blockers with distinct ISA.Other sympatholytics such as reserpine, methyldopa, debrisoquine, urapidil, clonidine, labetalol, or postsynaptic α-blockers (prazosin, trimazosin, doxazosin etc.) did not affect or, postsynaptic α-blockers in particular, sometimes even slightly decreased Tg or LDL-C and very LDL-C values.During combination therapy, diuretic-induced increases in LDL-C were at short term prevented or reversed by the concomitant administration of certain β-blockers, but not by sympatholytics such as reserpine, methyldopa or clonidine. With combined diureticpra-zosin treatment, a tendency for slightly higher HDL-C was reported.Angiotensin converting enzmye inhibitors (captopril, enalapril) and calcium channel blockers (verapamil, nifedipine, nitrendipine, diltiazem) seem to be largely devoid of undesirable effects on serum lipoproteins.Monotherapy with the potent direct vasodilator carprazidil improved blood pressure and significantly increased HDL-C.Whether and to what extent the observed variations in lipoproteins may persist beyond 1 year of treatment is as yet unclear. Therefore, at present these lipoprotein effects should be categorised as associated biochemical effects and no more. Long term studies are needed to clarify the pathogenic and prognostic relevance oflipoprotein changes induced by certain diuretics and/or β-blockers. In the meantime, it is of clinical interest that several of the generally available antihypertensive drugs seem to be ‘neutral’ or sometimes perhaps even potentially beneficial with regard to lipoprotein metabolism.

Randomized, Double-Blind Comparative Trial of Subunit and Virosomal Influenza Vaccines for Immunocompromised Patients

BACKGROUND To our knowledge, no study to date has compared the effects of a subunit influenza vaccine with those of a virosomal influenza vaccine on immunocompromised patients. METHODS A prospective, double-blind, randomized study was conducted to compare the immunogenicity and reactogenicity of subunit and virosomal influenza vaccines for adult patients who had an immunosuppressive disease or who were immunocompromised as a result of treatment. RESULTS There were 304 patients enrolled in our study: 131 with human immunodeficiency virus (HIV) infection, 47 with a chronic rheumatologic disease, 74 who underwent a renal transplant, 47 who received long-term hemodialysis, and 5 who had some other nephrologic disease. There were 151 patients who received the subunit vaccine and 153 patients who received the virosomal vaccine. A slightly higher percentage of patients from the subunit vaccine group were protected against all 3 influenza vaccine strains after being vaccinated, compared with patients from the virosomal vaccine group (41% vs. 30% of patients; P = .03). Among HIV-infected patients, the level of HIV RNA, but not the CD4 cell count, was an independent predictor of vaccine response. Among renal transplant patients, treatment with mycophenolate significantly reduced the immune response to vaccination. The 2 vaccines were comparable with regard to the frequency and severity of local and systemic reactions within 7 days after vaccination. Disease-specific scores for the activity of rheumatologic diseases did not indicate flare-ups 4-6 weeks after vaccination. CONCLUSIONS For immunosuppressed patients, the subunit vaccine was slightly more immunogenic than the virosomal vaccine. The 2 vaccines were comparable with regard to reactogenicity. Vaccine response decreased with increasing degree of immune suppression. Among HIV-infected patients, the viral load, rather than the CD4 cell count, predicted the protective immune response to the vaccine. CLINICAL TRIALS REGISTRATION NCT00783380 .

Identification of IGFBP-7 by urinary proteomics as a novel prognostic marker in early acute kidney injury

Early diagnosis of acute kidney injury (AKI) and accurate prognostic stratification is a prerequisite for optimal medical management. To identify novel prognostic markers of AKI, urine was collected on the first day of AKI in critically ill patients. Twelve patients with early recovery and 12 matching patients with late/non-recovery were selected and their proteome analyzed by gel electrophoresis and mass spectrometry. We identified eight prognostic candidates including α-1 microglobulin, α-1 antitrypsin, apolipoprotein D, calreticulin, cathepsin D, CD59, insulin-like growth factor-binding protein 7 (IGFBP-7), and neutrophil gelatinase-associated lipocalin (NGAL). Subsequent quantification by ELISA showed that IGFBP-7 was the most potent predictor of renal recovery. IGFBP-7 and NGAL were then chosen for further analyses in an independent verification group of 28 patients with and 12 control patients without AKI. IGFBP-7 and NGAL discriminated between early and late/non-recovery patients and patients with and without AKI. Significant upregulation of the urinary markers predicted mortality (IGFBP-7: AUC 0.68; NGAL: AUC 0.81), recovery (IGFBP-7: AUC 0.74; NGAL: AUC 0.70), and severity of AKI (IGFBP-7: AUC 0.77; NGAL: AUC 0.69), and were associated with the duration of AKI. IGFBP-7 was a more accurate predictor of renal outcome than NGAL. Thus, IGFBP-7 is a novel prognostic urinary marker that warrants further investigation.

Increase in circulating insulin induced by atrial natriuretic peptide in normal humans.

To search for possible metabolic interactions of α-human-atrial natriuretic peptide (αhANP), we evaluated in 20 normal subjects blood levels of αhANP, glucose, insulin, cortisol, electrolytes, catecholamines, free fatty acids, carnitine and amino acids, blood pressure (BP), and heart rate before, during, and after a 45-min infusion of synthetic αhANP. Group A [n = 10] was studied on liberal and Group B on three consecutive sodium (Na) intakes of 17, 140, and 310 mM/day. Plasma αhANP was slightly but not significantly higher following 5 days on “normal” or high than on low Na+ intakes. ahANP infused at 0.1 μg/kg/min produced on all Na+ intakes comparable percentage increases in plasma insulin (+ 34 to 63%, p < 0.001), norepinephrine (+ 76 to 155%, p < 0.001) and heart rate (p < 0.001), and a similar fall in diastolic BP (p < 0.001). Plasma glucose tended to be decreased slightly and cortisol was reduced; epinephrine, dopamine, and potassium levels were not significantly modified. As evaluated in group A, serum free fatty acids were increased (p < 0.01), plasma free carnitine levels were reduced (p < 0.001), and amino acids were not consistently altered. These findings indicate that in normal humans ahANP may, on various sodium intakes, modulate insulin secretion and/or metabolism and elicit a possibly baroreflex-mediated sympathetic activation and lipolysis.

Pressure dependence of atrial natriuretic peptide during norepinephrine infusion in humans

The relative contribution of increased blood pressure (BP) or norepinephrine (NE), or both, to the stimulatory effect of an NE pressor infusion on circulating immunoreactive atrial natriuretic peptide (ANP) was evaluated in 10 healthy young men. They were studied during an infusion of NE, which was applied initially alone and then in combination with sodium nitroprusside. NE infusion rate was increased in four 30-minute intervals to a final dose of 200 ng/kg body weight per minute, leading to 12-fold higher plasma NE levels than were seen during control conditions. This increased mean BP (from a mean basal value of 94 +/- 3 to 119 +/- 4 [SEM] mm Hg; p less than 0.001) and plasma immunoreactive ANP (from 50 +/- 7 to 112 +/- 17 pg/ml; p less than 0.001), whereas heart rate decreased (p less than 0.001). The NE infusion was continued at the highest dose and an additional infusion of sodium nitroprusside was started to titrate mean BP in 30-minute intervals down to control values; a mean sodium nitroprusside dose of 0.95 micrograms/kg/min restored mean BP to 93 +/- 4 mm Hg (p less than 0.001), decreased plasma immunoreactive ANP to basal values (51 +/- 4 pg/ml; p less than 0.001), increased heart rate (p less than 0.001), and left plasma levels of NE largely unchanged. Plasma protein and hematocrit rose about 5 to 6% (p less than 0.001) during the NE infusion and then decreased about 3 to 4% (p less than 0.001 and p less than 0.01) when sodium nitroprusside was added.(ABSTRACT TRUNCATED AT 250 WORDS)