Barbara A. Clark

Plasma endothelin levels in preeclampsia: Elevation and correlation with uric acid levels and renal impairment

OBJECTIVE: The purpose of this study was to determine if endothelin levels are elevated in women with preeclampsia and if these levels correlated with other laboratory features of disease severity. STUDY DESIGN: Parameters were compared in four groups of women volunteers by means of analysis of variance: (1) 16 women with preeclamptic pregnancies, (2) 11 pregnant women without preeclampsia, of similar lengths of gestation, (3) six otherwise normal women with pregnancies at term or beyond (>38 weeks), and (4) 22 nofmotensive young women. RESULTS: Endothelin levels were elevated in women with preeclampsia as compared with those of gestation-matched pregnant and nonpregnant controls (22.6 ± 2.0 vs 12.0 ± 1.0 vs 10.4 ± 1.3 pmol/L, p r = 0.698, p r = −0.659, p CONCLUSION: Circulating endothelin levels are elevated in women with preeclampsia and correlate closely with serum uric acid levels and measures of renal dysfunction. These observations suggest that endothelin may contribute to renal vasoconstriction in preeclampsia.

Endothelin and atrial natriuretic peptide levels following radiocontrast exposure in humans

Radiocontrast exposure is associated with vasoconstriction of the renal vascular bed and, in certain circumstances, with acute renal failure. This may be influenced by the volume of contrast infused or underlying disease, such as diabetes or renal failure. Changes in circulating vascular regulators, such as endothelin and atrial natriuretic peptide (ANP), may play a role in the development and/or prevention of acute renal failure. Nineteen patients undergoing arteriographic procedures were divided into two groups: large-volume contrast (> or = 150 mL; n = 7) and small-volume contrast (< 150 mL; n = 12). Circulating endothelin levels increased significantly (from 12.3 +/- 1.1 pmol/L to 19.4 +/- 2.2 pmol/L; P < 0.05) following large-volume contrast exposure (group 1) but not following small-volume contrast exposure (group 2) (13.9 +/- 1.7 pmol/L to 12.2 +/- 0.09 pmol/L). ANP levels increased significantly in both groups: 43 +/- 15 pg/mL to 75 +/- 21 pg/mL in group 1 and 33 +/- 16 to 106 +/- 39 pg/mL in group 2. Data from an additional eight patients with underlying diabetes mellitus and/or renal insufficiency also were obtained and were considered separately. Endothelin levels were higher at baseline and increased significantly after contrast (25.7 +/- 5 pmol/L to 55.4 +/- 18 pmol/L) despite the relatively small average volume of contrast infused (112 +/- 15 mL). ANP levels were also highest in these patients (211 +/- 43 pg/mL precontrast and 323 +/- 65 pg/mL postcontrast). No group had a significant change in serum creatinine following contrast exposure. In conclusion, large-volume radiocontrast exposure is associated with an increase in both circulating endothelin and ANP levels. Patients with underlying diabetes or renal insufficiency may have higher baseline levels and a greater tendency to increase endothelin after contrast exposure. While an increase in endothelin may contribute to renal vasoconstriction following radiocontrast exposure, simultaneous increases in ANP may serve to offset this response and protect against changes in renal function.

Effects of ioversol versus iothalamate on endothelin release and radiocontrast nephropathy.

RATIONALE AND OBJECTIVES.Certain radiocontrast agents, including iothalamate, iohexol, and ioxaglate, release the renal vasoconstrictor peptide endothelin from vascular endothelium in a way that might contribute to radiocontrast nephropathy. The effects of the nonionic, low osmolar agent, ioversol, on endothelin release and renal function are investigated. METHODS.Effects of ioversol were compared with equiiodine doses of iothalamate when applied to cultured bovine aortic endothelial cells or injected into normal rats and rats preconditioned by uninephrectomy, salt depletion, and indomethacin (USIC) to develop radiocontrast nephropathy. RESULTS.In comparison with iothalamate, ioversol had a greatly reduced propensity to stimulate the release of endothelin, from cultured cells and when injected into anesthetized rats. Ioversol produced less renal vasoconstriction than did iothalamate, in control and in USIC rats, and the development of radiocontrast nephropathy, assessed by creatinine clearance and morphologic damage to the renal medulla, was largely avoided. CONCLUSIONS.These results strengthen the hypothesis that endothelin release induced by radiocontrast agents is correlated with their renal toxicity and therefore, may play a role in radiocontrast nephropathy.

Unsuspected Morbid Hypermagnesemia in Elderly Patients

This study was designed to determine the incidence, etiology and consequences of severe hypermagnesemia. We retrospectively reviewed all hospital admissions over a 5-year period from 1984 to 1989 and identified 8 cases of severe hypermagnesemia (serum Mg > or = 6.0 mg/dl) due to magnesium ingestion. All but 1 patient were elderly (mean age 70 +/- 6 years). The etiology when identified was due to magnesium-containing cathartics (n = 3) or antacids (n = 3). The total amount of magnesium ingested was not excessive, but bowel disorders that may have enhanced absorption (such as active ulcer disease, gastritis, colitis, perforated viscus, massive gastric dilatation) were present in 7 of the 8 patients. Unexpectedly, only 1 had preexisting renal failure. Renal function was found to be normal in 1, only mildly to moderately impaired in 5 (creatinine < 3.6 mg/dl) and severely impaired in 2 (creatinine 7.6, 15.7 mg/dl). Clinical sequelae of hypermagnesemia were hypotension (n = 7), bradycardia (n = 2), respiratory depression (n = 3), EKG abnormalities (n = 6), depressed mental status (n = 5). Hypocalcemia (range 5.7-7.4 mg/dl) more severe than could be attributed to either hypoalbuminemia or acute renal failure was present in 7. A low anion gap (range-2 to 9) was present in 5. Most striking was the fact that despite clinical sequelae, the hypermagnesemia was unsuspected in 6 of the 8 cases. Hypermagnesemia can occur without severe renal insufficiency in association with bowel disease, particularly in elderly individuals, and may be a clinically unrecognized cause of cardiovascular dysfunction, hypocalcemia and neurologic or respiratory depression.

Altered dopaminergic responses in hypertension.

Biogenic amine metabolism may be altered in hypertension and thus contribute to its pathophysiology. This report describes an abnormality in dopamine excretion in hypertensive subjects in the postabsorptive state that persists despite an increase in dietary precursors for dopamine supplied by a protein meal. We studied seven normotensive and six nonmedicated hypertensive men after two different meals: 60 g protein and a noncaloric electrolyte-equivalent broth. Overall mean sodium excretion was 56% higher in the hypertensive group throughout both meal studies (p less than 0.01), implying higher chronic dietary sodium intake. Despite this, overall urinary excretion of dopamine tended to be lower in hypertensive than in normotensive subjects (p = 0.06). Hypertensive also differed from normotensive subjects in their response to protein feeding. In the normotensive subjects there was a 23% increase in urinary dopamine excretion (p less than 0.05), which was not seen after the noncaloric meal. In the hypertensive subjects, there was no change in urinary dopamine after the protein meal. In the normotensive subjects there was a 74% increase in sodium excretion (p less than 0.01) after the protein meal, but no significant change was seen in the hypertensive subjects. There were no differences in baseline renal plasma flow or glomerular filtration rate between the groups and no statistically significant differences between the groups in their renal hemodynamic responses to the meals. In summary, hypertensive subjects have less renal dopamine production for the amount of sodium ingested and a decreased renal dopamine production in response to a protein load as compared with normotensive subjects, consistent with a renal defect in conversion of DOPA to dopamine.

Effects of hypertonicity on water intake in the elderly: An age-related failure

Dehydration is a common clinical syndrome associated with many illnesses and treatments in the elderly. Prior studies have shown diminished sensation of thirst during water deprivation. It is currently unclear whether age-related decreases in thirst perception impair the defense against a hyperosmolar challenge. To examine the impact of water ingestion during hyperosmolality, young and old subjects were allowed free access to water during and after an intravenous infusion of 5% hypertonic saline. Cumulative water intake and serum osmolality were compared between seven healthy young (20-28 yrs) and seven healthy old (72-89 yrs) volunteers during and following a two hour hypertonic saline infusion at a rate of 0.06 mlxkg(-1) min(-1). Serum osmolality and water intake were markedly different between the two groups. In the old group, serum osmolality increased by 17 mosmol/kg above baseline despite free access to water. In contrast, serum osmolality increased to only 7 mosmol/kg above baseline in the young group and did not rise further. By ingesting water, the young were able to defend against an additional increase in serum osmolality. The young drank approximately twice that of the old during the infusion period. Healthy older individuals drink less than young despite a significantly increased serum osmolality. This hypodipsia in old individuals increases their susceptibility to hypertonicity.

Sequential evaluation of islet cell responses to glucose in the transplanted pancreas in humans

We evaluated the hormonal and metabolic responses of denervated pancreas allografts in nine volunteers 3 to 12 months after the transplant (initial) and again 1 year later (follow-up). Eight of the patients received simultaneous pancreas-kidney transplants. The glucose clamp technique was used to create a square wave of hyperglycemia 5.5 mmol/L above the basal glucose level for 2 hours. A biphasic insulin response was evident in each subject, both initially and at follow-up. The initial plasma insulin response was fourfold higher in patients with pancreas-kidney transplants than in normal volunteers. However, the plasma insulin response of the patients with pancreas-kidney transplants at the follow-up study was more similar to that of the normal controls. The plasma glucagon levels were elevated in follow-up clamp studies. Hepatic glucose production and glucose disposal were similar in both studies. At the follow-up examination only, GLUT4, the major insulin-sensitive glucose transporter, was measured in muscle homogenates by immunoblotting. GLUT4 levels in the patients with pancreas-kidney transplants were only 55% as abundant as in normal volunteers. This may be due, in part, to immunosuppressive therapy or to persistent, albeit reduced, levels of hyperinsulinemia even 2 years after transplantation. We concluded that, despite systemic drainage of the pancreas and immunosuppressive therapy, pancreatic insulin secretion, peripheral insulin levels, and muscle insulin responsiveness are restored toward normal levels approximately 2 years after the transplant.

Urinary prostaglandin E2 and dopamine responses to water loading in young and elderly humans

Background: Human aging is associated with a number of unexplained changes in renal function, including a diminished capacity to excrete water and sodium loads and an increased susceptibility to acute renal failure. PGE2 and dopamine are intrarenal autocrine factors important in diuresis, natriuresis and also serve to protect against ischemic renal injury. Responses of these autocoids to provocative maneuvers such as water loading have not previously been studied in the elderly. Methods: Five healthy young (25±1 yrs) and five healthy elderly (70±1 yrs) women underwent a 20 ml/kg oral water load in the Clinical Research Center.

RENAL RESPONSE TO ACUTE DIETARY PROTEIN LOADING IN YOUNG AND OLD PEOPLE

In reply: Bedard and Molloy state in their Letter’ commenting our report,l that the increase in accident rates, and especially in the initiation of accidents, has created a pressing need for the development and testing of screening tools for older drivers. However, there are other possible interpretations than their being a threat to traffic safety for the fact that older drivers are overrepresented as legally responsible parties or “initiators” in fatal collision accidents. First, given the greater frailty of the aging organism, the likelihood of a collision accident being fatal is much greater when an older driver is involved.3 Second, the “overrepresentation” of older drivers as initiators or as parties at fault can equally well be described the other way round, namely as “underrepresentation” or parties not at fault. In any given traffic conflict, a driver potentially at fault is most likely to avoid the collision with a partner driving slowly and defensively, like the typical older driver. Thus, even though older drivers initiate accidents, they do not often get involved in accidents as the not-guilty party. Conclusions about older drivers’ risk based on different forms of guilty-not guiltycomparisons (like the one made by by Perneger and Smith4 and others using measures of induced exposure“‘) should, therefore, be made with great caution (for a more detailed discussion of this methodological problem, see ref. 7). Nevertheless, we agree with Bedard and Molloy about the need to develop and test screening tools. This work should not, however, be done with the aim of creating tools for an indiscriminate screening of all drivers at a given age. Rather, it is our view that future research efforts in driver diagnostics should address the problem area on two levels: (1) how do we identify those subgroups of older drivers that have, on group level, an increased risk of accident and should, therefore, be screened; and (2) having defined and found the target groups, what testing methods could we use in order to identify with sufficient specificity and sensitivity those individuals who actually do have a higher-than-acceptable accident risk? Under these strategic questions, more specific research problems can be formulated, e.g., what are the critical functions for safe driving, how is the effect of a given functional deficit mediated to traffic behavior, and how can we define thresholds of acceptable function. This is an area of societal decision-making where the demands for practical solutions threaten to become pressing long before we have scientific evidence upon which to base these decisions. Not only are general health controls for older drivers ineffective as a safety measure, it has also been shown that, if implemented, dementia screening of the older driver population would have a very poor cost-benefit relationship.’ At the same time, it is contrary to existing ethical standards in medicine to submit people to medical interventions, including controls, the usefulness of which has not been clearly demonstrated. Research on older drivers should, therefore, have high priority in our society in order to avoid the establishment, on the basis of insufficient knowledge, of institutions LETTERS T O THE EDITOR 389

Glucose Tolerance, Insulin Sensitivity, and Age

Impaired glucose tolerance has been a well-described characteristic of human aging.1–3 Epidemiologic studies have demonstrated modest changes in fasting glucose levels (approximately 1 to 2 mg/dl for each decade over 50) as well as more marked changes in the 2-hour postprandial glucose level (5 to 10 mg/dl for each decade over 50).1–3