Jacques A. Durr

Diabetes Insipidus in Pregnancy Associated with Abnormally High Circulating Vasopressinase Activity

SEVERAL authors have described syndromes of diabetes insipidus that begin during gestation and remit after delivery.1 Barron et al.2 recently described three pregnant women with diabetes insipidus ...

Osmoregulation during Pregnancy in the Rat: EVIDENCE FOR RESETTING OF THE THRESHOLD FOR VASOPRESSIN SECRETION DURING GESTATION

Osmoregulation was studied in near term and age-matched Sprague-Dawley rats. Basal plasma osmolality (P(osm)) and plasma sodium (P(Na)) were 281+/-3 mosmol/kg and 134+/-3 meq/liter, respectively, on the 20th gestational day compared with 292+/-3 mosmol/kg and 140+/-1 meq/liter in virgin animals (P < 0.001), whereas P(urea) and plasma water content were similar in pregnant and control rats. These differences could not be reproduced in animals receiving progesterone, estrone, or a combination of progesterone and estradiol for 2 wk. Pregnant and control rats were deprived of water for periods ranging from 0 to 48 h. P(osm), always lower in gravidity, was 290+/-3 mosmol/kg after 2 d of water deprivation in pregnant animals compared with 300+/-2 mosmol/kg in controls (P < 0.001). Thus 48 h of dehydration were required before P(osm) in gravid rats was similar to basal values in the age-matched virgins. Despite strikingly lower P(osm), plasma arginine vasopressin (P(AVP)) and urinary osmolality (U(osm)) were similar in the basal state averaging 2.16+/-0.78 pg/ml and 1,652+/-406 mosmol/kg, respectively, during pregnancy compared with 2.08+/-2.17 pg/ml and 1,483+/-203 mosmol/kg in controls (NS). Water deprivation increased P(AVP) and U(osm) similarly in pregnant and virgin rats: these values reached 22.7+/-3.3 pg/ml and 3,300+/-123 mosmol/kg at 48 h in gravid compared with 26.0+/-6.4 pg/ml and 3,342+/-141 mosmol/kg in the controls (NS). Regression equations for P(AVP)vs. P(osm) which were highly significant (P < 0.001) in both groups demonstrated an apparent threshold for AVP secretion approximately 11 mosmol lower in gravid animals. Intravascular volume decreased, and plasma aldosterone increased during water deprivation, and both changes (Delta%) were significantly greater in the gravid animals (P <0.01). Therefore, P(osm) was increased without concomitant volume depletion by intraperitoneal hypertonic saline. Again P(AVP)vs. P(osm) correlated significantly (r > 0.9; P < 0.001) in each group, and the apparent threshold was 14 mosmol lower in pregnant animals. Diluting ability, tested by oral water loading, was not impaired in the pregnant animals which excreted a 30 ml/kg load as well as controls. Also, chronically hydrated virgin animals whose fluid intake was more than twice that of pregnant rats (for 19 d) did not lower their P(osm). In separate studies homozygous Brattleboro rats, which produce no endogenous vasopressin, were also shown to have a decreased P(osm) (pregnant 292+/-4 mosmol/kg; virgin 310+/-6 mosmol/kg P < 0.001), but unchanged U(osm) during pregnancy. Data demonstrate a resetting of the osmostat in gravid Sprague-Dawley rats as P(osm) and the threshold for AVP secretion both decrease significantly during gestation in this species. Studies in homozygous Brattleboro animals with hereditary diabetes insipidus suggest that the osmotic threshold for thirst is reset as well.

Correlates of Brain Edema in Uncontrolled IDDM

Blood glucose, plasma sodium, bicarbonate (HCO−3), vasopressin, and hematocrit were monitored before and during treatment in patients with uncontrolled insulin-dependent diabetes mellitus (IDDM). These parameters were correlated with simultaneous serial cranial computed tomography readings of brain edema. Six of seven patients had positive computed tomography readings for brain edema on admission. Initial brain edema correlated directly with blood glucose (r = 0.79, P = 0.033) and inversely with HCO−3 (r = −0.76, P = 0.047). At 6 h, brain edema still correlated with acidosis (HCO−3; r = −0.79, P = 0.033) but no longer with blood glucose. At that time, however, brain edema correlated with the rate of change in blood glucose (r = 0.915, P = 0.005). Results of interactive stepwise regression analysis suggest that the change in the calculated effective plasma osmolality plays a predominant role in the progression of brain edema during therapy (r = 0.995, P < 0.001). Thus, although hyperglycemia and acidosis probably predispose to diabetic brain edema, osmotic factors may be major predictors of its evolution. No relationships were detected between brain edema and initiation of insulin therapy, plasma vasopressin, or changes in hematocrit. The factors responsible for initial brain edema and its progression, statistically identified in this study, require reassessment of common theories that attribute brain edema exclusively to therapy.

Aldosterone in Congestive Heart Failure: Analysis of Determinants and Role in Sodium Retention

In patients with congestive heart failure (CHF), the role of aldosterone in the abnormal sodium (Na+) retention and the determinants of plasma aldosterone (PA) including plasma atrial natriuretic factor (hANF), plasma renin activity (PRA), and plasma potassium (K+) have not been fully elucidated. We therefore studied the effect of the specific aldosterone antagonist, spironolactone, on urinary Na+ and K+ excretion and plasma hormone responses in 6 Na(+)-retaining CHF patients. After withdrawal of diuretics 4 days prior to the study, the CHF patients were placed on a Na+ intake of 100 mmol/day for 9 days. Spironolactone, 200 mg p.o. bid, was administered for the last 4 days of the 9-day study period. PRA and norepinephrine increased with spironolactone treatment (both p less than 0.05). Plasma hANF before spironolactone was significantly elevated and decreased during spironolactone therapy (p less than 0.05). Urinary Na+ excretion significantly increased during spironolactone administration and the positive Na+ balance was reversed in the CHF patients. Moreover, the urine Na+:K+ concentration ratio significantly increased during spironolactone administration. Analysis of the relationship between PA, plasma K+, PRA, and plasma hANF indicated that PRA is the primary determinant of PA in patients with CHF. Thus, the present results indicate that the renin-angiotensin-aldosterone system is an important mediator of Na+ retention in CHF, as evidenced by the reversal of the positive Na+ balance with a specific aldosterone antagonist. This natriuretic effect can be demonstrated in the presence of potential antinatriuretic influences including stimulation of the renin-angiotensin and sympathetic nervous systems and a decrease in plasma hANF.

Calcitonin gene-related peptides: their binding sites and receptor accessory proteins in adult mammalian skeletal muscles

This work addresses the presence, pharmacological properties, and anatomical localization of calcitonin gene-related peptide-alpha (CGRPalpha) binding sites and the receptors accessory proteins in endplate-enriched and non-endplate muscle membrane samples from adult rat gracilis muscles. We examined the binding of (125)I-[Tyr(0)]-CGRPalpha, the competitive binding of CGRPalpha analogs, the immunohistochemical localization of the receptors accessory proteins, and Western blots of the receptor component protein. Results show that: (a). (125)I-[Tyr(0)]-CGRPalpha binding is saturable, specific, and consistent with the presence of a homogeneous population of binding sites (Hill coefficients=1.0) in endplate and non-endplate samples exhibiting dissociation constants of 0.39 nM and 0.38 nM, respectively; (b). the density of binding sites in the endplate samples (71.0 fmoles/mg protein) is considerably higher than that in their non-endplate counterparts (34.6 fmoles/mg protein); (c). unlabeled CGRPalpha, hCGRP8-37 and calcitonin compete with the radioligand with the same order of potency in the endplate and non-endplate samples; and (d). the localization of the receptor accessory proteins, including the receptor activity-modifying protein (RAMP1) and the receptor component protein (RCP), for the most part matches that of the motor end-plates. Thus, gracilis muscles express CGRPalpha-specific binding sites which are predominantly localized in the muscles motor endplate regions where RAMP1, RCP, CGRPalpha, acetylcholine receptors, and acetylcholinesterase are detected in high concentrations. These findings imply that the CGRPalpha binding sites reflect the presence of physiologically functional receptors with a pharmacological profile consistent with that of the CGRPalpha receptor type 1 (CGRP1). When considered together with earlier studies on the same neuromuscular preparation, the present work further suggests that the motoneuron-dependent trophic control of acetylcholine receptors and acetylcholinesterase in skeletal muscle endplates is partly mediated by nerve-derived CGRPalpha activating specific receptors which are highly sensitive to the truncated peptide hCGRP8-37.

DIAGNOSIS AND MANAGEMENT OF DIABETES INSIPIDUS DURING PREGNANCY

OBJECTIVE To provide an overview of diagnostic and treatment strategies in pregnant patients with diabetes insipidus (DI). METHODS We review the changes in osmoregulation during normal pregnancy, characterize the various types of DI that can occur during pregnancy, and discuss the recommended management. RESULTS The incidence of DI is 2 to 4 cases per 100,000 gestations. Central DI can precede pregnancy or manifest initially during gestation. With preexistent central DI, pregnancy usually aggravates the disorder, and the requirements for antidiuretic hormone (ADH) usually increase. Such an effect is less likely to be noted in ADH-independent nephrogenic forms of DI. Currently, the major type of DI associated with pregnancy is a transient syndrome that is resistant to arginine vasopressin (AVP) but responsive to desmopressin (dDAVP); such cases of DI are often associated with liver abnormalities or preeclampsia. This syndrome is explained by excess vasopressinase, a placental enzyme which degrades AVP but not dDAVP. A transient recurrent type of DI can occur during gestation in patients with limited ADH-secreting capacity and is responsive to both AVP and dDAVP. Latent central DI manifesting after complicated delivery and transient nephrogenic DI, resistant to both AVP and dDAVP, have also been reported. CONCLUSION The differential diagnosis of polyuric and polydipsic states during pregnancy is broad, and precise diagnosis may be difficult. The use of dDAVP to treat DI during gestation has proved effective and safe for both the mother and the fetus.

Elevated Plasma Atrial Natriuretic Factor and Vasopressin in High-Altitude Pulmonary Edema

A diagnosis of acute high-altitude pulmonary edema was made in five male skiers (age, 35.0 +/- 1.8 years) by history and physical examination and was confirmed by a characteristic chest radiogram showing alveolar infiltrates associated with a normal cardiac silhouette. Five healthy age- and sex-matched subjects with similar physical activity at the same altitude served as controls. Plasma sodium was 135.0 +/- 1.5 mmol/L in the acutely ill patients compared with 144.0 +/- 3.3 mmol/L in the controls (P less than 0.025). Mean plasma atrial natriuretic factor immunoreactivity averaged 17.6 +/- 5.6 pmol/L in patients with high-altitude pulmonary edema compared with 6.8 +/- 0.7 pmol/L in the controls at the same altitude (P less than 0.05). Elevated atrial natriuretic factor levels normalized to 7.5 +/- 1.9 pmol/L (P less than 0.05) during recovery in Denver (altitude, 1600 meters) 24 hours later. Plasma arginine vasopressin levels were 1.8 +/- 0.37 pmol/L in patients with high-altitude pulmonary edema at diagnosis compared with 0.92 +/- 0.28 pmol/L in controls (P = 0.07). The inappropriately elevated arginine vasopressin levels decreased to 1.29 +/- 0.37 pmol/L during recovery (P less than 0.025), but the lowered plasma sodium concentration had not normalized by discharge within 24-hours of transfer to Denver and averaged 135.8 +/- 1.2 mmol/L. The pathophysiologic implications of these findings are discussed.

Measurement of Endogenous Lithium Levels in Serum and Urine by Electrothermal Atomic Absorption Spectrometry: A Method with Potential Clinical Applications'

A highly sensitive flameless atomic absorption method has been adapted for the determination of endogenous trace lithium levels in serum and urine. With ammonium nitrate as the only matrix modifier, serum levels of Li as low as 0.03 mumol/liter are measured accurately and there is no requirement for standard additions. The need for background correction during analysis was clearly established, and tungsten and Zeeman-effect background corrections were compared. The tungsten correction offered superior sensitivity and linearity of standards. Recoveries in urine and serum average 94.8 +/- 7.7 and 95.3 +/- 6.1% (+/- SD), respectively. The endogenous serum Li levels were 0.16 +/- 0.08 mumol/liter for normal subjects dwelling in the Denver metropolitan area. The mean 24-h excretion rate was 5.24 +/- 1.4 mumol/day. The mean fractional excretion of endogenous Li (clearance Li/clearance creatinine) was 23.2 +/- 3.0%, a value similar to values published for exogenously administered Li and measured by conventional methods.

Discontinuation of Tenofovir Disoproxil Fumarate for Presumed Renal Adverse Events in Treatment-Naïve HIV-1 Patients: Meta- analysis of Randomized Clinical Studies

Abstract Background: Safety and efficacy of tenofovir disoproxil fumarate (TDF) as a component of antiretroviral therapy (ART) have been demonstrated in clinical trials. TDF nephrotoxicity has been reported in both HIV-infected and noninfected patients. This meta-analysis explored the frequency of discontinuation attributed to renal adverse events (AEs) in randomized, controlled clinical studies that used TDF-containing regimens for ART-naïve, HIV-infected patients. Methods: A literature search of 4 electronic databases through October 31, 2013 was utilized. RCTs included were limited to randomized, prospective, comparative design in ART treatment-naïve adults with HIV-1 infections receiving ART. Studies included trials containing TDF treatment regimens, with or without a non-TDF control group. Study design, follow-up, size of study population, treatment group, patient demographics, number of patients exposed to TDF or non-TDF control, baseline characteristics, investigator-defined criteria for renal AEs, and number of discontinuations due to a presumed renal AEs were extracted. Results: Twenty-one clinical studies met the selection criteria. Treatment duration ranged from 48 to 288 weeks. Renal AEs led to study drug discontinuation in 44 of 10,129 patients exposed to TDF (0.43%; 95% CI, 0.32%-0.58%) and 2 of 2,013 patients exposed to non-TDF-containing regimens (0.10%; 95% CI, 0.01%-0.36%). In 5 randomized, controlled studies that included a non-TDF comparator, the estimated risk difference between the treatment groups (TDF vs non-TDF) was 0.50% (95% CI, 0.13%-0.86%; P = .007). Conclusions: In clinical studies using TDF-containing regimens, the rate of discontinuations due to renal AEs was low, but was slightly higher than in studies using non-TDF comparators.

Plasma Osmolality Predicts Extracellular Fluid Catechol Concentrations in the Lateral Hypothalamus

Abstract: The lateral hypothalamus has an important role in regulating food and water intake. We have investigated the endogenous release of monoamines from the lateral hypothalamus during manipulations of plasma osmolality and circulating volume. Adult male Sprague‐Dawley rats implanted with carbon paste in vivo electrochemical (EC) electrodes in the lateral hypothalamus were placed on a 72‐h water deprivation schedule. Although the carbon paste EC electrode has an intrinsically ambiguous signal in which changes in ascorbic acid may appear as changes in catechol concentrations, pharmacologic studies in lateral hypothalamus indicated that the electrode most likely measured nor‐epinephrine and possibly epinephrine. On the test day, the EC electrodes were scanned with linear sweep voltammetry from ‐0.2 to +0.4 V at a rate of 5 mV/s. Semiderivative signal processing showed catechol and hydroxyindole peaks at +0.11 and +0.23 V, respectively. Baseline recordings were made prior to rats drinking distilled water, 10% sucrose, 5% dextrose, 0.30% NaCl, 0.90% NaCl, or 10%D‐mannitol. To control for the act of drinking, other implanted dehydrated rats were intraperitoneally injected with 5% dextrose, 0.30% NaCl, or 0.90% NaCl. To dissociate the effects of osmolality and circulating volume on the EC response, hydrated rats implanted with EC electrodes were subcutaneously injected with 12% NaCl or intraperitoneally injected with 35% polyethylene glycol. Other rats subjected to water deprivation and osmotic challenges were decapitated and trunk blood was collected for measurements of plasma osmolality and hematocrit. Similar experiments were conducted using homozygous Brattleboro rats which lack arginine vasopressin (AVP) but which preserve normal plasma osmolality with prodigious drinking. The use of these rats provided a way to dissociate monoamine changes related to AVP release from changes related to plasma osmolality. Results in Sprague‐Dawley and Brattleboro rats showed that the EC catechol signal was lower in rats with high plasma osmolality and rose with drinking or intraperitoneal fluid administration as a direct function of the fall in plasma osmolality. Manipulations of plasma osmolality had a greater effect on the EC catechol signal than did manipulations of circulating volume. Thus, we conclude that changes in extracellular fluid catechol concentrations in the lateral hypothalamus linearly reflect changes in plasma osmolality.