Gary L. Robertson

The standardization of terminology in nocturia: report from the standardization subcommittee of the International Continence Society

P. VAN KER REBROECK 1 , P. ABRAMS 2 , D. CHAIKIN 3 , J. DONOVAN 4 , D. FONDA 5 , S. JACKSON 6 , P. JENNUM 7 , T. JOHNSON 8 , G.R. LOSE 9 , A. MATTIASSON 10 , G.L. ROBER TSON 11 and J. WEISS 12 1 Chairman of the International Continence Society Standardization Committee, Department of Urology, University Hospital Maastricht, the Netherlands, 2 Bristol Urological Institute, Southmead Hospital, Bristol, UK, 3 Morristown Memorial Hospital, Morristown NJ, and Department of Urology, Weill Medical College of Cornell University, USA, 4 Department of Social Medicine, University of Bristol, Bristol, UK, 5 Aged Care Services, Caulfield General Medical Centre, Victoria, Australia, 6 Department of Gynaecology, John Radcliffe Hospital, Oxford, UK, 7 Department of Clinical Neurophysiology, University of Copenhagen and Sleep Laboratory, Glostrup, Denmark, 8 Rehabilitation Research and Development Center, Atlanta VA Medical Centre, Georgia, USA, 9 Department of Obstetrics and Gynaecology, Glostrup County Hospital, University of Copenhagen, Denmark, 10 Department of Urology, Lund University Hospital, Lund, Sweden, 11 Northwestern University Medical School, Chicago, USA, 12 Department of Urology, Weill Medical College of Cornell University and The New York Presbyterian Hospital, New York, NY, USA

Familial forms of diabetes insipidus: clinical and molecular characteristics

Over the past two decades, the genetic and molecular basis of familial forms of diabetes insipidus has been elucidated. Diabetes insipidus is a clinical syndrome characterized by the excretion of abnormally large volumes of diluted urine (polyuria) and increased fluid intake (polydipsia). The most common type of diabetes insipidus is caused by lack of the antidiuretic hormone arginine vasopressin (vasopressin), which is produced in the hypothalamus and secreted by the neurohypophysis. This type of diabetes insipidus is referred to here as neurohypophyseal diabetes insipidus. The syndrome can also result from resistance to the antidiuretic effects of vasopressin on the kidney, either at the level of the vasopressin 2 receptor or the aquaporin 2 water channel (which mediates the re-absorption of water from urine), and is referred to as renal or nephrogenic diabetes insipidus. Differentiation between these two types of diabetes insipidus and primary polydipsia can be difficult owing to the existence of partial as well as complete forms of vasopressin deficiency or resistance. Seven different familial forms of diabetes insipidus are known to exist. The clinical presentation, genetic basis and cellular mechanisms responsible for them vary considerably. This information has led to improved methods of differential diagnosis and could provide the basis of new forms of therapy.

Vaptans for the treatment of hyponatremia

The vaptans constitute a new class of pharmaceuticals developed for the treatment of the hypervolemic and euvolemic forms of hyponatremia. These agents are nonpeptide vasopressin antagonists that interfere with the antidiuretic effect of the hormone by competitively binding to V2 receptors in the kidney. This blockade results in water diuresis (aquaresis) that, if not offset by increased fluid intake, reduces body water content and raises plasma sodium levels. Probably as a result of this rise in plasma sodium, thirst and plasma vasopressin concentration increase, potentionally limiting the effects of the vasopressin antagonists. Nonetheless, vaptans are particularly useful to treat hypervolemic hyponatremia associated with severe congestive heart failure or chronic liver failure, as the only other treatments currently available, such as fluid restriction and diuretics, are slow-acting and minimally effective. Vaptans are also useful for treating euvolemic hyponatremia associated with the syndrome of inappropriate antidiuretic hormone (SIADH), at least when it is chronic and/or minimally symptomatic. However, because their effects vary unpredictably from patient to patient, vaptans are less useful than hypertonic saline infusion in cases of acute, severe and symptomatic hyponatremia. Vaptan therapy is absolutely contraindicated in hypovolemic hyponatremia (in which total body water is reduced) and is ineffective in the vasopressin-independent form of inappropriate antidiuresis caused by constitutive activating mutations of V2 receptors.

Genetic Basis of Familial Neurohypophyseal Diabetes Insipidus

Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant (adFNDI) or X-linked recessive (xrFNDI) disorder characterized by the development in early childhood of an irreversible deficiency of arginine vasopressin (AVP) secretion. Autopsy data in adFNDI reveal selective destruction of the posterior pituitary magnocellular neurons that normally produce the hormone. These abnormalities are due to a variety of mutations in the gene that encodes the AVP-neurophysin II precursor. Each one predicts a change in the primary structure of the preprohormone, and all but one are of a type known or reasonably presumed to impair the folding and cellular trafficking of the preprohormone. This pattern and the uniform clinical characteristics of adFNDI suggest that the disease is due to the production of a mutant precursor that is toxic for magnocellular neurons, because it cannot be folded, processed, or otherwise disposed of efficiently. Although the gene responsible for xrFNDI has not yet been cloned, the striking clinical similarities between adFNDI and xrFNDI suggest that similar pathophysiologic mechanisms may be involved.

Pathophysiology and Treatment of Enuresis in adults

Monosymptomatic nocturnal enuresis (MNE) in children is partly the result of inadequate reduction in the rate of urine output at night. This nocturnal polyuria is due to the lack of a rise in the anti-diuretic hormone, arginine vasopressin (AVP), and can be reduced or eliminated by treatment with desmopressin at bedtime. Since there is a 1% incidence of MNE among adults, this study investigated the circadian pattern of solute and water balance in nine young adult enuretics before and during desmopressin therapy and compared the results with nine-age- and sex-matched, healthy controls. Before treatment, enuretics and controls had similar total fluid intake, urine output, urine osmolality, plasma osmolality, plasma total protein, mean arterial pressure and plasma AVP. The circadian pattern of fluid intake was also normal in enuretics. This abnormality could not be attributed to a deficiency of plasma AVP or an increase in solute excretion, since both variables were similar to controls. Rather, their nocturnal polyuria appeared to be due to a marked nocturnal reduction in renal sensitivity to the antidiuretic effect of vasopressin. In seven enuretics, restudied during treatment with desmopressin (10-30 micrograms o.d.), circadian urine output was normal and enuresis was absent. These results indicate that: (i) The circadian pattern of urine output in healthy adults is largely due to a nocturnal decrease in solute excretion rather than a rise in plasma AVP; (ii) The subset of adults with persistent MNE also have nocturnal polyuria as a result of insensitivity to the antidiuretic action of AVP; (iii) These defects can be corrected by treatment with desmopressin.

Cerebrospinal Fluid Vasopressin and Vasotocin in Health and Disease

It is now recognized that integrative central nervous system function involves not only electrophysiological phenomena and chemical neurotransmission, but also interaction between brain and endocrine hormones. With the recent upsurge in interest in “peptidergic” neurons, it has become evident that many hypothalamic and pituitary peptides occur in brain outside the boundaries of the hypothalamo-pituitary axis. Anterior and posterior pituitary peptides, hitherto characterized as “peripheral hormones,” have now been identified in cerebrospinal fluid (CSF). This Chapter reviews our current knowledge about the occurrence of the antidiuretic hormone, arginine vasopressin (AVP), and the closely related nonapeptide hormone, arginine vasotocin (AVT), in human CSF.

The effect of the cold pressor test on vasopressin secretion in man

Stress has been thought to induce the release of arginine vasopressin (AVP). We evaluated this claim by studying the effects of a modified cold pressor test on plasma AVP, plasma cortisol, blood pressure, pulse rate, and a number of variables known to affect AVP secretion. In a cross-over study design, test and control values were obtained in seven male subjects. The pressor test was found to induce painful stress as evidenced by subjective reports and the objective findings of increased mean arterial pressure (13.9 +/- 3.1 mm Hg; p less than 0.004), pulse rate (9.2 +/- 2.8 beats/min; p less than 0.02), and plasma cortisol (3.5 +/- 0.8 micrograms/dl; p less than 0.005). In contrast, there were no significant changes in plasma AVP that could be attributed to the cold pressor test. There also were no changes in plasma osmolality, measured plasma solutes, hematocrit or body temperature. An unexpected finding was a premonitory drop in plasma AVP occurring just prior to the pressor test (2.5 +/- 2.0 pg/ml; p less than 0.04) and at the comparable time point in the control study (3.1 +/- 1.2 pg/ml; p less than 0.001). There were no changes in any of the other measured variables which could account for this drop. We conclude that the cold pressor test is not a stimulus to AVP release and that anticipation of stress may inhibit secretion of this hormone.

Six novel mutations in the arginine vasopressin gene in 15 kindreds with autosomal dominant familial neurohypophyseal diabetes insipidus give further insight into the pathogenesis.

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is caused by postnatal arginine vasopressin (AVP) deficiency resulting from mutations in the AVP gene encoding the AVP pre-prohormone. To advance the understanding of adFNDI further, we have searched for mutations in the AVP gene in 15 unrelated kindreds in which diabetes insipidus appeared to be segregating. In nine kindreds, seven different previously described mutations were identified. In each of the other six kindreds, unique novel mutations were identified. Two of these (225A>G and 227G>A) change a nucleotide in the translation initiation codon of the signal peptide, whereas the other four (1797T>C, 1884G>A, 1907T>G, and 2112C>G) predict amino-acid substitutions in the neurophysin II moiety of the AVP prohormone, namely V67A (NP36), G96D (NP65), C104G (NP73), and C116W (NP85). Among these, the mutation predicting the V67A (NP36) substitution is remarkable. It affects a region of the neurophysin II not affected by any other mutations, produces only a minor change, and its inheritance suggests an incomplete penetrance. Our findings both confirm and further extend the mutation pattern that has emerged in adFNDI, suggesting that the mutations affect amino-acid residues known or reasonably presumed to be important for the proper folding and/or dimerization of the neurophysin II moiety of the AVP prohormone.

Treatment of Neurohypophyseal Diabetes Insipidus

CONTEXT In recent years, there have been several improvements in the treatment of neurohypophyseal diabetes insipidus (DI). They include new formulations of the vasopressin analog, desmopressin; a better understanding of the effect of fluid intake on dosing; and more information about treatments of infants, children, and pregnant women who present special challenges. This review aims to summarize past and current information relative to the safety and efficacy of treatments for the types of DI caused by a primary deficiency of vasopressin. EVIDENCE ACQUISITION The review is based on publications identified primarily by a PubMed search of the international literature without limitations of date. EVIDENCE SYNTHESIS In acute settings where fluid intake is determined by factors other than thirst, desmopressin should be given iv in doses that have a short duration of action and can be adjusted quickly in accordance with changes in hydration as indicated by plasma sodium. In ambulatory patients, the oral formulations (tablet or melt) are preferred for their convenience. If fluid intake is regulated normally by the thirst mechanism, the tablets or melt can be taken safely 1 to 3 times a day in doses sufficient to completely eliminate the polyuria. However, if fluid intake consistently exceeds replacement needs as evidenced by the development of hyponatremia, the dose should be reduced to allow higher than normal rates of urine output or intermittent breakthrough diuresis. This regimen is often indicated in infants or children because their rate of fluid intake tends to be greater than in adults. In all cases, the appropriate dose should be determined by titration, owing to considerable interindividual differences in bioavailability and antidiuretic effect. CONCLUSIONS Desmopressin can provide effective and safe therapy for all patients with neurohypophyseal or gestational DI if given in doses and by a route that takes into account the determinants of fluid intake.

Radioimmunoassay of vasopressin in familial central diabetes insipidus

We examined plasma arginine-vasopressin concentrations by radioimmunoassay in two brothers, aged 6 and 7.5 years, with familial central diabetes insipidus inherited as an autosomal dominant trait. Plasma AVP was measured in relation to increasing plasma osmolality induced by water deprivation and hypertonic saline infusion. The brother with the more severe urinary concentrating defect had no detectable AVP when his plasma osmolality was as high as 306 mOsm/kg; the other brother had detectable but clearly subnormal AVP concentrations. The one brother tested had an apparently normal end-organ response to exogenous vasopressin. Chlorpropamide had a significant antidiuretic effect in the brother with detectable AVP levels, and a lesser effect in the other brother . Our findings suggest that intrafamilial variation in the severity of congenital DI is related to the degree of vasopressin deficiency.