410 CME July 2004 Vol.22 No.7 M E D I F I L E
This edition of Medifile concludes the series of overviews of the less common PMB Chronic Disease List (CDL) conditions and focuses on diabetes insipidus.
Diabetes insipidus (DI) is a condition resulting from insuffi- cient production of the antidiuretic hormone (ADH) by the hypothalamus (central DI), or resistance to its renal effects (nephrogenic DI). Another type of diabetes insipidus is gestagenic DI. These subtypes will be discussed in more detail below. Please note that the legislated PMB algorithm for DI specifically refers to central DI and not nephrogenic or gestagenic DI.
CENTRAL DIABETES INSIPIDUS (CDI)
CDI or cranial DI is characterised by decreased release of vasopressin (ADH), resulting in a reduction in reabsorption of water from the collecting renal tubule. Lack of ADH can be caused by disorders at one or more of the sites involved in ADH secretion:
• the hypothalamic osmoreceptors
• the supraoptic or paraventricular nuclei, or
• the superior portion of the supraopticohypophyseal tract.
The most common causes of CDI include idiopathic disease, familial disease, neurosurgery or trauma and cancer.
NEPHROGENIC DIABETES INSIPIDUS (NDI) NDI refers to a decrease in urinary concentrating ability that results from resistance to the action of ADH. In its mild form, NDI is relatively common, since most patients who are sick, elderly or have acute or chronic renal insufficiency have a reduction in urine concentrating ability. The modest reduction seen in these disorders is generally not severe enough to produce polyuria, but some patients complain of nocturia.
The most common causes of NDI include hereditary NDI in children, lithium toxicity, hypercalcaemia, hypokalaemia and sickle cell disease.
GESTAGENIC (GESTATIONAL) DI
An uncommon form of transient ADH resistance may occur in some women during the second half of pregnancy. In pregnancy there is a release of the enzyme vasopressinase from the placenta, leading to rapid degradation of endoge- nous or exogenous ADH, but not of dDAVP (desmopressin).
Rarely patients may develop true NDI during pregnancy, but the mechanism of how this might occur is not clear.
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS The correct diagnosis may be suggested by the history and the plasma sodium concentration. The patient should be
questioned on possible causes of DI and about the rate of onset of the polyuria: this is normally abrupt in CDI, but gradual in NDI or polydipsia.
Water restriction test
The diagnosis should be confirmed by raising the plasma osmolality by means of water deprivation.
The test involves measurement of the urine volume and osmolality every hour and plasma sodium concentration and osmolality every 2 hours. Each of the causes of polyuria produces a distinctive pattern to water deprivation and ADH administration:
• CDI is normally partial and hence both ADH release and urine osmolality may increase as the plasma osmolality rises. However, since the ADH release is inadequate and the degree of urinary concentration submaximal, exoge- nous ADH will lead to an increase in urine osmolality.
Patients generally achieve a urine osmolality of at least 300 mOsm/kg after water restriction. The rise in urinary concentration is then associated with an equivalent fall in urine volume.
• NDI is also characterised by a submaximal increase in urine osmolality to water restriction. Most patients are not completely resistant to ADH and an increase in plas- ma osmolality will induce a modest increase in urine osmolality. Patients typically have a persistently dilute urine that increases after ADH administration, but remains well below isosmotic.
• Primary polydipsia will demonstrate an increase in urine osmolality, mostly to above 500 moOsm/kg, but no response to exogenous ADH since endogenous release is intact. Often the concentrating ability is impaired, result- ing in a maximum urine osmolality of 600 mOsm/kg, as compared with at least 800 mOsm/kg in normal individ- uals. This effect on the kidney is due to long-term overhy- dration and downregulation of ADH release.
TREATMENT
The treatment of CDI and NDI is summarised in Table I (p.411).
References available on request.
Elsabé van der Merwe
DIABETES INSIPIDUS
Medifile is initially published as a supplement to the SA Pharmaceutical Journal. It is adapted and reprinted in CMEwith the kind permission of MediKredit. For further information about Medifile, contact MediKredit, tel (011) 770-6000, fax (011) 770-6325.
M E D I F I L E
July 2004 Vol.22 No.7 CME 411
Table I.Treatment of diabetes insipidus
Drug Regimen Comments
Desmopressin Intranasal solution or spray Effective in CDI, but limited data on 5 - 20 µg once or twice a day efficacy in NDI
(dDAVP – 1-deamino-8-D-arginine (adults: 10 - 20 µg) Absorption from nasal mucosa may be
vasopressin) Tablets erratic in cases of upper respiratory
A substitute of ADH; potent 0.1 – 0.2 mg three times a day infection or allergic rhinitis antidiuretic but no vasopressor Injection (IM or SC) Oral absorption is decreased by activity Adults: 1 - 4 µg once or twice daily 40 - 50% when taken with meals
Children over 1 year: 0.4 - 1 µg 0.1mg tab is equivalent to 2.5 - 5 µg of once or twice daily the nasal spray, but changing from a Children below 1 year: nasal dose may require retitration 0.2 – 0.4 µg once or twice daily Risk of water retention and development Injection not registered for treatment of hyponatraemia — hence use minimum of DI in SA, but mostly used for dose needed to control polyuria
diagnosis
Chlorpropamide 125 - 250 mg once or twice a day Useful in partial CDI, but generally not (3 - 5 mg/kg once or twice a day) effective in NDI
Not registered for treatment of DI Promotes the renal response to ADH or
in SA desmopressin due to enhanced NaCl
reabsorption or by augmented collecting tubules permeability to water
May lower urine output by as much as 50%
Risk of hypoglycaemia at high doses Carbamazepine 100 - 400 mg twice daily Useful in partial CDI, but generally not
Not registered for treatment of DI effective in NDI
in SA Enhances the response to ADH in CDI
May lower urine output by as much as 50%
Clofibrate 500 mg every 6 hours or 1 000 mg Useful in partial CDI, but generally not
twice daily effective in NDI
Not registered for treatment of DI May increase ADH release
in SA May lower urine output by as much as
50%
Hydrochlorothiazide 25 mg once or twice daily Useful in both CDI and NDI
Mild volume depletion in combination with low sodium diet may be extremely effective; effect is additive to that of other modalities
Tends to modestly raise the plasma concentration, thereby decreasing likelihood of hypoglycaemia if given with chlorpropamide
Amiloride or other 2.5 - 5 mg daily Additive effect with thiazide; useful in potassium-sparing diuretic Not registered for treatment of DI lithium-induced disease
in SA
Non-steroidal anti-inflammatory Indomethacin 1.5 - 3 mg/kg/day in Useful in both CDI and NDI
drugs (NSAIDs) divided doses Inhibition of renal prostaglandin
Not all NSAIDs are equally effective synthesis may increase urine concentrat- in a given patient — some have a ing ability, because prostaglandins good response to indomethacin, but normally antagonise ADH action have little benefit from ibuprofen Results in a 25 - 50% reduction in urine Not registered for treatment of DI output — partially additive to that of a
in SA thiazide diuretic
Intravenous fluid replacement IV dextrose and water at a rate of Necessary for patients who cannot less than 1 000 ml/hour replace the water loss orally via
stimulation of thirst
Diet Low salt and low protein intake May diminish the urine output in NDI via reduced solute (sodium salts and urea) excretion
Correcting underlying disorder Normalisation of the plasma calcium in
NDI
Lithium-induced NDI may be irreversible Experimental approaches Administration of selective, In an in vitrosystem this resulted in the
cell-permeable non-peptide receptor expression of fully functional cell
antagonists surface V2-receptors
