Current Paediatrics (2001) 11, 352d356 ^ 2001 Harcourt Publishers Ltd doi:10.1054/cupe.2001.0208, available online at http://www.idealibrary.com on 0146
Investigation of polyuria and polydipsia S. Glass* and T. CheethamR *SpR in Paediatrics, Department of Child Health, Royal Victoria Infirmary, RConsultant Paediatric Endocrinologist, Queen Victoria Road, Newcastle upon Tyne NE1 4LP UK KEYWORDS diabetes insipidus, polyuria, polydipsia, investigation
Summary The causes of polyuria and polydipsia in childhood can be subdivided into three groups; cranial diabetes insipidus, nephrogenic diabetes insipidus and primary polydipsia. A detailed history and examination alone may suggest an underlying explanation for the child’s symptoms but a range of baseline and then more extensive investigations are usually required before a diagnosis can be reached. These investigations are not without risk to the patient and it is of paramount importance that they are conducted safely and in a logical manner. In a small number of cases referral to a specialist centre will be required. ^ 2001 Harcourt Publishers Ltd
PRACTICE POINTS E
The more profound the desire for fluid and associated sleep disturbance, the more likely it is that a child has cranial or nephrogenic DI The measurement of osmolality is not as accurate as the measurement of serum sodium in most laboratories. Interpret a single serum osmolality with caution An elevated serum osmolality and sodium outwith the normal range suggests diabetes insipidus irrespective of urine osmolality A low serum sodium may reflect glucocorticoid deficiency as well as primary polydipsia Beware iatrogenic hyponatraemia. When administering desmopressin as a therapeutic trial, water intake and output will need to be assessed to avoid fluid overload in a child with primary polydipsia Many of the doses of desmopressin recommended in the textbooks are generous
DEFINITION Polyuria is defined as the voiding of abnormally large amounts of urine. It usually results in increased thirst and polydipsia, which may be defined as excessive fluid intake. Fluid intake may be high in the absence of polyuria
Correspondence to: SG. E-mail: [email protected]
because of fluid loss from sites such as gut or skin. Daily volumes of urine that exceed 1000 ml in pre-school children, 2000 ml in school-aged children and 3000 ml in adults are considered abnormal. A more precise definition of polyuria is the passage of a daily urine volume in excess of 2000 ml/m2 body surface area.1 In some children the primary problem is polydipsia and in some the primary problem is polyuria.
NORMAL WATER HOMEOSTASIS Volumes of intracellular and extracellular body water must remain stable in order for normal cellular functions to occur. In many mammals water intake is the minimum necessary to meet requirements; consequently, their urine is highly concentrated and produced in small amounts. In humans, primarily due to cultural factors, water intake frequently exceeds that required and so relatively large volumes of dilute urine are voided. Normal water balance is regulated by thirst which controls fluid intake and by the kidneys, under the influence of 8-arginine vasopressin (AVP), controlling fluid excretion. The major stimuli for thirst are a rise in the tonicity of the extracellular fluid in the central nervous system and a decrease in circulating plasma volume. Renal concentrating and diluting mechanisms control water excretion. These depend on the kidney’s ability to reabsorb solute in excess of water and the variable water permeability in the distal nephron controlled by AVP. AVP is produced in the paraventricular and supraoptic
INVESTIGATION OF POLYURIA AND POLYDIPSIA
Table 1 Major causes of polyuria
Figure 1 Vasopressin and renal water reabsorption.
hypothalamic nuclei and stored in the posterior pituitary. AVP release is primarily regulated by changes in plasma osmolality but also occurs in response to non-osmotic stimuli such as changes in total circulating blood volume, the distribution of extracellular fluid, pain or emotional stress. Circulating AVP binds to type-2 (V2) receptors at the apical surface of renal tubular and collecting duct cells. This results in a rise in intracellular cyclic adenosine monophosphate (cAMP) which in turn leads to a marked increase in water permeability. This is due to its effect on a number of water channel proteins or aquaporins.2 Water thus flows from the tubular lumen into the hypertonic medullary interstitium via the aquaporin channels and the urine becomes more concentrated (Fig. 1). Plasma osmolality is tightly maintained by these mechanisms between 282 and 295 mmol/kg.
CAUSES OF POLYURIA The causes of polyuria can be divided into three groups according to the underlying pathophysiological mechanism. The first is decreased secretion of AVP otherwise known as cranial diabetes insipidus. The second is renal tubular unresponsiveness to adequate concentrations of circulating AVP otherwise known as nephrogenic diabetes insipidus. This may be due to an intrinsic renal problem such as chronic renal failure, or extrinsic factors such as hypercalcaemia or hyperglycaemia affecting renal function. The third group is primary polydipsia where the principal problem is fluid intake and not excessive urinary output (Table 1).
ASSESSMENT AND INVESTIGATION History The age at which symptoms developed and the pattern of fluid intake are important features and may
1. Cranial diabetes insipidus Familial Autosomal dominant Wolfram (DIDMOAD) syndrome7 Cerebral malformations In association with septo-optic dysplasia Acquired Trauma (neurosurgery, head injury) Tumours (craniopharyngioma, germinoma, leukaemia) Hypoxic-ischaemic brain damage Granuloma (tuberculosis, sarcoid, histiocytosis) Infections (congenital CMV, toxoplasmosis, encephalitis, meningitis) 2. Nephrogenic diabetes insipidus Familial X-linked recessive inheritance (V2 receptor gene defect) Autosomal recessive inheritance (aquaporin 2 gene defect) Acquired Osmotic diuresis (diabetes mellitus, total parenteral nutrition) Metabolic (hypercalcaemia, hypokalaemia) Chronic renal disease (including obstructive uropathy) Drugs (amphotericin, tetracycline, lithium) 3. Primary polydipsia Behavioural/psychogenic Secondary to hypothalamic damage/dysfunction
influence subsequent investigation. Children with major abnormalities of AVP release (cranial diabetes insipidus) or with nephrogenic diabetes insipidus are usually polyuric day and night. Children with diabetes insipidus are not usually fussy about the fluid type, or source and will drink from the tap, toilet or bath. Children with the familial forms of nephrogenic diabetes insipidus are symptomatic from early life and fail to thrive.3 Their parents do not, however, always recognize the link between polydipsia, polyuria and the child’s illness. This early presentation reflects the very low maximum urine osmolality in most children with this disorder in whom the desire to drink exceeds the desire for calories. A short history of polydipsia and polyuria with nocturia or nocturnal enuresis is commonly seen in children with diabetes mellitus. The clinical picture is usually less florid in children with cranial diabetes insipidus but there may be helpful pointers such as cranial trauma prior to the development of symptoms. Diabetes insipidus is more likely if the child has established renal
Table 2 Baseline investigations Blood E Plasma sodium, potassium, bicarbonate, chloride, urea, creatinine, phosphate, calcium E Random glucose E Random plasma osmolality E Liver function tests E Full blood count and blood film E $TORCH screen Urine Random urine osmolality E Urinalysis and microscopy E
disease or histiocytosis. Polydipsia in excess of 5 l/m2 per 24 h may suggest primary polydipsia because a typical daily osmolar load (500 mOsm) can be excreted even with very dilute urine (100 mOsm/l).
Examination Clinical examination may provide important clues about possible underlying diagnoses. An assessment of the child’s nutritional status and examination of the skeleton, abdomen and central nervous system including fundoscopy is particularly important (Table 1).
Initial investigations A range of baseline investigations at the time of the first assessment may point towards the diagnosis (Table 2). Many of the acquired causes of nephrogenic diabetes insipidus such as diabetes mellitus, hypercalcaemia and chronic renal failure will be detected at this early stage. A baseline sodium and osmolality may also be informative (see below).
Further investigations Second line Detailed fluid balance assessment. If it is unclear how much a child drinks or micturates then a more formal assessment of fluid balance may be appropriate. Parents may be prepared to measure input and output carefully at home or this can be undertaken as an inpatient. Water deprivation testing. In the absence of a diagnosis the child’s fluid intake and output should be studied in more detail. The ability of the central nervous system to make, and the kidney to respond to AVP should be established by a formal water deprivation test. The protocol for a water deprivation test is detailed in Table 3, and Table 4 outlines its interpretation. The test should start in the morning so that the child can be adequately supervised and the laboratory should be
Table 3 Water deprivation/desmopressin test protocol
Preparation E Fluid given overnight before test. Avoid caffeine E Weigh patient E Liaise with laboratory before test begins Dehydration phase (Start at 0800) E Draw blood and collect urine for assessment of sodium and osmolality E Restrict fluidsean 8 h fast will usually suffice E Weigh patient at two hourly intervals E Collect blood and urine for sodium, osmolality and volume measurements at regular intervalseideally every 2 h. Assess results as soon as availableeit may be possible to terminate the test E Stop test if weight loss exceeds 5% of starting weight, if thirst becomes intolerable or if plasma or urine osmolalities confirm or exclude diabetes insipidus Renal desmopressin responseeto differentiate between cranial and nephrogenic diabetes insipidus This test can be undertaken separately and does not have to follow the dehydration phase of a water deprivation test. E Inject intramuscular, subcutaneous or intravenous desmopressin 0.4 lg ((2 years) !1 lg ('2 years) or 1}5 lg intranasally. This can be given by fine needle ‘insulin’ syringe if administered subcutaneously or ‘dropped’ onto the nasal mucosa if given nasally. E Allow patient to eat and drink the urine volume passed plus insensible losses. If the test follows the dehydration phase of a deprivation test then the patient can drink a volume equivalent to that passed during the dehydration phase and beyond plus insensible losses. E Collect voided urine for assessment of volume and osmolality with measurement of serum osmolality at regular 4}6 hourly intervals.
INVESTIGATION OF POLYURIA AND POLYDIPSIA
Table 4 Interpretation of fluid deprivation and desmopressin tests in polyuric patients Urine osmolality (mmol/kg) After fluid deprivation
After desmopressin Diagnosis
(300 (300 '500
'750 (300 '750
Primary polydipsia (if serum osmolality N) Cranial diabetes insipidus Nephrogenic diabetes insipidus ? primary polydipsia, ? partial cranial diabetes insipidus ? partial nephrogenic diabetes insipidus, ? primary polydipsia
The vast majority of children with urine osmolalities of 600 or more at the time of a normal serum osmolality do not have diabetes insipidus.
aware of the need to provide rapid feedback of urine and plasma osmolalities. Urine osmolality can only be properly interpreted when compared to a paired serum osmolality and the interpretation of serum osmolality requires a serum sodium. Paediatricians are often faced with equivocal results at the end of a water deprivation test. A normal serum osmolality and a urine osmolality less than 600 mOsm/l are not uncommon following an 8 h fast and may reflect the reduced urinary concentrating ability in a child with primary polydipsia. However, there are other useful pieces of information acquired before or during the water deprivation test, which may help to make a diagnosis. These include: (1) A relatively low serum sodium and osmolality prior to fasting which suggests primary polydipsia. In untreated cranial diabetes insipidus the serum sodium or osmolality is typically normal to highnormal.4 (2) The maintenance of a normal serum sodium and osmolality during an 8 h fast with minimal weight loss makes an underlying abnormality of AVP production or action unlikely. (3) If a urine sample is unobtainable because the child will not micturate and the weight is stable then major abnormalities of AVP production or action are unlikely. The well, young child with pronounced daytime polydipsia, a low or low}normal sodium at baseline, oliguria with minimal weight loss and maintainance of a normal serum sodium/osmolality on deprivation testing will almost certainly have primary polydipsia.
Renal response to desmopressin administration. The administration of DDAVP at the end of a deprivation test should not be undertaken as a matter of routine. Should investigations confirm diabetes insipidus, then an assessment of renal responsiveness may be more appropriate at a later stage, providing the child with an opportunity to recover as well as avoiding the need for sample collection out of hours. If DDAVP is administered eeither at the end of a deprivation test or on another dayethen it is crucial to monitor fluid balance and ensure that input does not exceed output plus insensible losses. If the serum osmolality is elevated at baseline because of diabetes insipidus, then the calculated deficit can be added to this figure. The test should differentiate between cranial diabetes insipidus and nephrogenic diabetes insipidus but does not always help to establish whether a child has partial cranial diabetes insipidus or primary polydipsia (Tables 3 and 4).
Third-line investigations Cranial MRI. This is mandatory in all children with cranial diabetes insipidus.5 Important questions to be answered include the following: E
Is there loss of the posterior pituitary bright spot on T1 weighted images in keeping with cranial diabetes insipidus? The posterior pituitary bright spot represents stored AVP. As well as being absent in cranial diabetes insipidus it may also be absent in nephrogenic diabetes insipidus because of increased hormone production.6 Is there evidence of an inflammatory or neoplastic process?
AVP levels. Nomograms describing the relationship between plasma and urine osmolality and AVP concentrations have been published.7 Measuring AVP levels at the end of a water deprivation test can also be helpful. They are typically increased in patients with familial nephrogenic diabetes insipidus but a single value will not always help to differentiate between partial cranial diabetes insipidus and primary polydipsia. This assay is only performed in a small number of centres in the UK. Hypertonic saline infusion. Water deprivation testing assesses the ability of the kidney to generate concentrated urine during fasting. However, the hypertonic saline infusion assesses the ability of the hypothalamus/pituitary to produce AVP in response to a rising serum osmolality. Hypertonic saline is infused and AVP measured sequentially.8 Nomograms describing the relationship between osmolality and AVP can then be used to determine whether a child has cranial diabetes insipidus. This investigation may be of value when a water deprivation test has been unsuccessful or has revealed equivocal results. Disadvantages of the test include the
356 irritant nature of hypertonic saline (two cannulae are usually needed to allow the required volume to be infused) and the relatively large sample volumes needed for AVP measurements. Additional care is required in younger children.
DDAVP ‘trial’. If it is still unclear whether a child has partial cranial DI or primary polydipsia then some physicians administer a small dose of DDAVP at night. Should this have a profound impact on symptoms, with resolution of overnight polyuria and sleep disturbance, cranial diabetes insipidus is likely. It is wise to conduct this assessment in hospital so that fluid balance and behaviour can be carefully monitored and hyponatraemia prevented.9
Subsequent assessment By this stage it should be reasonably clear into which of the three main categories of polyuria a patient falls. However, cranial diabetes insipidus is not in itself a final diagnosis5 and it is important to establish an underlying cause. It is well known that children with ‘idiopathic diabetes insipidus’ may have a small but as yet unidentified tumour.10 Tumour markers (e.g. human chorionic gonadotrophin and alpha feto-protein in serum and cerebrospinal fluid) should be measured and the cranial MRI will need to be repeated at a later stage. A significant number of children with cranial diabetes insipidus will have other pituitary hormone deficiencies and most patients should undergo formal pituitary function testing.5, 11 A patient with nephrogenic diabetes insipidus secondary to hypercalcaemia will need further investigations to determine the cause of the elevated serum calcium levels. Older patients with primary polydipsia may require a detailed psychological assessment.
SUMMARY AND CONCLUSIONS It is frequently possible to establish the cause of polydipsia or polyuria on the basis of a history, examination and baseline investigations. Not all children
CURRENT PAEDIATRICS with polyuria and polydipsia will need a water deprivation test. This test is not popular with parents and children and can be difficult to perform. It is potentially dangerous andelike all testsecan give false positive and false negative results. Differentiating between partial cranial diabetes insipidus and primary polydipsia may not be straightforward. Children with cranial diabetes insipidus or who lack a definitive diagnosis should be referred to a paediatric endocrinologist.
REFERENCES 1. Muglia L J, Majzoub J A. Disorders of the posterior pituitary. In: Sperling M A (ed.), Pediatric Endocrinology. London: WB Saunders, 1996; 195}227. 2. King L S, Agre P. Pathophysiology of the aquaporin water channel. Ann Rev Physiol 1996; 58: 619}648. 3. Knoers N, Monnens H A L. Nephrogenic diabetes insipidus: clinical symptoms, pathogenesis, genetics and treatment. Pediatr Nephrol 1992; 6: 476}482. 4. Richman R A, Post E M, Notman D N, Hochberg Z, Moses A M. Simplifying the diagnosis of diabetes insipidus in children. Am J Dis Child 1981; 135: 839}841. 5. Maghnie M, Cosi G, Genovse E, Manca-Bitti M L, Cohen A, Zecca S, Tineeli C, Gallucci M, Bernasconi S, Boscherini B, Severi F, Arico M. Central diabetes insipidus in children and young adults. N Engl J Med 2000; 343: 998}1007. 6. Sato N, Ishizaka H, Yagi H, Matsumoto M, Endo K. Posterior lobe of pituitary in diabetes insipidus: dynamic MR imaging. Radiology 1993; 186: 353}360. 7. Baylis P H, Cheetham T. Diabetes insipidus. Arch Dis Child 1998; 79: 84}89. 8. Angelica M, Acerini C L, Cheetham T D, Lightman S L, Dunger D B. Hypertonic saline test for the investigation of posterior pituitary function. Arch Dis Childhood 1998; 79: 431}434. 9. Harris A S. Clinical experience with desmopressin: efficacy and safety in central diabetes insipidus and other conditions. J Pediatr 1989; 114: 711}718. 10. Mootha S L, Barkovich A J, Grumbach M M, Edwards M S, Gitelman S E, Kaplan S L, Conte F A. Idiopathic hypothalamic diabetes insipidus, pituitary stalk thickening, and the occult intracranial germinoma in children and adolescents. J Clin Endocrinol Metab 1997; 82: 1362}1367. 11. Lukezic M, Righini V, di Natale B, De Angelis R, Norbiato G, Bevilacqua M, Chiumello G. Vasopressin and thirst in patients with posterior pituitary ectopia and hypopituitarism. Clin Endocrinol 2000; 53: 77}83.