SCIENCE REVIEW
most cases of acquired nephrogenic DI. Chronic hypokalaemia, chronic hypercalcaemia and certain drug therapies (most notably lithium) are alternative causes. Inherited nephrogenic DI is rare and most
cases (80%) are due to inherited mutations in the gene that codes for the V2 receptor that mediates AVP action. This gene is located on the X chromosome so the condition is inherited in an X-linked recessive manner. Mutations in the AQP2 gene have also been described and these account for most of the remaining 20% of inherited nephrogenic DI cases. Whether the primary defect is in the brain
or the kidneys, diabetes insipidus is a condition of AVP deficiency or reduced AVP effect and therefore uncontrolled urinary excretion of free water.
Central diabetes insipidus The first case history (Hayanga AJ, Kohen R, Egeland B et al. Central diabetes insipidus: a rare perioperative cause of severe hypernatraemia. Anaesth Intensive Care 2008; 36 [2]: 235–41) provides detail of the symptomatic and clinical effect of this AVP deficiency. Disturbances of water balance were
presumably far from the thoughts of the emergency room doctor as he examined the horrific hand injury sustained by a 21-year- old female while operating an electric saw. Initial assessment revealed multiple, deep soft-tissue lacerations, fractures of bones in the wrist and thumb, and severed nerves and tendons. The patient was transferred immediately to a specialist unit for surgical debridement and repair of her wounds. During an eight-hour operation, the complex hand injuries were repaired successfully and an uneventful recovery was anticipated. However, that was not to be. Within hours of the operation, the patient
became confused and agitated, lost consciousness and, in a state of clinical shock, was rushed to intensive care. Blood testing revealed that her plasma sodium concentration, which had been normal (142 mmol/L) before the operation and raised (156 mmol/L) during the operation, had risen to a life-threatening 196 mmol/L. Her plasma osmolality was now >400 mOsmol/kg. The severe hypernatraemia (ECF hyperosmolality) caused a shift of water from ICF to ECF (to equalise osmolality), leaving tissue cells relatively dehydrated. The patient's altered mental state and
lapse into coma could thus be attributed to rapid-onset severe cerebral cell dehydration. But why had she become so severely hypernatraemic? The answer lay in her urine
‘The antidiuretic action of AVP operates via V2 receptors located on the basolateral membrane of renal collecting duct tubule cells’
output chart, which revealed that she was producing over a litre of urine every two hours – equivalent to a 24-hour urine output of over 15 litres (10 times normal). With limited fluid intake (provided solely by intravenous fluids) during the operation, by the time the patient arrived in intensive care her calculated body water deficit was 10 litres. The hypernatraemia was not the result of too much sodium but an ever- shrinking plasma volume (ie too little water). The continuing excessive urine free water
loss, despite progressively worsening whole body water deficit, suggested AVP deficiency and a diagnosis of diabetes insipidus. In support of this was the revelation by relatives that during the past year she had developed a need to drink copious amounts of water, routinely in excess of 10 litres per day. She would need to urinate frequently and it was normal for her to have to wake six times a night to urinate and satiate her thirst. Polydipsia (increased thirst) and polyuria
(increased urine output) are classical symptoms of DI. In order to maintain water balance and avoid dehydration, those with untreated DI must compensate for the massive water loss in urine that results from AVP deficiency by increasing their water intake. Constant thirst and the increased fluid intake it induces becomes the only protection against potentially fatal dehydration. While under the anaesthetic, the patient’s normally protective thirst response was not operative and the resultant inevitable severe dehydration and hypovolaemia brought her close to death. The diagnosis of central DI was confirmed
by intravenous (iv) administration of desmopressin (DDAVP), a synthetic form of AVP. This restored the ability to concentrate urine and conserve water. Within three hours, urine flow was reduced from 500 mL/hour to a near-normal rate of 50 mL/hour, and urine osmolality increased from 133 mOsmol/kg to 587 mOsmol/kg. With aggressive iv fluid resuscitation, the 10-litre water deficit was corrected and plasma sodium concentration gradually returned to normal over the following 24 hours.
‘Diabetes insipidus is a consequence of either inadequate AVP secretion from the posterior pituitary or decreased response to AVP by the kidney tubule cells’
402 Once out of immediate danger, the
patient was submitted for a brain magnetic resonance imaging (MRI) scan, which revealed an abnormality in the posterior pituitary that was “consistent with a diagnosis of central DI”. She now has a lifetime requirement for a daily dose of replacement AVP (desmopressin) to ensure a normal rate of urine production and therefore normal fluid requirement.
Drug-induced nephrogenic diabetes insipidus Pemetrexed is an approved antimetabolite agent, now widely used for treating locally advanced or metastatic non-squamous non-small-cell lung cancer. Although no electrolyte abnormalities are described in the prescribing information for this drug, several case reports have noted nephrogenic diabetes insipidus with associated acute kidney injury. A recent case report (Fung E, Anand S,
Bhalla V. Pemetrexed-induced nephrogenic diabetes insipidus. Am J Kidney Dis 2016 May 28. Epub ahead of print) illustrated a case of nephrogenic diabetes insipidus without severely reduced kidney function, and the authors proposed a mechanism for the isolated finding. Severe hypernatremia can lead to encephalopathy and osmotic demyelination, and this report, from the Stanford University School of Medicine, Palo Alto, California, highlighted the importance of careful monitoring of electrolytes and kidney function in patients with lung cancer receiving pemetrexed.
Congenital nephrogenic diabetes insipidus As outlined above, nephrogenic diabetes insipidus (NDI) is a condition resulting from the kidney’s impaired response to circulating AVP (antidiuretic hormone [ADH]), leading to polydipsia and polyuria. Urinary tract dilatation caused by NDI is a rare condition. A report from China (Zheng K, Xie Y, Li H.
Congenital nephrogenic diabetes insipidus presented with bilateral hydronephrosis and urinary infection: a case report. Medicine [Baltimore] 2016; 95 [22]: e3464) highlighted a case of congenital NDI presenting with bilateral hydronephrosis. A 15-year-old boy, who voided 10–15 L urine daily and complained of a history of intermittent fever, was admitted to Peking Union Medical College Hospital. Radiographic examination revealed severe bilateral dilatation of renal pelvis, ureter and bladder, and urinalysis showed hyposthenuria (urine of low specific gravity). The patient was diagnosed with congenital NDI, and the insertion of a urethral catheter helped to relieve his fever. Treatment with hydrochlorothiazide and amiloride was prescribed and proved effective. Dilatation of the urinary tract caused by diabetes insipidus is rare, but it is crucial that clinicians introduce early treatment to avoid impairment of renal function.
AUGUST 2016 THE BIOMEDICAL SCIENTIST
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