20/04/16 ObjecHves for talk 1. to understand the pathophysiology of DI Polyuria and Polydipsia Syndrome: 2. to understand the differenHal diagnosis is it Diabetes Insipidus? 3. to understand how we can differenHate between the different causes Prof Tricia Tan 4. to understand treatment strategies Consultant in Metabolic Medicine & Endocrinology Clinical Chemistry DefiniHon of Polyuria Basic First Line InvesHgaons • A urine output exceeding • U&E, Ca, Glucose – exclude diabetes mellitus! – 3 L/day in adults • Urinalysis for glucose and S.G. – 2 L/m2 body surface area/day in children. – S.G. <1.005 is suspicious • Must be differenHated from • Paired serum and urine osmolaliHes – – Frequency of urinaon Normal serum osmo = 275-295 mOsm/kg – Urine osmo ranges from 100 to 1200 mOsm/kg – Nocturia – Baseline serum osmo of >295 with urine osmo – These are not associated with an increase in the <200 is diagnosHc of DI total urine output. • Bladder diary 1 20/04/16 Osmolality Bladder diary Time In Out ‘Wet’ Urgency rang • Concentraon of osmoHcally acHve parHcles in a soluHon 0700 300 ml ✔✔ A = felt no need to void but did so for (expressed per kg solvent) other reasons • Measure using freezing point depression (proporHonal to 0800 Tea 1 cup B = could postpone voiding as long as osmolality) necessary without fear of ‘weng’ 0900 C = could postpone voiding for a short Hme without fear of ‘weng’ 1000 300 ml D = could not postpone voiding and had to rush to void in toilet 1100 Water 1 E = leaked before geng to toilet cup … 0400 200 ml 0500 0600 Osmoreceptors vs baroreceptors AVP secreon is ↑osmo → ↑AVP Osmoreceptors measure related to concentraon of plasma osmolality and blood volume ↓volume → ↑AVP Baroreceptors ↓volume modifies AVP response measure blood to osmolality ADH = arginine vasopressin (AVP) pressure and volume 2 20/04/16 AVP controls aquaporin recruitment in the collecHng duct of kidney Relaonship of AVP release to plasma When polyuria proven… osmolality and urine osmolality • Exclude uncontrolled diabetes mellitus • Three major causes of polyuria in the outpaent seng: – primary polydipsia – central diabetes insipidus (DI) – nephrogenic DI 3 20/04/16 Primary polydipsia Cranial DI Ø A primary increase in water intake. Ø Deficient secreHon of AVP from posterior • Most oqen seen in pituitary – middle-aged women • Oqen idiopathic – paents with psychiatric illnesses – including those taking a phenothiazine which can lead – possibly due to autoimmune injury to the ADH- to the sensaon of a dry mouth producing cells • Primary polydipsia can also be induced by • Trauma (head injury) – hypothalamic lesions that directly affect the thirst • center, e.g. sarcoidosis Pituitary surgery – Xerostomia (lack of saliva) leading to excessive • Hypoxic or ischaemic encephalopathy drinking • Familial: mutaons in pro-AVP gene Nephrogenic DI Case 1 Ø High AVP but kidneys insensiHve to this • 40 year old lady • Familial • Bipolar disorder on Lithium carbonate – Mutaons in V2 receptor or aquaporin • Polyuria and polydipsia (up to 10 litres a day) • Li toxicity • Complains of a dry mouth all the Hme • Hypercalcaemia • What are the possible diagnoses? • Hypokalaemia • Renal disease (e.g. CKD) • Pregnancy – placental vasopressinase 4 20/04/16 Case 1 Tests • Nephrogenic DI • Baseline – Due to chronic Li treatment – Na 145, K 4.5, Ca normal, glucose normal – Li-induced hyperparathyroidism and hyperCa? – Li undetectable • Primary polydipsia • Went on to water deprivaon test – Due to underlying psychiatric disorder? • Cranial DI less likely What is a water deprivaon test? Interpretaon of water deprivaon • First stage Pre-test Water deprived (8h) Given DDAVP Serum Urine Serum Urine Serum Urine – Serial measurements of serum and urine osmo under 295 460 305 605 306 598 condiHons of water deprivaon – • Pre-test Differenates primary polydipsia (urine osmo ↑) – Serum top end of normal from DI (urine osmo fails to ↑ beyond a limit) – Urine can’t comment • Water deprived • Second stage – Serum too high – If DI proven, give DDAVP – Urine is inappropriately low (would expect >750) • DDAVP given – Differenates cranial DI (urine osmo ↑ to DDAVP) vs – Serum is sHll too high nephrogenic DI (urine osmo does not respond) – Urine is sHll not concentrated enough • Needs to be done under supervision for safety Ø Nephrogenic DI 5 20/04/16 Nephrogenic DI due to Lithium Treatment of Nephrogenic DI • 20-40% taking Li have ↑urine vol (2-3 L/d) • IV fluids (if paent very hypovolaemic) • 12% of paents have frank polyuria (>3 L/d) – Need to use fluid of similar osmo to urine • Direct inhibitory effect of Li on aquaporin otherwise instability of [Na] may ensue expression and recruitment • Low protein/Na diet • Chronic effect: Li-induced intersHHal nephriHs – ↓amount of solute that needs to be excreted and can contribute to DI therefore ↓urine volume needed • Usually reversible with disconHnuaon, but can • Thiazide diureHcs persist long-term – Causes mild volume depleHon • In this case disconHnuaon led to sevling of DI – ↑resorpHon of Na and water in proximal tubule Treatment of Nephrogenic DI Case 2 • NSAIDs (e.g. indomethacin) • 25 year old woman – Prostaglandins antagonise effect of AVP • “Always drunk lots and passed lots” – Therefore inhibiHng producHon of PG causes • No other relevant past history increased water reabsorpHon • Baselines • High dose DDAVP – Na 136, K 3.6, Ca and Glucose normal – Most paents with non-familial nephrogenic DI – Serum osmo 277, urine osmo 100 have parHal defects that may respond to DDAVP 6 20/04/16 Interpretaon of water deprivaon Treatment of primary polydipsia Pre-test Water deprived (8h) • Serum Urine Serum Urine Fluid restricHon 275 100 280 850 • Consider arHficial saliva if problem driven by • Pre-test dryness of buccal mucosa (e.g. with – Serum low end of normal xerostomia) – Urine is dilute • Water deprived – Serum rises to normal range – Urine rises to >750 – Note would expect Urine osmo to rise to >1000 in a young person – Chronic polydipsia causes ‘washout’ of medullary concentraon and therefore some reducHon in ability to concentrate urine Ø Primary polydipsia Case 3 Case 3 intepretaon Pre-test Water deprived (8h) Given DDAVP • 24 y.o. man, RTA last year, polyuric Serum Urine Serum Urine Serum Urine • Baselines 295 300 302 295 285 1154 • Baseline – Na 145, K 4.0, Ca normal, glucose normal – Serum top end of normal – Urine not interpretable • Went on to water deprivaon test • Water deprived – Serum clearly high – Urine inappropriately dilute (should be >750 at least or even >1000 in young person) • DDAVP given – Sharp rise in urine osmo seen – Recovery of serum osmo to normal Ø Cranial DI 7 20/04/16 Cranial DI due to head injury Other causes of cranial DI • Acutely aer head injury in 1 in 5 paents • Pituitary tumours – Not common in pituitary adenoma • Seen chronically in 1 in 12 paents – More common with other types of tumours (e.g. • Associated with other pituitary problems or craniopharyngioma, metastasis) • can be isolated Pituitary surgery • Infiltrave disease – Sarcoidosis, hisHocytosis X • DDAVP Rx: • InfecHon Tablets Nasal spray – MeningiHs, encephaliHs • Hereditary (rare) Sublingual melts How to monitor a Paent on DDAVP DDAVP is a vital drug • DDAVP has different doses depending on Pa4ents must receive steady suppLies of DDAVP preparaon, e.g. – Tablets: 100 µg nocte to 200 µg TDS – Nasal spray: 10-20 µg (1-2 sprays) OD-TDS – Melts: 60, 120, 240 µg OD-TDS – Subcutaneous injecHon: 0.5-1 µg OD-BD • Different duraons of acHon – Tablets ~4-6 h – Nasal Spray ~8 h – InjecHon ~12 h Paents are entLed to exempon from prescripon charges 8 20/04/16 How to monitor a Paent on DDAVP Some common quesons • Two key parameters for monitoring: • Blockage of nasal passages in paents using spray – Body weight (reflects body water) (e.g. URTI) – Na+ – Consider Rx tablets • Warning signs: – Tiredness • Pregnancy – Confusion – May require increased dose: placental vasopressinase – Ataxia breaks down AVP/DDAVP – Nausea and vomiHng • Travelling – Headaches – Paents may require a lever for airport security to – Acute change of >2 kg from baseline body weight carry medicaon through screening • CHECK U&E URGENTLY – Paents should take doses according to local Hme 9 .