Chapter 10 Polyuria

Usually defined as a urine volume > 3.0 L per day (or 40 ml/kg body weight per day or 2 ml/hr).

10.1 Causes

Differential diagnosis of a polyuria-polydipsia syndrome:

water diuresis (high C_H2O): U_Osm < 100
- primary polydipsia
- iatrogenic water overload (IV 5%G)
- AVP-D (central *** or gestational DI - may be complete or partial)
- AVP-R (nephrogenic DI - may be complete or partial)

solute diuresis (high C_Osm): U_Osm > 300
- electrolytes: pure NaCl (IV NaCl, dietary NaCl, salt-wasting nephropathy)
- electrolytes: HCO3 (vomiting…)
- electrolytes: ketones (DKA…)
- non-electrolytes: urea (high-protein nutritional supplements, post-rhabdomyolysis, massive haematoma)
- non-electrolytes: glucose
- mixed urea and NaCl: post-obstructive uropathy, resolving ATI

mixed: U_Osm 100 – 300
- partial DI (central)
- partial DI (nephrogenic)
- CKD
- tubular injury, diuretics, ATN recovery

Water diuresis may be appropriate (polydipsia, IV dextrose) or inappropriate (DI). Similarly, solute diuresis may be appropriate (IV NaCl, post-obstructive) or inappropriate (hyperglycaemia, high-protein feed, salt-wasting nephropathy).

During prolong diuresis from any initiating cause, washout of the medullary concentration gradient can lead to a temporary inability to concentrate the urine (i.e. an acquired NDI). Thus, the initial UOsm will tend towards isothenuria. Therefore even with heavy solute diuresis, UOsm ranges 300 – 500 mOsm.

*** Arginine-vasopressin is synthesised in the magnocellular neurones in the supraoptic & paraventricular nuclei of the hypothalamus and stored and released from the posterior pituitary. Cranial DI is caused by damage to supraoptic / paraventricular nuclei in hypothalamus (NOT merely compression of pituitary).

10.2 Investigation of polyuria

See Bhasin & Velez, 2016 & Oster et al., 1997.

First exclude common causes (EtOH, DM, Ca2+, K+, CKD, drugs…)

Then measure UOsm (see above):

if water diuresis: classically water deprivation test but now better copeptin testing (see below)
if solute diuresis: 24 hr urine collection:
- urine Osm, Cr, Na, K, Cl, urea, glucose
- …and also pH, specific gravity
- calculate daily osmole excretion (see below)
if mixed: both

\[\begin{equation} \text{daily total solute excretion, } U_{TS} =U_{Osm} \times V \tag{10.1} \end{equation}\]

\[\begin{equation} \text{daily electrolyte solute excretion, } U_{E} =2\times (U_{Na} + U_{K}) \times V \tag{10.2} \end{equation}\]

\[\begin{equation} \text{daily non-electrolyte solute excretion, } U_{NE} = U_{TS} - U_{E} \tag{10.3} \end{equation}\]

Use Cr excretion to assess completeness of 24 hr collection. Expect 150 +/- 40 micromol/kg in women or 190 +/- 40 micromol/kg in men.

Usual daily osmolar exretion is 10 mOsm/kg on a standard Western diet:

when this exceeds 900 mOsm, urine volumes are appreciably larger
when this exceeds 1200 - 1400 mOsm, there is a bona fide solute diuresis

Then assess electrolyte vs. non-electrolyte solute excretion:

if electrolyte solute excretion, U_E > 600 mOsm = electrolyte solute diuresis
if non-electrolyte solute excretion, U_NE > 600 mOsm = non-electrolyte solute diuresis

In electrolyte solute diuresis, look at urine pH and uAG to determine main anion. If very +ve uAG and alkaline urine (pH > 7.4) then likely to be bicarbonate. If very +ve uAG and non-alkaline urine (pH < 7.4) then may be ketones or anionic medications. If very -ve uAG then may be ammonium chloride. If within 50 - 70 mM of zero, then likely to be NaCl diuresis.

Non-electrolyte may be gluose, urea (expect > 250 mM urine urea) or mannitol. 70 g protein is be metabolised into 400 mmol urea.

10.3 Uses for copeptin testing

10.3.1 Assay details

Co-peptin is highly stable ex-vivo: can store samples at room temperature for 7 days prior to analysis. Normal healthy values under basal conditions = 1 - 14 pM (median 4 pM).

10.3.2 Polyuria-polydipsia (hypotonic polyuria)

Role of copeptin testing most clearly established.

See review as well as original description of this approach and validation in NEJM of the saline-stimulated copeptin test.

First use a random copeptin (obtained without prior water deprivation) to differentiate AVP-R (NDI = high copeptin) from either AVP-D (CDI) or primary polydipsia (= low copeptin). Using a cut-off of 21.4 pM, can differentiate AVP-R from alternative causes with 100% sensitivity and specificity.

Therefore:

random copeptin (without water deprivation) high (> 21.4 pM) = AVP-R (NDI)
random copeptin (without water deprivation) low (< 21.4 pM) = partial AVP-D (CDI) or primary polydipsia - proceed to stimulated copeptin test below
random copeptin (without water deprivation) very low (< 2.6 pM) = complete AVP-D - no need for simulated copeptin test

To differentiate AVP-D from primary polydipsia, use [saline-stimulated copeptin test]:

infuse 3% NaCl over 3 hrs then measure co-peptin once PNa > 150 mM
low co-peptin (< 4.9 pM) = ADP-D (CDI)
high co-peptin (> 4.9 pM) = primary polydipsia
less cumbersome alternative to standard water-deprivation test (17 hrs)…
…and also more accurate (AUC 0.97!)

10.3.3 Hypernatraemia

Evolving role in identifying AVP-D (CDI) and need for ddAVP treatment. Main evidence from Co-MED observational study of patients presenting to A&E with severe hypoNa (Na > 155 mM).

Low copeptin (< 4.4 pM) = AVP-D (CDI).

Copeptin levels tend to be very high in other causes of hyperNa (i.e. dehydration, salt overload, AVP-R): median c. 50 pM.

Urea levels also correlated pretty well with diagnosis (< 5 mM = AVP-D with 98% specificity and 100% sensitivity). Median c. 18 mM in other causes of hyperNa.

Urine osmolality c. 300 mOsm in AVP-D and AVP-R c.f. 500 mOsm in dehydration or salt overload.

If there is an associated polyuria-polydipsia syndrome then can evaluate as above.

10.3.4 Hyponatraemia

No major role for copeptin testing. Because (Hoorne) we have the perfect biomarker of AVP action: UOsm and because copeptin levels are elevated in most cases of hypoNa, including SAID, hypo- and hypervolaemia. Possibly a role in identifying the very rare cases of nephrogenic SAID, prior to genetic testing.