Stimulation of ADH independent urine concentration in healthy volunteers

Nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by
resistance of the kidney tubules to the action of the anti-diuretic hormone
ADH, resulting in a decrease in the capacity of the kidney to concentrate
urine. Water reabsorption in the collecting duct is initiated by ADH that binds
to its receptor (type 2 vasopressin receptor, V2R) in collecting duct principal
cells, which activates intracellular processes such as adenylyl cyclase. This
causes the insertion of water channels (AQP2) into the apical membrane through
which water can enter the cell. The most common cause of hereditary NDI are
mutations of the V2R and the most common cause of acquired NDI is chronic
lithium therapy which reduces adenylyl cyclase activity. The inability to
concentrate the urine results in high urine volumes, which can be as high as 15
liters a day. This cab lead to several secondary problems, such as
hypernatremia and rapid dehydration when water intake is restricted. Current
treatment consists of drinking large amounts of water and attempts to lower the
urine output by a low-salt and low protein diet, diuretics (inducing
hypovolemia-induced proximal sodium and water re-absorption) and the use of
anti-inflammatory drugs. These measures however are only partly able to correct
the polyuria. NDI therefore is a chronic disease affecting the quality of life.
Recent reports have suggested novel therapeutic possibilities that could be
more effective than the current standard of care.

The first potential drug is sildenafil. Sildenafil increases cyclic GMP which
is thought to induce phosphorylation of AQP2. Sildenafil indeed increased the
apical accumulation of AQP2 in rats with central diabetes insipidus [Bouley
2005, Sanches 2012]. Assadi described a child with a mutation in V2R who showed
a greater decrease in urine volume and a greater increase in urine osmolality
after 10 days treatment with sildenafil compared to conventional treatment with
hydrochlorothiazide, amiloride and indomethacin [Assadi 2015].

The second potential drug is metformin. Metformin activates adenosine
monophosphate kinase (AMPK), which increases phopshorylation and accumulation
of AQP2 resulting in an increase of urine osmolality in rats and mice [Klein
2016, Efe 2016]. The effect of metformin was maintained for 10 days in
tolvaptan treated rats (a model for nephrogenic diabetes insipidus) [Efe,
2016].

The third potential drug is simvastatin. Simvastatin is thought to enhance the
expression of AQP2 through downregulation of Rho GTPase activation and the
inhibition of endocytosis [Li 2011]. In line with this finding it was shown
that patients treated with simvastatin show an increase in urinary AQP2 and
increase in urine osmolality [Procino, 2016].

These three drugs thus might have an ADH independent effect on AQP2 and water
transport in the collecting duct and could thereby serve as a treatment option
of patients with NDI.

are sildenafil, metformin and simvastatin effective in stimulation of ADH
independent urine concentration in man?

This is a prospective intervention study in which healthy volunteers will
receive sildenafil, metformin or simvastatin during one week. At a baseline
moment and at the end of the week we will perform a water loading test which
will suppress ADH.

use of sildenafil, metformin or simvastatin

Healthy volunteers will only have a small risk for small harm.