Water Therapy in ADPKD
ADPKD is the fourth leading cause of renal insufficiency and leads to ESRD in most patients by the 6th decade. It accounts for about one-tenth of kidney-related health-care expenditures, so any therapy that could significantly ameliorate the natural history of the disease would likely have a major cost benefit. Prolific research advances in this group of renal disorders have been recounted in several recent reviews.
Understanding the central role that cyclic 3'-5'-adenosine monophosphate (cAMP) has in cyst growth has shed considerable light on potential therapeutic mechanisms that could alter the course of the disease. In both in vivo and in vitro studies, cAMP has been shown to promote cellular proliferation and transepithelial fluid secretion, key processes in cyst formation and expansion. Vasopressin (AVP) enhances cyst expansion by increasing the cAMP levels in the epithelial cells comprising cysts. It is not generally recognized that terrestrial animals, including normal humans, persistently excrete urine with osmolalities greater than plasma, meaning that cAMP-generating levels of vasopressin are constantly stimulating cyst growth in those with renal cystic disorders. The administration of an AVP-V2 receptor inhibitor to rats and mice with renal cystic disorders strikingly reduced the rate of kidney enlargement and reduced the decline in renal function.
Tolvaptan, a highly specific AVP-V2 receptor inhibitor, blocks the action of vasopressin to increase the rates of proliferation and of anion-dependent fluid secretion by cyst epithelial cells. In an open-label pilot study of 63 subjects with ADPKD lasting 3 years, administration of tolvaptan reduced the rate of cyst growth and slightly slowed the rate of eGFR decline compared with historical controls. The dose of tolvaptan was titrated to give a trough Uosm of <300mosm/kg H2O thereby producing urine volumes of ~3–4l/day. However, the most definitive evidence to date of the potential benefits of this treatment strategy has recently been published. The long-awaiting double-blinded, placebo-controlled TEMPO 3:4 clinical trial enrolled 1445 ADPKD patients with preserved eGFR and followed them for 3 years. Torres et al. found that tolvaptan-induced aquaresis can alter the natural history of the disorder, demonstrating a significant reduction in the primary endpoint of annual kidney volume growth (2.8% in the tolvaptan group vs. 5.5% in the placebo group, P<0.001). In addition to the profound anatomical implications reported, there was also a significantly slower rate of kidney function decline in the tolvaptan-treated patients (a 1/serum creatinine annualized rate of −2.61 (mg/ml)/year vs. −3.81 (mg/ml)/year, P<0.001). While the authors were careful not to endorse universal use of tolvaptan in ADPKD patients at this juncture, TEMPO 3:4 provides the clearest evidence to date that therapies inducing aquaresis via V2 receptor blockade could fundamentally alter the progression of the disorder.
A closely related question is whether a reduction of plasma AVP levels, without the use of pharmacolgical blockade of AVP, can decrease disease progression. Nagao et. al. tested the effect of increased water intake sufficient to lower Uosm in rats with the homolog of autosomal recessive PKD. The resultant polyuria and Uosm below that of plasma was associated with a reduction in renal weight (volume), reduced renal cyst area, and a decrease in the blood urea nitrogen levels below the controls, consistent with a positive therapeutic effect. Increased amounts of ordinary water would seem, therefore, to be a rational prescription for ADPKD patients in lieu of AVP-V2 receptor inhibitors, but this hypothesis has not yet been tested in humans.
As the amount of water required to achieve the same degree of urinary dilution varies considerably between individuals, a quantitative method was developed to determine the amount of water to prescribe to achieve a Uosm goal in a particular patient. The total amount of fluid needed to achieve a mean daily Uosm of 285mosm/kg H2O was computed based on the day-to-day 24-h urine osmolar excretion rate. Using this individually tailored method, extra water, prescribed in addition to eight ADPKD patients' usual intake, caused a 50% increase of urine volume and a 35% decrease of mean Uosm without altering weight, blood pressure, serum sodium, or eGFR. The regimen was generally well tolerated by the patients: 62.5% (n=5) of participants were highly adherent (defined as being able to drink water sufficient to lower Uosm to the target of 285mosm/kg), 12.5% (n=1) were somewhat adherent (defined as drinking enough to lower Uosm to 50% of the baseline value), and 25% (n=2) were able to drink sufficiently to lower Uosm by a more modest 20%. However, this small group of participants was highly selected, and their results may not be representative of the effects achievable in an undifferentiated group of patients. Complementing this work, Barash et al. confirmed in ADPKD patients that the acute ingestion of water reduced Uosm below that of plasma, and that the low Uosm could be maintained by drinking supplemental water for at least 7 days.
If the lowering of AVP effect by pharmacologic inhibition is eventually shown to be effective in slowing cyst growth, the potential benefits of water as a therapy in ADPKD lie not only with its wide availability and trivial cost, but also with its tonic effect on AVP. Tonic inhibition has considerable appeal because, as a potent vasoconstrictor, AVP has been shown to have a role in animal models of hypertension. Although it is the case that there have been no reports that tolvaptan use aggravates hypertension when used in the treatment of hyponatremia or ADPKD, elevation of plasma AVP levels might nevertheless be expected in response to extracellular fluid (ECF) volume contraction that may accompany the use of tolvaptan (or, indeed, any diuretic), making water an attractive alternative to pharmacotherapy as AVP levels may be continuously suppressed when surplus water is drunk throughout the waking hours (Figure 3).
(Enlarge Image)
Figure 3.
Cases of autosomal dominant polycystic kidney disease (ADPKD) illustrating the pattern of daily urine osmolality on a fixed or changing fluid intake. A 50-year-old woman (creatinine (Cr) 1.7mg/dl) and her 20-year-old daughter (Cr 0.9mg/dl) maintained a fixed water prescription for several weeks. Urine osmolality was recorded at 0800, 1600, and 0000 hours daily. (a) The urine osmolality (Uosm) of a young woman with relatively normal serum Cr fell below 285mosm/kg H2O on only one occasion while drinking 1.5l of fluid daily. Morning (first void) Uosm values exceed 800mosm/kg H2O, indicating preserved medullary function. (b) By contrast the older person had elevated serum Cr levels and the morning Uosm was about 400mosm/kg H2O reflecting decreased renal function. Nonetheless, she established a new steady state when the fluid intake increased to 2.5l/day by excreting urine with an osmolality between 200 and 400mosm/kg H2O. Body weight did not change appreciably in either person.
How Much Water is Safe and Appropriate in ADPKD?
Lacking specific studies that directly tested the long-term impact of high urine flow rates on renal structure and function, we have attempted to define a safe upper limit that is experience based. The average daily Uosm is 1.7–2.5 times greater than plasma osmolality in non-diseased women and men, respectively. Assuming (1) that plasma AVP is effectively suppressed to a nominal amount (2.5pg/ml) when Uosm is diluted to 285mosm/kg H2O, and (2) that the daily osmolar excretion is assumed to be 800mosm for women and 1100mosm for men, urine volume would have to increased to 2.8 and 3.7l/day, respectively. Thus, daily water intakes of ~3l for women and ~4l for men in temperate climates would be sufficient to lower plasma AVP, levels which in nephrolithiasis and CKD progression have been shown to be beneficial and relatively safe. Indeed, based on the Uosm troughs of 228–310mosm/kg H2O in the open-label tolvaptan study, we estimate that daily urine volume would have ranged from 2.6 to 4.8l, an amount of urine output that was associated with better preservation of renal function relative to individuals who did not receive tolvaptan. We think it is therefore reasonable to suggest that 3–4l of water daily can be safely prescribed for individuals with ADPKD at stage 4 CKD or better. Admittedly, meeting water intake goals by volitional drinking alone has been shown to be difficult in the setting of stone prevention and is likely be proven difficult when medicinal water is recommended for ADPKD patients.