ADPKD, Tolvaptan, and Nephrolithiasis Risk

Patients with autosomal dominant polycystic kidney disease (ADPKD) have a higher risk of nephrolithiasis (1). When using unenhanced computed tomography, calculi can be identified in up to 25% of patients with ADPKD (2). Kidney stones in patients with ADPKD are usually composed of uric acid or calcium oxalate (1). Among patients with ADPKD, those with nephrolithiasis have more and larger cysts and greater total kidney volumes (2). In addition to these anatomic risk factors, metabolic risk factors are also common in patients with ADPKD, including hypocitraturia, hyperoxaluria, hyperuricosuria, and low urine pH (1,2). In kidney stone clinics, metabolic risk factors for nephrolithiasis are investigated not only by analyzing urinary excretions but also, by calculating urinary supersaturation ratios (3). Urine supersaturation profiles are tightly linked to kidney stone composition and events because supersaturation is the main source of free energy that promotes crystal nucleation and growth (3,4). However, supersaturation profiles have not been systematically analyzed in patients with ADPKD.

In this issue of CJASN, Bargagli et al. (5) report the results of a study in which they analyzed the urinary lithogenic profile in patients with ADPKD, including supersaturation profiles. In addition, they analyze how this urinary lithogenic profile is influenced by tolvaptan. Tolvaptan inhibits the vasopressin V2 receptor in principal cells, which increases aquaresis, and in ADPKD, also reduces disease progression (6). Because tolvaptan increases urine volume, one might also predict a positive effect on nephrolithiasis risk (7). This idea was tested previously by Cheungpasitporn et al. (3) who showed that tolvaptan reduced the supersaturation ratios for calcium oxalate, calcium phosphate, and uric acid in idiopathic calcium kidney stone formers. To address this in ADPKD, Bargagli et al. (5) used a registry including 125 patients with ADPKD who were followed for at least 1 year and of whom 38 were treated with tolvaptan. They show that, at baseline, hypocitraturia was present in 45% of patients and that hyperoxaluria was present in 18% of patients, confirming the relatively high incidence of metabolic risk factors for nephrolithiasis in ADPKD. Multivariable regression analysis was used to analyze if treatment with tolvaptan was associated with any changes in the urinary lithogenic risk profile. As expected, tolvaptan treatment was associated with higher urine volume and higher plasma copeptin (a surrogate marker for plasma vasopressin). In addition, the use of tolvaptan was associated with a reduction in the relative supersaturation ratios for calcium oxalate, calcium phosphate, and uric acid and with increased urinary citrate excretion. In contrast to these antilithogenic effects, tolvaptan use was also associated with an increase in urinary calcium excretion. Finally, tolvaptan use was associated with an increase in net gastrointestinal alkali absorption and reduction in net acid excretion.

The study by Bargagli et al. (5) is of interest because it suggests that tolvaptan not only is effective in reducing the progression of ADPKD but may also reduce kidney stone risk. If so, the use of tolvaptan in ADPKD might kill two birds with one stone. A larger prospective study would be necessary to evaluate if tolvaptan also reduces kidney stone events. Of note, in a secondary analysis of the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 trial, tolvaptan did reduce the risk of kidney pain in patients with ADPKD, including a 37% lower incidence of kidney stones (6). A limitation of the study by Bargagli et al. (5) is selection bias because tolvaptan was given for a reason and not by randomization. The authors attempt to remedy this by multivariable correction, but the question is if this sufficiently eliminates the imbalance between the treated and untreated patients. This leaves some uncertainty as to what the reported associations really mean. However, if we assume causality, the study by Bargagli et al. (5) raises two intriguing pathophysiologic questions. First, what explains the association between tolvaptan and reduced kidney stone risk—is it related to inhibition of the V2 receptor or a secondary effect of hypotonic polyuria or increased plasma vasopressin levels acting through vasopressin V1a or V1b receptors? Second, more speculatively, could the antilithogenic effect be an additional explanation of why tolvaptan slows the progression of ADPKD, given the recently established link between crystal deposition and disease progression (8)? These two questions will be discussed in more detail below.

The simplest explanation of why tolvaptan may reduce kidney stone risk is that it dilutes the urine (3,7). The inputs for the calculation of relative supersaturation ratios—typically performed using the so-called EQUIL-2 program—are urinary cation and anion concentrations, which will be decreased by tolvaptan. Indeed, increasing fluid intake has also been shown to reduce supersaturation ratios and the risk of incident and recurrent kidney stones (7). Accordingly, it would be interesting to analyze if increasing fluid intake in ADPKD would have the same effects on the urinary lithogenic risk profile as tolvaptan. Increased water intake suppresses vasopressin, and this is considered another effective approach to reduce disease progression in ADPKD, although a definitive trial is lacking. More unexpected was the association that Bargagli et al. (5) found between tolvaptan treatment, increased net gastrointestinal alkali absorption, increased citrate excretion, and reduced net acid excretion. All three associations point in the direction of a higher alkaline load, although it is not clear if this is related to tolvaptan or to changes in dietary intake. It is conceivable that increased fluid intake due to tolvaptan has an alkalinizing effect either because of the type of fluids or because high fluid intake changes dietary habits. The question is if higher plasma vasopressin levels could also have an alkalinizing effect. If so, this is unlikely to be mediated by the kidney because it was recently shown that vasopressin increases net acid excretion through an effect on the V1a receptor in intercalated cells (9). Vasopressin, however, does also act on the colon, where it stimulates the release of glucagon-like peptide and peptide YY from colonic L cells through activation of V1b receptors (10). In turn, this will reduce colonic anion secretion, possibly explaining the association with increased net gastrointestinal alkali absorption. The association between tolvaptan and higher urinary calcium excretion may also be explained by plasma vasopressin on the basis of findings in the field of hyponatremia. High vasopressin levels are the main cause of hyponatremia, which is associated with an increased risk of osteoporosis, hypercalciuria, and kidney stones (4,11). These complications of hyponatremia have been attributed to an effect of vasopressin on bone, which consists of increased bone resorption mediated through V1a receptors (11). However, scrutiny is recommended because higher urinary calcium excretion would be expected to promote kidney stone formation, and this effect was not observed in the tolvaptan trial by Cheungpasitporn et al. (3). On the basis of these considerations, it would have been informative if Bargagli et al. (5) would have added urine osmolality and plasma copeptin to the multivariable analysis. Such an analysis would have helped to dissect whether tolvaptan, urinary dilution, or plasma vasopressin explains the associations with an improved urinary lithogenic risk profile.

The renoprotective effect of tolvaptan has been attributed to the role of plasma vasopressin and the V2 receptor in ADPKD, which can promote cystogenesis through cAMP-mediated proliferation and fluid secretion. Recently, a novel pathway for cystogenesis in ADPKD was characterized, linking it to crystal deposition. In a series of elegant experiments, Torres et al. (8) showed that in mice and rats the induction of calcium oxalate depositions triggers a rapid response of macrophage recruitment, tubule dilation, activation of polycystic kidney disease–related mammalian target of rapamycin and signal transducer and activator of transcription 3 (STAT3) signaling in tubule cells, and subsequent clearing of lodged crystals. When rats with polycystic kidney disease (Han:SPRD rats) were challenged with calcium oxalate (by administration of ethylene glycol), this defense mechanism was shown to be impaired, accelerating cystogenesis and disease progression. Concurrent treatment with citrate largely prevented these effects. In another rat model of polycystic kidney disease (PCK rats), a high-phosphate diet also led to accelerated crystal deposition and disease progression, illustrating that the mechanism is not unique for calcium oxalate. Finally, in patients with ADPKD, urinary citrate levels were inversely correlated with total kidney volume, a marker of disease severity. Taken together, the studies by Bargagli et al. (5) and Torres et al. (8) suggest that an additional or even alternative explanation for the renoprotective effect of tolvaptan in ADPKD could be its antilithogenic properties. Perhaps insufficient light has been shed on the role of nephrolithiasis in ADPKD progression because it is not detected by magnetic resonance imaging (5,6). Although ADPKD may predispose to nephrolithiasis because of disturbed crystal clearance—as proposed by Torres et al. (8)—this does not explain why metabolic risk factors for kidney stones are so common in patients with ADPKD. This suggests that ADPKD also affects the tubular handling of citrate, oxalate, and uric acid. How the effect of tolvaptan on the urinary lithogenic risk profile relates to the effects of increased water intake or other dietary interventions (lowering oxalate and uric acid and increasing citrate) is deserving of further study.

Disclosures

All authors have nothing to disclose.

Funding

None.