Nephrol Dial Transplant (2022) 37: 825–839 https://doi.org/10.1093/ndt/gfab312 Advance Access publication date 19 November 2021 An update on the use of tolvaptan for autosomal dominant SPECIAL polycystic kidney disease: consensus statement on behalf of the Downloaded from https://academic.oup.com/ndt/article/37/5/825/6431643 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 ERA Working Group on Inherited Kidney Disorders, the European Rare Kidney Disease Reference Network and REPORT Polycystic Kidney Disease International Roman-Ulrich Müller 1,2 , A. Lianne Messchendorp3 , Henrik Birn4,5 , Giovambattista Capasso 6,7 , Emilie Cornec-Le Gall8 , Olivier Devuyst 9,10 , Albertien van Eerde11 , Patrick Guirchoun12 , Tess Harris13 , Ewout J. Hoorn 14 , Nine V.A.M. Knoers15 , Uwe Korst16 , Djalila Mekahli17,18 , Yannick Le Meur19 , Tom Nijenhuis 20 , Albert C.M. Ong 21,22 , John A. Sayer23 , Franz Schaefer24 , Aude Servais25 , Vladimir Tesar26 , Roser Torra 27,28 , Stephen B. Walsh29 and Ron T. Gansevoort3 1 Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany, 2 CECAD, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany, 3 Department of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands, 4 Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark, 5 Departments of Clinical Medicine and Biomedicine, Aarhus University, Aarhus, Denmark, 6 Department of Translational Medical Sciences, Vanvitelli University, Naples, Italy, 7 Biogem Institute for Molecular Biology and Genetics, Ariano Irpino, Italy, 8 University Brest, Inserm, UMR 1078, GGB, CHU Brest, Brest, France, 9 Institute of Physiology, University of Zurich, Zurich, Switzerland, 10 Division of Nephrology, UCL Medical School, Brussels, Belgium, 11 Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands, 12 Association PolyKystose France (PKD France), Saclay, France, 13 PKD International, Geneva, Switzerland , 14 Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands, 15 Department Genetics, University Medical Centre Groningen, Groningen, The Netherlands, 16 PKD Familiäre Zystennieren e.V., Bensheim, Germany, 17 PKD Research Group, Laboratory of Pediatrics, Department of Development and Regeneration, KU Leuven, Leuven, Belgium , 18 Department of Pediatric Nephrology and Organ Transplantation, University Hospitals Leuven, Leuven, Belgium, 19 Department of Nephrology, Hemodialysis and Renal Transplantation, CHU and University of Brest, Brest, France, 20 Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboudumc Center of Expertise for Rare Kidney Disorders, Radboud University Medical Center, Nijmegen, The Netherlands, 21 Academic Nephrology Unit, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, UK, 22 Sheffield Kidney Institute, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK, 23 Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK, 24 Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany, 25 Nephrology and Transplantation Department, Necker University Hospital, APHP, Paris, France, 26 Department of Nephrology, 1st Faculty of Medicine, General University Hospital, Prague, Czech Republic, 27 Inherited Kidney Diseases Nephrology Department, Fundació Puigvert Instituto de Investigaciones Biomédicas Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain, 28 REDINREN, Barcelona, Spain and 29 Department of Renal Medicine, University College London, London, UK Correspondence to: Roman-Ulrich Müller; E-mail: roman-ulrich.mueller@uk-koeln.de Watch the video of this contribution at https://academic.oup.com/ndt/pages/author_videos ABSTR ACT Approval of the vasopressin V2 receptor antagonist tolvaptan—based on the landmark TEMPO 3:4 trial—marked a transformation in the management of autosomal dominant © The Author(s) 2021. Published by Oxford University Press on behalf of the ERA. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com polycystic kidney disease (ADPKD). This development has kidney function in the past—the only real evidence of actual advanced patient care in ADPKD from general measures to rapid progression. However, since cyst formation precedes the prevent progression of chronic kidney disease to targeting decline in eGFR, ADPKD may be progressing rapidly in young disease-specific mechanisms. However, considering the patients despite a normal eGFR, and such patients should long-term nature of this treatment, as well as potential side not be excluded by a very restrictive algorithm. Furthermore, effects, evidence-based approaches to initiate treatment pivotal information obtained from the REPRISE (Replicating only in patients with rapidly progressing disease are crucial. Evidence of Preserved Renal Function: an Investigation of In 2016, the position statement issued by the European Tolvaptan Safety and Efficacy in ADPKD) trial [10] in 2018 has Renal Association (ERA) was the first society-based allowed for an extension of eligibility criteria to older patients recommendation on the use of tolvaptan and has served and later-stage ADPKD [11]. Consequently, an update of the Downloaded from https://academic.oup.com/ndt/article/37/5/825/6431643 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 as a widely used decision-making tool for nephrologists. Since position statement based on these data as well as accumulating then, considerable practical experience regarding the use of real-world experience with tolvaptan is timely and required. tolvaptan in ADPKD has accumulated. More importantly, This update was developed by a panel of experts and endorsed additional data from REPRISE, a second randomized clinical by the boards of the European Renal Association (ERA) trial (RCT) examining the use of tolvaptan in later-stage WGIKD and the European Rare Kidney disease reference disease, have added important evidence to the field, as have NETwork (ERKNet). post hoc studies of these RCTs. To incorporate this new All recommendations are based on the following simple knowledge, we provide an updated algorithm to guide patient notion: patients expected to reach kidney failure due to selection for treatment with tolvaptan and add practical advice ADPKD before the average age at which ADPKD leads to the for its use. need for renal replacement therapy (RRT) are by definition subjects with rapid disease progression and thus candidates for Keywords: ADPKD, polycystic kidney disease, position state- this therapy. The following sections present and rationalize the ment, tolvaptan, vasopressin V2 receptor antagonist updated recommendations for the clinical parameters allowing the actual selection of patients who should be offered treatment I N T RODU C T ION with tolvaptan. Specific changes in the recommendations In the past 5 years the vasopressin V2 receptor (V2R) antago- compared with the original position statement are highlighted nist tolvaptan has become an important treatment option in the in Supplementary data, Table S1. management of patients with autosomal dominant polycystic kidney disease (ADPKD) [1–3]. Two randomized clinical trials (RCTs) have shown a beneficial effect of tolvaptan regarding An update on the efficacy of tolvaptan in ADPKD the ADPKD-associated estimated glomerular filtration rate While TKV increase is a surrogate marker of disease (eGFR) decline in patients with rapid disease progression. progression in ADPKD, the actual aim of medical treatment Considering the potential drawbacks—including its side ef- is to slow the loss of kidney function in order to delay the fects and cost—associated with this treatment, the selection of onset of kidney failure. In the TEMPO (Tolvaptan Efficacy patients who are most likely to show a positive benefit:risk ratio and Safety in Management of Autosomal Dominant Polycystic regarding this therapy—i.e. individuals showing rapid disease Kidney Disease and its Outcomes) 3:4 study, tolvaptan reduced progression—is important and required. eGFR decline by ∼1 mL/min/1.73 m2 /year (from −3.70 to Tolvaptan is a V2R antagonist that blocks vasopressin −2.72 mL/min/1.73 m2 ) in early-stage ADPKD (18–50 years signaling, a key driver of cyst growth in ADPKD due of age, estimated creatinine clearance >60 mL/min) [12] to the resulting intracellular increase in cyclic adenosine over a period of 3 years. The effect size of tolvaptan is monophosphate [4]. Polyuria is the logical consequence of V2R comparable to other agents considered the gold standard blockade and as such is expected to occur in every patient for prevention of kidney function loss in CKD, e.g. renin- on treatment. Nonetheless, adherence to tolvaptan appears to angiotensin-aldosterone system blockade in diabetic kidney be well-feasible in the majority of patients [5–7]. Importantly, disease [13–15]. In 2017, data from the open-label extension only a subset of ADPKD patients suffers from rapid disease study TEMPO 4:4 showed that the eGFR benefit accumulated progression and will reach early kidney failure due to ADPKD, in TEMPO 3:4 was maintained over 2 additional years, resulting in the need for guidance regarding patient selection. while the effect on TKV appeared not to be sustained [16]. Following the Working Group on Inherited Kidney Disease However, the interpretation of these findings was limited (WGIKD) 2016 position statement [8], several treatment by the non-randomized design, resulting in imbalances in decision algorithms have been published for different countries baseline characteristics, including gender, TKV and eGFR, [9] in order to identify ADPKD patients with rapid disease which may at least explain in part the loss of sustained effect progression. Most of these recommendations mainly rely on on TKV. Later, the randomized controlled REPRISE trial added predictors of rapid disease progression, with a central role substantial evidence to the use of tolvaptan in ADPKD [10]. for total kidney volume (TKV) [2]. In contrast, the original REPRISE examined tolvaptan in later-stage ADPKD (eGFR WGIKD position statement put the most weight on measured 25–65 mL/min/1.73 m2 in subjects 18–55 years of age and rapid progression based on the historical decline in eGFR. eGFR 25–45 mL/min/1.73 m2 in subjects 55–65 years of age). This resulted in a more conservative algorithm that primarily Here, tolvaptan slowed the decrease in eGFR by 1.27 mL/min/ recommended treatment for patients showing rapid loss of 1.73 m2 /year (from −3.61 to −2.34 mL/min/1.73 m2 )—an 826 R.-U. Müller et al. effect size comparable to TEMPO 3:4. REPRISE and several REPRISE study (solely based on age-adjusted eGFR cut-offs), subgroup analyses of this trial have added much to our current patients >55 years of age with an eGFR ≥25 mL/min/1.73 m2 , knowledge on the use of tolvaptan in ADPKD and will be are likely to have slowly progressing disease. Most patients discussed in more detail below in the context of the updated with rapidly progressing disease will have reached kidney recommendations. While neither TEMPO 3:4 nor REPRISE failure before the age of 55 years, given that the average age provide data on long-term outcome, a more recent study of kidney failure requiring RRT is 58 years for patients with addressed this issue based on a retrospective analysis of 97 ADPKD [21]. patients who had been treated with tolvaptan for up to 11 When current eGFR loss points towards rapid disease years (median 4.0, range 1.1–11.2) [17]. A comparison with progression in elderly subjects, it is extremely important to both matched controls from several ADPKD studies and with identify whether this decline is indeed due to ADPKD or Downloaded from https://academic.oup.com/ndt/article/37/5/825/6431643 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 predicted eGFR decline again revealed an effect size similar to rather the consequence of other causes. Notably, in young the two randomized trials. In addition to the reported effects patients, reduced kidney function is very likely to be the on eGFR loss and TKV increase, TEMPO 3:4 also showed result of ADPKD itself and to reflect rapid disease progression a tolvaptan-associated reduction in kidney pain and urinary (e.g. in a 30-year-old with an eGFR of 50 mL/min/1.73 tract infections [12, 18]. It should be noted that, in general, m2 and no comorbidities). With increasing age, additional currently available data for tolvaptan in ADPKD are derived comorbidities—such as vascular/hypertensive nephropathy or from clinical trials that primarily recruited people of European diabetes mellitus—become more important and may con- descent and to a lesser extent Asians and people of African tribute to or govern the eGFR loss recorded. It is not expected descent and therefore may not account for ethnic differences. that V2R blockers will have a beneficial impact on these Importantly, before starting the evaluation of a patient for comorbidities. Based on this, the proposed new algorithm treatment with tolvaptan, the diagnosis of ADPKD needs to recommends evaluation of patients up to the age of 55 years be confirmed. The diagnostic approach to ADPKD is not and emphasizes the need to consider other, non-ADPKD- the focus of this consensus statement. Nonetheless, this is a related causes for eGFR decline in elderly subjects. Since the point that needs increasing attention when targeted treatments indication by the EMA does not specify an upper age limit for become available for polycystic kidney disease. Briefly, in treatment initiation, such a limit cannot be definitive and— the presence of a positive family history, classic ADPKD in the context of individualized decisions (e.g. in a highly can be diagnosed using imaging criteria [19]. Consequently, motivated 56-year-old patient)—we do not necessarily exclude kidney imaging (preferably by MRI) is a prerequisite before treatment with tolvaptan based on this age limit. evaluation of patients for tolvaptan. Cases with atypical Taken together, eGFR indexed for age should not be clinical presentation or kidney morphology usually require higher than expected in individuals assessed for tolvaptan (see confirmation by genetic testing [20]. recommendation below). This entry criterion remains very important to exclude individuals who clearly do not have rapid disease progression at an early stage in the decision- Thresholds for treatment initiation—outer eGFR and making process. In retrospect, the thresholds defined in age limits the original WGIKD algorithm were rather conservative, The TEMPO 3:4 trial—the basis for the approval of potentially excluding patients who could have been eligible tolvaptan for ADPKD by the European Medicines Agency for therapy [9, 22]. Based on the additional evidence and (EMA)—enrolled patients 18–50 years of age [12]. Therefore, increased experience in real-life settings, these limits are most previous recommendations limited the use of tolvaptan revised in the updated version to allow more patients to benefit to this age group. The succeeding REPRISE trial included from treatment. The alleviation of age-adjusted eGFR cut- individuals in later-stage ADPKD up to the age of 65 years offs comes at the risk of including more patients with slow [10] showing a similar and significant reduction in eGFR disease progression. However, this aspect is addressed by the decline. However, a subgroup analysis suggested that this additional steps in the algorithm regarding, for example, past was not the case for patients >55 years of age, implying that eGFR loss (see section ‘Evidence of rapid disease progression’ tolvaptan should only be offered up to this age. Nonetheless, it below). Taken together, age-adjusted eGFR cut-offs should is important to recognize that the group of patients in REPRISE exclude individuals with a clearly high eGFR for their age, who were 56–65 years of age comprised only 190 individuals include those with a clearly low age-adjusted eGFR and allow in total (<15% of the study population). Also, despite the fact for further assessment using additional criteria for all others. that only individuals with an eGFR <45 mL/min/1.73 m2 Based on the REPRISE trial, we suggest that the lower were enrolled in this age group, these patients showed a slower eGFR threshold for treatment initiation should be lowered to decline of kidney function—both on placebo (−2.34 mL/min/ 25 mL/min/1.73 m2 , as subgroup analyses show efficacy also 1.73 m2 /year) and on tolvaptan (−2.54 mL/min/ at this late stage. As there are no data from RCTs regarding 1.73 m2 /year)—compared with participants <55 years of age. patients with an eGFR <25 mL/min/1.73 m2 , our algorithm Thus this group of patients would usually not be considered adopts this lower eGFR limit. Even if the effect of tolvaptan rapidly progressing. This finding highlighted two key aspects can be extrapolated to patients with an eGFR <25 mL/min/ when evaluating patients for tolvaptan. First, only patients with 1.73 m2 , the potential delay in the time of RRT as a rapid disease progression should be treated. Second, when consequence of treatment would only be a few months to applying an algorithm similar to the inclusion criteria in the 1 year [2]. An update on the use of tolvaptan for ADPKD 827 Downloaded from https://academic.oup.com/ndt/article/37/5/825/6431643 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 FIGURE 1: Extrapolations from the results of the (A) TEMPO 3:4 and (B) REPRISE trials allow estimations of the potential benefit of tolvaptan treatment in delaying the need for RRT (adapted from Chebib et al. [2]). Recommendation 1.1: We suggest that treatment with tolvap- young patients with an eGFR >90 mL/min/1.73 m2 does not tan can be initiated in adult ADPKD patients ≤55 years of age exclude a beneficial effect of tolvaptan on kidney function with with an eGFR ≥25 mL/min/1.73 m2 who have demonstrated a resulting delay of kidney failure, as kidney size and prognosis or who are likely to have rapidly progressive disease based on are closely associated. In this context, it is also important a hierarchical decision algorithm (see Recommendation 6). to point out the limitations of eGFR calculations in patients Recommendation 1.2: We recommend not to start tolvap- with (near-to) normal kidney function [25]. Also, a potential tan in patients with an eGFR indexed for age suggesting effect on structural changes in the kidney of any treatment slowly progressive disease (<40 years, no eGFR limit; 40– in ADPKD is expected to benefit from an early start. Since 44 years, ≥90 mL/min/1.73 m2 ; 45–49 years, ≥75 mL/min/ tolvaptan slows disease progression rather than bringing it to a 1.73 m2 ; 50–55 years, ≥60 mL/min/1.73 m2 ). halt or reversing the disease, the absolute effect of this therapy, i.e. years with maintained kidney function before reaching kidney failure, is expected to correlate with the duration of At what age should tolvaptan be started? When should it treatment. Consequently, the full benefit of treatment is likely be stopped? to be missed if tolvaptan is withheld until a decline in GFR is To date, no data from RCTs regarding the efficacy and safety apparent. As a result, young patients with normal GFR should of tolvaptan in children and adolescents are available and the not be excluded from treatment if other markers, such as TKV, drug has not been approved for this age group. The results suggest rapid disease progression. We therefore recommend of an ongoing pediatric study are expected soon but have starting treatment in an adult patient with ADPKD when rapid not been published to date [23]. Consequently, we currently disease progression has been established by a decline in GFR do not recommend initiating tolvaptan before the age of 18 or by accepted predictors of progression, such as TKV (see years. The optimal time point for initiating tolvaptan in an below). Since young patients fulfilling these criteria are likely adult patient with ADPKD has not been fully established. to be on treatment for many years, it is particularly important The fact that REPRISE showed a beneficial effect of tolvaptan to discuss side effects and potential impacts on lifestyle with even in older age groups may lead to the misunderstanding these patients before starting treatment (see below). that therapy should generally be delayed until sufficient data The REPRISE trial showed tolvaptan to be effective when are available to prove rapid disease progression based on commenced in patients with an eGFR down to 25 mL/min/ eGFR decline. While both the TEMPO 3:4 and REPRISE trials 1.73 m2 . No data have been published to suggest that the effect showed a reduction in the rate of eGFR loss in patients with is reduced or abolished if eGFR declines below 25 mL/min/ an eGFR <90 mL/min/1.73 m2 (Figure 1), a subgroup analysis 1.73 m2 during treatment. Consequently we recommend not of TEMPO 3:4 suggested that the effect on eGFR in patients to stop tolvaptan before kidney failure has been reached. with an eGFR >90 mL/min/1.73 m2 (CKD stage 1) was minor Notably, tolvaptan has been shown to cause an initial 3– and non-significant [10, 12]. It is important to recognize, 9% decrease in measured GFR, probably due to treatment- however, that ADPKD progresses even before GFR is declining associated haemodynamic effects, which is reversible upon and that the effect on kidney growth was comparable among withdrawal [10, 12, 16]. Thus it seems reasonable to stop patients across CKD stages. Young patients with preserved tolvaptan in patients approaching the start of RRT (e.g. kidney function will still have kidney function reserve capacity, reaching an eGFR <15 mL/min/1.73 m2 ), since they may which is used to compensate for a loss in kidney function. benefit from this predicted small increase in GFR. At this time Therefore a decrease in eGFR will become apparent only at point, the very limited expected remaining time on tolvaptan, an older age [24]. Thus the apparent non-significant effect in even if still effective, would not allow for any major benefits. 828 R.-U. Müller et al. Downloaded from https://academic.oup.com/ndt/article/37/5/825/6431643 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 FIGURE 2: Markers of disease progression and factors contributing to the information contained in these markers. Recommendation 2.1: We recommend tolvaptan treatment be In general, the predictive power of each individual marker started as soon as rapid disease progression can be determined depends on the amount of information on disease progression in patients ≥18 years of age. this marker incorporates. In ADPKD, different progression Recommendation 2.2: We suggest tolvaptan treatment be markers represent different stages in the pathophysiological discontinued when patients approach kidney failure (i.e. the cascade (Figure 2). The disease-causing genetic variant acts far need for RRT). upstream in its pathogenesis and drives downstream mecha- Although this prediction model is simplistic as it assumes nisms, which eventually lead to kidney failure. However, while that all patients progress linearly at the same slope to kidney the genetic mutation can be measured with high precision, it failure, it allows for visualization of the benefit gained by is also quite distant from the actual endpoint, kidney failure, patients if treated with tolvaptan early in their disease state. which is the treatment target. During this process, downstream measures of the disease may be influenced by other factors, e.g. environmental factors, comorbidities and treatment, which will be incorporated in the information provided by these Evidence of rapid disease progression measures [27, 28]. TKV reflects the severity of the genetic Markers of rapid disease progression. When assessing variant, but it also integrates additional disease modifiers such disease progression, it is important to distinguish markers that as intra-uterine programming or environmental factors (e.g. prove rapid disease progression from predictors of outcome. salt intake, obesity). Only eGFR loss—as the last step in this A historic fast decline in eGFR as well as rapid TKV growth cascade—incorporates all factors related to kidney disease can indeed be regarded as actual evidence of rapid disease progression. As a caveat regarding eGFR, comorbidities that progression. In contrast to eGFR, which can easily be measured are completely independent from ADPKD may contribute to in clinical practice, changes in TKV are difficult to assess the loss of kidney function. While such comorbidities do not using reliable methods in routine clinical practice and thus prohibit the use of tolvaptan per se, loss of kidney function have been excluded from the updated algorithm (see section should be primarily attributable to ADPKD when considering ‘The holistic approach’ below). Other markers, like the disease- eGFR loss as an indicator to select patients for treatment with causing genetic variant or age-related TKV, predict disease tolvaptan. progression. To allow for quantifiable use of these markers, Kidney function. When historic eGFR data are available, scoring systems have been established that use height-adjusted rapid disease progression can be identified by the rate of TKV (htTKV) in combination with age (Mayo Classification decline in eGFR. Kidney Disease: Improving Global Outcomes [26]) or mutation analysis in combination with clinical factors defines rapidly progressive CKD as an annual decline in to classify ADPKD patients by risk of disease progression. GFR ≥5 mL/min/1.73 m2 . However, observations suggest These tools are particularly useful regarding patients in CKD that in ADPKD, an annual eGFR decline less than that may stages G1 and 2, when there may be insufficient data on past be associated with kidney failure before the age of 58 years eGFR to assess a reliable slope of eGFR decline and to assess and is associated with other markers of rapidly progressive if the observed eGFR loss is indeed due to ADPKD or a disease. An annual loss of ≥2.5 mL/min/1.73 m2 over a consequence of other comorbidities. period of >5 years was chosen as a cut-off in the previous An update on the use of tolvaptan for ADPKD 829 Downloaded from https://academic.oup.com/ndt/article/37/5/825/6431643 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 FIGURE 3: Updated algorithm to assess (likely) fast disease progression as an indication for initiation of tolvaptan in ADPKD. This algorithm is only valid for individuals ≤55 years of age with an eGFR ≥25 mL/min/1.73 m2 and a confirmed diagnosis of ADPKD. We do not recommend treatment in patients who do not fulfill these criteria. If alternative explanations for eGFR loss are likely (e.g. vascular disease, diabetic nephropathy), initiation of treatment should be reconsidered even in the presence of rapid eGFR decline. The following indicators point towards potential alternative explanations: proteinuria ≥1 g/day, signs for vascular disease (e.g. coronary heart disease, stroke), uncontrolled severe arterial hypertension and diabetes mellitus. In these cases, additional information [including MRI (CT) imaging if not performed before] should be acquired to ensure ADPKD as the primary reason for eGFR loss (see also Table 1): Mayo Class 1 C–E, PROPKD score >6, early hypertension/urological manifestations, truncating PKD1 mutation, family history (onset kidney replacement therapy <60 years in two or more first-line family members). Mayo Class 1C can be found in individuals without rapid disease progression. Consequently, we recommend obtaining additional information in these patients to confirm the prediction (e.g. observe patients to see whether they actually lose eGFR compatible with rapid disease progression) and/or obtain additional arguments for an initiation of treatment such as (see also Table 1): a PROPKD score >6, early hypertension/urological manifestations, truncating PKD1 mutation, family history (onset dialysis <60 years in two or more first-line family members). version of the WGIKD algorithm. According to the Mayo on the availability of sufficient values and standardization of Imaging Classification system to assess the risk of progression creatinine measurements. However, both are required by most in patients with morphologically typical ADPKD, the annual European healthcare systems, making this approach feasible. In decline in eGFR in Mayo Class 1C was 2.63 mL/min/1.73 ADPKD, GFR has been shown to be adequately reflected by the m2 for men and 2.43 mL/min/1.73 m2 for women [26] Chronic Kidney Disease Epidemiology Collaboration equation (see Mayo Classification below). While Mayo Class 1C was for eGFR [31–33] and thus we suggest that this equation should associated with a significantly greater risk of kidney failure be used. However, even if historical eGFR data are limited, when applied to two different ADPKD cohorts, it may include the present eGFR provides a lot of information about the past. a significant proportion of individuals considered to have slow As an example, a normal eGFR in an individual >50 years of disease progression, especially in elderly individuals. Also, the age clearly indicates slow disease progression, while impaired placebo groups of the two large RCTs showing the efficacy kidney function in a patient below <30 years of age is very of tolvaptan (REPRISE, TEMPO 3:4) revealed an average likely the result of rapid disease progression (see age-adjusted decline of ∼3.5 mL/min/1.73 m2 /year. It should be noted, eGFR cut-offs in Recommendation 1.2). however, that these RCTs were enriched for subjects with rapid Recommendation 3.1: A confirmed annual eGFR decline disease progression. Consequently, we recommend that rapidly ≥3 mL/min/1.73 m2 defines rapid disease progression. The progressive disease may be defined by a yearly decline in GFR estimation of eGFR loss should be reliable and based on at least of ≥3.0 mL/min/1.73 m2 when this decline can be attributed five measurements over a period of ≥4 years. primarily to ADPKD (Figure 3). However, considering day- Recommendation 3.2: We recommend that other causes for to-day fluctuations in eGFR, especially in the higher range, eGFR decline should be assessed and excluded as major con- this criterion needs to be based on a sufficient number of tributing factors, especially in case of non-linear eGFR decline, measurements over a sufficient duration of follow-up. Also, in older patients and/or patients with multiple comorbidities non-linearity of eGFR loss in a subgroup of patients needs to that can have an impact on eGFR. be taken into consideration [29, 30]. Based on these points, we suggest obtaining at least five serum creatinine values Risk prediction: Mayo Classification and Predicting Re- over a period of ≥4 years when using the eGFR slope as the nal Outcomes in ADPKD (PROPKD) score. A number of criterion to define rapid progression. This criterion depends markers have been associated with a more severe disease 830 R.-U. Müller et al. course in ADPKD and thus may serve as predictors of kidney Table 1. Core set of clinical parameters for the assessment of rapid disease outcome even before any decline in eGFR has occurred. progression These have been reviewed extensively before [8, 34, 35]. Parameter Assessment of rapid progression A number of these have been incorporated into different Age-adjusted assessment of eGFR Is eGFR unexpectedly low (or prediction models based on age, sex, htTKV, mutation type high) for the age of the patient? and clinical complications. Such models include the Mayo Kidney volume/Mayo Class 1D/1E: rapid progression Classification, which integrates htTKV with age and sex and is Classification Class 1C: individual assessment If not possible, kidney length by >16.5 cm ≤46 years of age now widely used in the clinical setting [26]. The performance ultrasound of the Mayo Classification has been validated in independent PROPKD score >6: rapid progression cohorts and compared favorably to models based on genetic Downloaded from https://academic.oup.com/ndt/article/37/5/825/6431643 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 Genetics Truncating PKD1 mutation: rapid information [27]. The PROPKD score is an alternative model progression established in the large Analysis of Clinical and Molecular Early onset of urological Macrohematuria, cyst symptoms hemorrhage, flank pain, cyst Genetic Data Influencing the Evolution and Response to infection before the age of Therapy of ADPKD Patients (GENKYST) cohort and uses a 35 years combination of genetics and clinical parameters—specifically Early onset of arterial Before the age of 35 years early onset of arterial hypertension and urological symptoms hypertension [36]. Since the effect of the disease-causing gene variant has Family history Did most affected family members reach kidney failure? At been shown to be reflected in TKV [31], we suggest that the an age <58 years? Mayo Classification should be used as the standard model to predict kidney outcome for a decision to recommend the start of tolvaptan in ADPKD with a typical kidney morphology as Recommendation 4.2: Mayo Classes 1D and 1E indicate reflected by the updated algorithm (Figure 3). Importantly, rapid disease progression. Mayo Class 1C patients should be since measurement of kidney size along the three axes and carefully considered due to the overlap with slowly progressive calculation of kidney volume by the ellipsoid equation has been disease and additional evidence for rapid disease progression shown to be sufficient for a reliable estimate in the clinical should be sought in these patients. setting [26, 37], this appears feasible. However, real volumetry Recommendation 4.3: We suggest that rapid disease pro- by segmentation remains the most accurate approach and gression is unlikely in patients with atypical morphology of should thus be favored if available [38]. In any case, it is ADPKD, as described in the Mayo Classification (or with Mayo important to recognize that these measurements depend on an Classes 1A and 1B). experienced examiner skilled in the use of the size estimation Adding information when initial assessment is incon- tool and able to distinguish between typical and atypical clusive (a holistic approach). Due the individual variability morphology. In some cases, the inclusion of a second exam associated with all prediction models, it is important to include if available, or the use of a segmentation-based quantification all available clinical, genetic and imaging data to assess the of TKV may improve the precision of the TKV estimate. ADPKD-associated renal progression risk when considering Particular caution is warranted when distinguishing between treatment with tolvaptan. A list of such parameters—most Mayo Classes 1B and 1C, where a misclassification could of which are easily accessible—is shown in Table 1. In cases have a major impact on therapeutic decisions. Also, while with availability of genetic data and an age ≥35 years (also Classes 1A/1B and 1D/1E are clearly separated from each possible in younger patients if clinical complications have other regarding the rate of eGFR loss, Class 1C includes already occurred), the PROPKD score may be applied [39]. both rapidly and slowly progressive disease with respect to Even if a full PROPKD score cannot be calculated, each of the rate of eGFR decline [26, 31, 37]. Patients with atypical the individual parameters contained in the score (onset of morphology, also known as Mayo Class 2 patients, must be arterial hypertension or urological complications before the recognized since the TKV based model has not been validated age of 35 years, type of mutation and male sex) has been in these patients [26]. In fact, Class 2 patients generally show shown to be significantly associated with kidney survival on a mild disease course. Consequently, imaging data [magnetic its own and should be considered individually [39]. Regarding resonance imaging (MRI) or computed tomography (CT)] genetics, patients with PKD2 mutations, on average, reach should be reviewed by an ADPKD expert (usually a radiologist kidney failure ∼20 years later than patients with truncating or a nephrologist) at least once and should be—if available— PKD1 mutations, making PKD2 an important marker of slow complemented by other indicators of rapid disease progression disease progression [27, 39]. Although genotype is reflected by to increase confidence. Regarding the imaging modality, TKV TKV, adding genotype information has been shown to improve has primarily been validated using MRI scans. However, the the predictive power of the Mayo Classification regarding alternative use of CT scans is acceptable for this purpose. time to kidney failure [27]. If genetic data are missing, family Recommendation 4.1: We recommend the use of the Mayo history can be used to obtain insights regarding the genetic Classification as the primary method for risk prediction in component. However, based on the considerable potential for routine clinical care. MRI (or CT) scans should be reviewed by intrafamilial variability, this criterion must be interpreted with radiologists/nephrologists experienced in ADPKD to ensure caution [28]. In general, confirmation of kidney enlargement correct classification and exclude atypical cases (Class 2, see as a central aspect in ADPKD remains important in all patients Recommendation 4.3). even if treatment decisions are based on other criteria. Taken An update on the use of tolvaptan for ADPKD 831 together, a combination of all clinical, imaging and genetic decline. The following indicators point towards potential al- information can assist the decision-making process and should ternative explanations: proteinuria ≥1 g/day, signs of vascular be included in cases where historical eGFR decline and/or disease (e.g. coronary heart disease, stroke), uncontrolled Mayo Classification are inconclusive. severe arterial hypertension and diabetes mellitus. In these Including all available information also helps to ascertain cases, additional information [including MRI (CT) imaging if that eGFR decline is actually due to ADPKD and not explained not performed before] should be acquired to ensure ADPKD as by other causes. Comorbidities such as vascular disease, the primary reason for eGFR loss (see also Table 1): Mayo Class uncontrolled hypertension, diabetes mellitus as well as the 1C–1E, PROPKD score >6, early hypertension/urological presence of severe proteinuria (>1 g/day) point towards manifestations, truncating PKD1 mutation, family history additional factors that can explain the rate of eGFR decline. (onset of RRT at <60 years in two or more first-line family Downloaded from https://academic.oup.com/ndt/article/37/5/825/6431643 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 As mentioned above, imaging of the kidneys (preferably by members)? MRI) should be performed in all patients and the resulting Mayo Class 1C can be found in individuals without rapid Mayo Class is especially helpful in these cases. Also, serial disease progression. Consequently, we recommend obtaining measurements of TKV have previously been proposed as a additional information in these patients to confirm the method to assess progression. An increase in TKV ≥5% per prediction (e.g. observe patients to see whether they actually year was also included as a marker indicating rapid disease lose eGFR compatible with rapid disease progression) and/or progression in the original ERA position statement. However, obtain additional arguments for an initiation of treatment, such an approach would require at least three serial MRI or such as (see also Table 1) a PROPKD score >6, early hyper- CT scans that are usually not available in clinical practice tension/urological manifestations, truncating PKD1 mutation, [22]. Furthermore, variance of volume determination between family history (onset of RRT at <60 years of age in two or more different timepoints is a concern. In routine clinical care— first-line family members). and in contrast to clinical trials averaging measurements from Recommendation 6: We suggest using a hierarchical decision large cohorts—the involvement of different scanners, protocols algorithm to assess whether ADPKD patients are rapid and radiologists add to this variability. Furthermore, cysts may progressors or likely rapid progressors and accordingly may rupture, which makes the use of serial volumetry to assess qualify for treatment. the rate of disease progression impossible. While these factors may indeed influence the results of single measurements that are used for the Mayo Classification, their impact is much Applying the algorithm in the real-life setting larger regarding small relative changes over time. Thus the The proposed algorithm was applied to a cohort of 878 assessment of progression by consecutive estimates of TKV ADPKD patients managed by the Expertise Center for Polycys- is not generally recommended. We suggest using a one-time tic Kidney Diseases at the University Medical Center Gronin- MRI-based volume determination evaluated using the Mayo gen, Groningen, The Netherlands to assess the proportion of Classification. Measurement of kidney length by ultrasound patients qualifying for tolvaptan treatment (Table 2). A total is an alternative to MRI and may theoretically be used by of 415 (47%) were excluded from treatment due to an eGFR experienced examiners in individuals up to 46 years of age <25 mL/min/1.73 m2 or an age >55 years. Of the remaining [40]. However, we suggest using this criterion only in patients 463 patients, 248 (53.6%) were eligible for treatment based on with typical ADPKD and to take into account that it may documented rapid disease progression (19.7%) or predicted underestimate the risk of progression (especially in young rapid disease progression (33.9%). Of the 215 (48.4%) who did patients with short stature). We therefore do not include this not qualify for treatment, 11.0% revealed documented slowly approach in the updated algorithm (Figure 3), given the lack progressive disease and 17.1% had an eGFR that was too high of an age-adjusted ultrasound-based approach and the greater for their age, while 18.4% showed other evidence predicting precision as well as validation of MRI-based (or alternatively slowly progressive disease. CT scan) TKV estimates in relation to prognosis [41]. Nearly all patients with Mayo Class 1E would qualify Recommendation 5.1: When the initial assessment whether or for treatment, while by far the majority of subjects with not to treat with tolvaptan is inconclusive, we recommend that Mayo Class 1B and approximately half of the subjects with a full clinical picture should be obtained to allow for optimal Mayo Class 1C would not. Patients with an indication for counseling and decision-making. treatment are also enriched for the presence of a PKD1 Recommendation 5.2: In this regard, we suggest that the truncating mutation, albeit slightly less clear than for Mayo PROPKD score should be used in cases in which the eGFR Class 1E and 1D. Patients with an indication for treatment and/or Mayo Classification estimates are inconclusive or according to the algorithm had an average annual rate of contradictory. A score >6 is an indicator of rapid disease eGFR decline of 4.12 mL/min/1.73 m2 versus 2.12 mL/min/ progression. 1.73 m2 with no indication for treatment (Table 3). Obviously Recommendation 5.3: We recommend not to use TKV all possible progression criteria harbor a potential risk for changes over time as a marker of progression in individual misclassification, explaining the lack of complete concordance patients. between eGFR decline and Mayo Class. Nonetheless, eGFR loss If alternative explanations for eGFR loss are likely (e.g. is downstream to TKV in the pathogenesis of ADPKD (see vascular disease, diabetic nephropathy), initiation of treatment Figure 2) and as such shows the true velocity of disease pro- should be reconsidered even in the presence of rapid eGFR gression, while TKV/Mayo Class predicts disease progression 832 R.-U. Müller et al. Table 2. Baseline characteristics of adult ADPKD patients from the UMCG overall (N = 878) and according to outcome in the updated flowchart eGFR or age outside indication Indication for treatment No treatment eGFR too low Likely rapid eGFR indexed Slow Likely slow (<25 mL/min/1.73 Age too high (≥55 Rapid progression progression for age too progression progression Characteristics All (N = 878) m2 ) (n = 196) years) (n = 219) (n = 91) (n = 157) high (n = 79) (n = 51) (n = 85) Female, n (%) 507 (57.7) 89 (45.4) 128 (58.4) 49 (52.7) 91 (58.0) 53 (67.1) 35 (66.0) 64 (75.3) Age (years), mean ± SD 49.9 ± 11.1 54.2 ± 9.32 61.4 ± 5.17 44.7 ± 7.25 40.0 ± 8.89 48.7 ± 4.32 44.3 ± 6.10 41.2 ± 9.69 An update on the use of tolvaptan for ADPKD eGFR (mL/min/1.73 m2 ), 50.5 ± 28.8 16.4 ± 5.13 47.9 ± 17.4 48.5 ± 17.7 62.2 ± 28.6 83.4 ± 16.5 62.2 ± 19.2 75.5 ± 29.5 mean ± SD htTKV (mL/m), median 920 (571–1422) 1313 (963–1855) 837 (546–1351) 948 (699–1552) 1062 (740–1538) 580 (374–936) 647 (430–968) 430 (326–639) (IQR) CKD stage, n (%) 1 91 (10.4) 0 (0.0) 8 (3.7) 0 (0.0) 33 (21.0) 22 (27.8) 0 (0.0) 28 (32.9) 2 207 (23.6) 0 (0.0) 43 (19.6) 25 (26.9) 28 (17.8) 57 (72.2) 32 (60.4) 24 (28.2) 3a 144 (16.4) 0 (0.0) 55 (25.1) 22 (23.7) 39 (24.8) 0 (0.0) 9 (17.0) 19 (22.4) 3b 172 (19.6) 0 (0.0) 81 (37.0) 30 (32.3) 45 (28.7) 0 (0.0) 8 (15.1) 10 (11.8) 4 212 (24.1) 144 (73.5) 32 (14.6) 16 (17.2) 12 (7.6) 0 (0.0) 4 (7.5) 4 (4.7) 5 52 (5.9) 52 (26.5) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Mayo htTKV Class, n (%) 1E 116 (13.2) 33 (16.8) 1 (0.5) 25 (26.9) 51 (32.5) 2 (2.5) 4 (7.5) 0 (0.0) 1D 185 (21.1) 53 (27.0) 26 (11.9) 28 (30.1) 59 (37.6) 10 (12.7) 9 (17.0) 0 (0.0) 1C 271 (30.9) 73 (37.2) 64 (29.2) 26 (28.0) 41 (26.1) 16 (20.3) 19 (35.8) 32 (37.6) 1B 151 (17.2) 11 (5.6) 59 (26.9) 9 (9.7) 0 (0.0) 22 (27.8) 11 (20.8) 39 (45.9) 1A 36 (4.1) 1 (0.5) 18 (8.2) 0 (0.0) 0 (0.0) 8 (10.1) 4 (7.5) 5 (5.9) 2 25 (2.8) 4 (2.0) 14 (6.4) 0 (0.0) 0 (0.0) 2 (2.5) 1 (1.9) 4 (4.7) Missing 94 (10.7) 21 (10.7) 37 (16.9) 5 (5.4) 6 (3.8) 19 (24.1) 5 (9.4) 5 (5.9) PKD mutation, n (%) PKD1 truncating 345 (39.3) 86 (43.9) 38 (17.4) 54 (58.1) 106 (67.5) 22 (27.8) 23 (43.4) 16 (18.8) PKD1 200 (22.8) 47 (24.0) 46 (21.0) 25 (26.9) 21 (13.4) 17 (21.5) 14 (26.4) 30 (35.3) Non-truncating , n (%) PKD2 174 (19.9) 27 (13.8) 73 (33.3) 7 (7.5) 5 (3.2) 23 (29.1) 6 (11.3) 4 (4.7) PKD1 unknowna 11 (1.3) 3 (1.5) 12 (5.5) 0 (0.0) 2 (1.3) 1 (1.3) 1 (1.9) 0 (0.0) Other (e.g. GANAB) 2 (0.2) 0 (0.0) 2 (0.9) 0 (0.0) 0 (0.0) 1 (1.3) 0 (0.0) 1 (1.2) No mutation detected 38 (4.3) 5 (2.6) 18 (8.2) 0 (0.0) 3 (1.9) 3 (3.8) 5 (9.4) 4 (4.7) Missing 108 (12.3) 28 (14.2) 30 (13.7) 7 (7.5) 20 (12.7) 12 (15.2) 4 (7.6) 11 (13.0) a Not possible to decide truncating/non-truncating. 833 Downloaded from https://academic.oup.com/ndt/article/37/5/825/6431643 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 Table 3. Annual change in eGFR of adult ADPKD patients from the UMCG overall (N = 878) and according to outcome in the updated flowchart eGFR or age outside indication Indication for treatment No treatment eGFR too low Age too high Rapid Likely rapid eGFR indexed Slow Likely slow (<25 mL/min/1.73 (≥55 years) progression progression for age too progression progression Characteristics All (N = 878) m2 ) (n = 196) (n = 219) (n = 91) (n = 157) high (n = 79) (n = 51) (n = 85) Period of historical 4.15 ± 3.10 4.43 ± 3.25 4.00 ± 2.86 6.70 ± 3.08 2.65 ± 2.24 4.09 ± 3.29 6.45 ± 2.72 2.61 ± 1.90 measurements (years), mean ± SD Number of measurements, 8 (5–19) 18 (7–21) 7 (5–19) 18 (7–21) 6 (3–17) 6 (4–7) 7 (6–20) 5 (3–16) median (IQR) Downloaded from https://academic.oup.com/ndt/article/37/5/825/6431643 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 Annual change in eGFR −3.41 ± 2.19 −4.69 ± 1.53 −2.76 ± 1.44 −4.96 ± 1.31 −3.64 ± 1.90 −1.94 ± 3.87 −1.80 ± 1.06 −2.35 ± 1.90 (mL/min/1.73 m2 ), mean ± SD or allows attributing eGFR loss to ADPKD. Taken together, tissue composition beyond mere kidney volume. This source as indicated above, a holistic approach is indeed required in can be mined using novel approaches such as texture analyses all cases of doubt. Supplementary data, Figures S1 and S2 or T2 mapping [52, 53]. In conclusion, despite promising first underline the group separation achieved using the age/eGFR results, there are currently no newly established biomarkers thresholds of the algorithm based on individual patient data that can be used on a routine basis to improve selection plotting age versus eGFR, with patients categorized according algorithms for targeted treatment. to rate of eGFR decline before presentation (Supplementary Recommendation 7: We encourage further studies examining data, Figure S1) or Mayo htTKV Class (Supplementary data, novel imaging and molecular biomarker candidates as easy to Figure S2). measure, inexpensive tools for risk prediction, but currently The findings show that, based on a cohort of APDKD available evidence is not sufficient to support their use in patients followed at an expert center, ∼28% of all patient would clinical routine. qualify for treatment with tolvaptan using the proposed al- gorithm. Furthermore, the algorithm identified approximately half of the ADPKD patients with an age and eGFR within Monitoring of the response to tolvaptan and its the range of the indication as having (likely) rapid disease therapeutic efficacy progression, and these patients indeed have a rate of eGFR loss There are currently no validated markers that allow for that is compatible with such qualification. monitoring or predicting the effect of tolvaptan on TKV or GFR in an individual patient on treatment. Effective blockade of the V2 receptor (the target of tolvaptan) may New parameters to simplify the assessment of rapid be assessed by measuring urine osmolality [54]. Lowering of progression? urine osmolality and increased aquaresis/nocturia does indeed Currently risk prediction in ADPKD mainly relies on reflect adherence to treatment; however, there is insufficient TKV and is complemented by genetic information and evidence for this to be a marker of treatment efficacy and these clinical complications [42, 43]. Easily measurable blood or parameters are also subject in tolvaptan-independent changes urine markers that provide reliable predictive information are of fluid intake. A post hoc analysis of TEMPO 3:4 suggested lacking. So far, no studies have identified markers that are suffi- that suppression of urine osmolality in morning spot urine ciently validated for routine clinical use. Proposed biomarkers samples <250 mOsmol/L was not associated with an added include serum levels of the soluble urokinase plasminogen benefit [54]. However, patients with ADPKD show a baseline activator receptor (suPAR) [44] and copeptin [45]—serving defect in concentrating urine [55] and are often encouraged as a surrogate parameter for arginine vasopressin (AVP) to drink more water. Consequently, in the individual patient, levels—as well as urinary monocyte chemoattractant protein- this does not allow the use of this threshold to predict the 1 [46] and β2-microglobulin [47]. In general, blood-derived impact of tolvaptan on future GFR loss (see also section on marker discovery is hampered by renal clearance, making ‘Dose selection and titration of tolvaptan’ below). The relative serum levels dependent on GFR, which has been established increase in serum copeptin levels associated with tolvaptan has for several of the candidates examined. ADPKD-associated been shown to predict outcome in patients on tolvaptan [45]. proteinuria may complicate marker identification in urine While this may suggest copeptin is a potential biomarker to due to the resulting contribution of serum-derived proteins monitor the response to tolvaptan and identify individuals that to the peptides measured. In this regard, the quantification benefit most from this therapy, there are currently no sufficient of microRNAs and proteins in urinary extracellular vesicles data to recommend this for routine clinical practice. Changes opens up an entirely new opportunity for biomarker discovery in eGFR and TKV on tolvaptan treatment may be compared in kidney disease [48–51] and would also be applicable to with trends in pretreatment data or with predictions based ADPKD. In addition to biochemical markers, novel imaging- on the Mayo Classification, but the validity and sensitivity based predictors are actively being explored. MRIs are an of such an approach has not been established and is likely extremely rich source of data that provide information on to be hampered by individual fluctuations and non-linear 834 R.-U. Müller et al. courses of eGFR changes, lack of serial MRIs and variability independent of spot urine osmolality measurements. In case in TKV estimates as previously discussed. Consequently, even of drug interactions, mainly due to indispensable, concomitant though these approaches may be useful in large cohorts, they treatment with inhibitors or inducers of CYP3A, a tolvaptan should not be used in individual patients [13, 14]. Thus we do dose adjustment may be required. While we do not recom- not recommend monitoring treatment efficacy outside clinical mend the determination of urine osmolality to guide dosing, trials. Nonetheless, considering the interest in characteristics it may be useful to assist in the assessment of treatment that identify patients who will benefit from tolvaptan, future adherence. In cases in which titration to higher doses limits research in this field should be encouraged. Notably, in this tolerability, suppressed urine osmolality may indicate V2R regard, tolvaptan is no exception, since monitoring of direct blockade already at lower doses. However, for these patients, treatment efficacy—e.g. regarding eGFR loss—in individual treatment decisions will probably be guided by feasibility and Downloaded from https://academic.oup.com/ndt/article/37/5/825/6431643 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 patients is not possible for the vast majority of available drugs, quality of life rather than urine osmolality. e.g. sodium–glucose cotransporter-2 inhibitors for diabetic It is currently unknown if a specific titration regimen, e.g. nephropathy [56]. Nonetheless, determining urine volume, weekly or monthly, is associated with better tolerability, dose osmolality and body weight are helpful tools to monitor maximization and/or adherence, although current package adherence to and the feasibility of tolvaptan therapy (see sizing (with 28 daily doses) favors a monthly rather than weekly section on ‘Management of side effects of tolvaptan’ below). schedule. We suggest that the specific titration scheme adopted A more detailed discussion of potential markers to guide dose should be determined based on patient and/or physician selection is provided in the section ‘Dose selection and titration preferences as well as site-specific features of patient care, of tolvaptan’. including the possibilities for and frequency of outpatient Recommendation 8: We suggest that monitoring tolvaptan visits, taking into account that monthly liver function testing treatment efficacy has currently limited value in individual will need to be performed anyway. patients in routine care. Recommendation 9.1: We recommend tolvaptan treatment be started with a dose of 45 mg in the morning and 15 mg in the Dose selection and titration of tolvaptan afternoon. Tolvaptan for ADPKD comes in three different dose regi- Recommendation 9.2: We recommend that a target dose of mens (45/15, 60/30, 90/30 mg), all to be taken twice daily, with 90/30 mg/day should generally be aimed for in all patients the first dose taken early in the morning and the second dose unless this becomes intolerable or is contraindicated by drug 8 h later based on the pharmacokinetic profile of tolvap- interactions. tan [57]. In the TEMPO 3:4 trial the drug was titrated Recommendation 9.3: We suggest that titration to the target weekly to a target dose of 90/30 mg based on pharma- dose should be performed directly after initiation of treatment. cokinetic data showing that suppression of urine osmolality Both a weekly and a monthly dose escalation scheme are <300 mOsmol/L was achieved in more subjects on higher appropriate. doses, with 90/30 mg being the highest tolerated dose [57]. Since tolerability may be dose dependent, an initial titration was included allowing patients to slowly adjust to the effects Management of side effects of tolvaptan of the drug or to continue at a lower dose depending on Polyuria and the risk of hepatoxicity are the two most tolerability. Importantly, in TEMPO 3:4, 77% in the tolvaptan notable adverse effects of tolvaptan identified in all clinical group completed the trial and 55% of these patients reached trials of tolvaptan in ADPKD [10, 12, 59]. Polyuria is the 90/30 mg. As previously described, urine osmolality likely natural consequence of V2R blockade and is to be expected reflects the degree of V2R blockade and has been discussed in every patient on treatment. This is especially a problem as a marker to guide dosing of tolvaptan based on the finding in young patients with preserved kidney function. In later- that as a group, a urine osmolality <250 mOsmol/L was not stage disease—due to impaired urine concentrating capacity— associated with greater benefit in a post hoc analysis of TEMPO patients in general already have polyuria before treatment 3:4 [54]. However, the minimum level of blockade required is started. Since tolvaptan leads to a maximally diluted to provide treatment benefits in individual patients is not urine, the reduced number of nephrons in later-stage disease known. Furthermore, urine concentrating capacity is impaired will also lead to a lower 24-h urine volume on treatment in ADPKD, especially in later-stage patients [58], which may when compared to early-stage disease. It was shown that result in a urine osmolality below serum osmolality even before in younger ADPKD patients with near-normal GFR, urine starting tolvaptan. volume increases from 2 L in the untreated situation to Importantly, dosing by urine osmolality or by changes in 7 L on tolvaptan (an increase of 5 L), whereas in later- urine osmolality after starting tolvaptan has not been validated stage disease urine volume starts at 3 L in the untreated in clinical trials. Efficacy has been proven in RCTs only if situation and increases to 5 L on tolvaptan, an increase of only aiming for a daily dose of 90/30 mg, which was achieved 2 L [60]. This phenomenon is likely to be the reason why a in most patients in these trials. Furthermore, considering greater number of younger subjects stop treatment [5]. This that, from a pharmacodynamic point of view, maximal and is indeed a relevant problem in clinical practice because, as 24-h blockade of V2R should be attempted to also overcome reasoned above, starting treatment at a young age would yield the compensatory increase in vasopressin levels after starting the greatest absolute benefit with respect to delaying the onset tolvaptan, a maximal dose of 90/30 mg should be pursued of kidney failure. Carefully counselling younger patients and An update on the use of tolvaptan for ADPKD 835 providing practical suggestions on how to minimize problems drugs—polyuria is expected in almost all cases due to the with polyuria (see section ‘Practical considerations regarding mode of action of tolvaptan. Urine volume reaches ∼5–8 polyuria’ below) and how to deal with polyuria in daily life are L/day on average and patients should be informed that this therefore essential. volume increase results in the likely need to go the bathroom Hepatotoxicity is rare and the underlying mechanism is still hourly during daytime and two to three times per night. poorly understood [59]. An increase of transaminases more Importantly, as explained above, the increase in urine volume than 3-fold the upper limit of normal (ULN) is observed in is expected to be most pronounced in individuals with a ∼5% of patients in clinical trials and appears to be idiosyn- higher GFR. Simple measures such as starting treatment on cratic. This increase is generally reversible following cessation a weekend rather than on a working day or avoiding taking of tolvaptan. Rare severe cases fulfilling the Hy law criteria, the second pill too late in the afternoon to prevent excessive Downloaded from https://academic.oup.com/ndt/article/37/5/825/6431643 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 which implies a significant risk of acute liver failure, have been nocturia may be helpful advice. In our experience, nocturia described and led to the introduction of a risk management is indeed an issue that may limit tolerability. Nonetheless, plan and the requirement for blood testing of hepatic transam- tolvaptan has been surprisingly well-tolerated by the majority inases and bilirubin. Liver function tests are required prior to of patients, both in clinical trials and in real-life settings the initiation of treatment and monthly for 18 months and at [5, 7]. If polyuria becomes a major issue that may limit 3-month intervals thereafter [59, 61]. This approach was based drug adherence, additional measures may be recommended. on the finding that nearly all cases of treatment-associated Lowering dietary sodium intake may reduce urine output liver abnormalities in clinical trials occurred within the first by reducing the amount of osmotically active solutes to be 18 months and was included in the REPRISE trial, in which excreted [63]. Sodium intake can be assessed using repetitive no more cases fulfilling Hy law criteria were detected [10]. 24-h urine collections in order to quantitate this problem and A recent publication provides an updated and well-structured to increase patient adherence to dietary advice. In addition, algorithm to guide the need for pausing or stopping tolvaptan lowering dietary sodium intake may have protective effects depending on the pattern of liver function test abnormalities by improving blood pressure control and kidney outcome [2]. Besides monitoring liver enzymes, the risk management in ADPKD [64]. If nocturia remains a significant problem, plan implemented by the EMA includes education of both decreasing the (second) dose may be an option; however, prescribing physicians and patients, and the manufacturer as previously discussed, dose reduction may affect treatment of tolvaptan (Otsuka Pharmaceutical, Tokyo, Japan) has also efficacy. The use of thiazide diuretics to reduce urinary issued information [62]. output similar to their use in nephrogenic diabetes insipidus Additional changes in serum electrolytes (e.g. a slight has been discussed in a recent case report [65]. However, increase in sodium) and urate may be observed after starting published experiences regarding the combination of diuretics tolvaptan. However, this rarely becomes clinically signifi- and tolvaptan are limited [66]. Hence additional studies are cant, although stopping tolvaptan should be considered in required, considering that in the clinical trials of tolvaptan for the rare cases of recurrent gout after initiation. In any ADPKD, concomitant treatment with diuretics was discour- case, both parameters—alongside body weight and serum aged because of theoretical concern for electrolyte disturbances creatinine/blood urea nitrogen (BUN)—provide information and volume contraction. An additional point that needs to be regarding water–salt balance and volume status in patients on discussed with all patients before initiating treatment is the tolvaptan. advice that tolvaptan has to be stopped in situations that are Recommendation 10.1: We recommend discussing adverse associated with a risk of dehydration, e.g. diarrhea, vomiting effects and impacts on lifestyle with patients when considering or limited access to water. Furthermore, ADPKD patients starting tolvaptan. Treating physicians need to be aware of can—in addition to counselling by their nephrologists—access the adverse effects, contraindications and drug interactions of information on practical aspects regarding tolvaptan provided tolvaptan. by (inter)national patient organizations, which is freely offered Recommendation 10.2: We recommend measuring liver through brochures, symposia and social media groups. function monthly during the first 18 months of treatment and Recommendation 11.1: Polyuria and its practical conse- every 3 months thereafter. quences should be addressed specifically with all patients Recommendation 10.3: Patients showing signs of relevant before starting tolvaptan. liver toxicity upon exposure to tolvaptan should not be Recommendation 11.2: Counseling should be provided to pa- re-exposed. Alternative causes of liver damage should be tients starting tolvaptan regarding measures that can decrease excluded. polyuria, with a focus on reducing sodium intake. Recommendation 10.4: We recommend that plasma sodium Recommendation 11.3: Potential situations in which tolvap- levels as well as serum creatinine/BUN and body weight should tan should be temporarily stopped due to the risk of dehydra- be checked regularly in patients on tolvaptan. tion should be discussed with all patients before initiation. Practical considerations regarding polyuria Increasing fluid intake as an alternative to tolvaptan It is essential that patients are informed of polyuria as the treatment? most common adverse effect of tolvaptan before treatment Increased fluid intake is one of the supportive measures initiation and that—unlike common side effects of most other commonly recommended to ADPKD patients based on its 836 R.-U. Müller et al. suppression of vasopressin secretion and the consequent physicians should also be aware of national reimbursement potential to ameliorate the rate of disease progression [67–69]. criteria that may differ from the updated algorithm. It is important to note that this specifically refers to water Recommendation 13: We suggest that the initial treatment intake since other fluids, like sodas, come at added health decision and patient counseling regarding this treatment risks when consumed in large volumes. Compared with the option should be performed by a nephrologist experienced in impact of increased fluid intake, tolvaptan treatment leads to the use of tolvaptan for ADPKD. a strong increase of vasopressin levels (AVP) [45]. While V2R signaling in tubular epithelial cells is blocked by tolvaptan, the increase in AVP may have an impact on other vasopressin C ONC LU SION receptor subtypes, e.g. V1a receptors in the renal vasculature Since its approval for ADPKD by the EMA in 2015, tolvaptan Downloaded from https://academic.oup.com/ndt/article/37/5/825/6431643 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 [70]. An ongoing multicenter randomized clinical trial is has become an important component in the management of currently investigating the effect of increased fluid intake in ADPKD patients. Based on the EMA ruling, patient selection ADPKD on TKV, vasopressin activity and eGFR [71]; however, for this treatment was perceived as a challenge by many to date there are no data available showing a benefit of nephrologists, leading to the issue of the first ERA position this approach, and a tolvaptan group was not included in statement in 2016 to provide practical guidance for tolvaptan the cited study for comparison. Importantly, all participants prescribing in clinical care. Since then, the REPRISE trial has in TEMPO 3:4 were advised to increase fluid intake and provided additional evidence and allows for the extension of this advice was indeed followed by the placebo patients, tolvaptan to later-stage ADPKD patients. This fact, as well as as evidenced by a significant decrease in urine osmolality the increased clinical experience in real-world settings, are the [54]. Despite this, tolvaptan was superior in reducing a basis for these updated recommendations and the modified TKV increase and eGFR decline, as described above. When selection algorithm. Finally, it is likely that the selection comparing the potential benefit of increased fluid intake with algorithm will be applicable to other emerging treatments tolvaptan treatment, it should be considered that the twice- besides tolvaptan in coming years. daily dosing strategy and pharmacokinetic profile of tolvaptan results in efficient, 24-h V2R blockade [57, 72]. This is likely difficult to replicate by lowering vasopressin levels through SU P P L E M E N TA RY DATA high fluid intake, especially at night. Also, excessive fluid Supplementary data are available at ndt online. intake involves a risk of hyponatremia, which may increase as the capacity for urine dilution is reduced upon a loss of kidney function [73]. Thus, while ample fluid intake remains AC K NOW L E D G E M E N T S an important supportive measure, there is currently no This article was prepared on behalf of the WGIKD, which evidence supporting its use as an equally effective alternative to is an official body of the ERA and the Working Group on tolvaptan. Autosomal Dominant Disorders of the ERKNet by members Recommendation 12: We suggest that increased fluid intake of these parties (WGIKD: G.C., E.C.-L.G., A.v.E., E.J.H., N.K., should not be recommended as an alternative equal to R.-U.M., T.N., J.S., A.S. and S.B.W.; ERKNet: O.D., D.M. and tolvaptan. This notwithstanding, although formal evidence is F.S.) in cooperation with a number of external experts in the lacking, it seems prudent to advise ADPKD patients not treated field of ADPKD (H.B., R.G., A.L.M., Y.L.M., A.O. and R.T.) with a V2R blocker to adhere to a low-salt diet (3–5 g/day) and and PKDInternational (P.G., T.H. and U.K.). ERKNet is co- high water (3–4 L/day) intake to improve the rate of disease funded by the European Union within the framework of the progression. Third Health Programme ‘ERN-2016–Framework Partnership Agreement 2017–2021’. R.-U.M. is supported by the German Research Foundation and the PKD Foundation. The need for expertise regarding the decision-making and counselling process According to the provisions set by the EMA, tolvaptan C ON F L IC T OF I N T E R E ST STAT E M E N T treatment must be initiated and monitored under the super- Department 2 of Internal Medicine received grants from vision of physicians with expertise in managing ADPKD and a Otsuka (manufacturer of tolvaptan) and Thermo Fisher full understanding of the risks of tolvaptan therapy, including Scientific (manufacturer of assays to determine copeptin). hepatotoxicity and monitoring requirements. The proposed R.-U.M. received remuneration as an advisor and lecturer algorithm provides guidance to assist general nephrologists from the same companies. R.T.G. was a member of the in the selection and management of ADPKD patients on Steering Committee of the TEMPO 3:4 and REPRISE trials tolvaptan treatment. However, it is advisable that small centers and received grants and/or remuneration from Otsuka, Ipsen, with only a few ADPKD patients who are potentially eligible Sanofi-Genzyme and Galapagos (manufacturers of tolvaptan, for tolvaptan treatment take the opportunity to consult lanreotide, venglustat and GLP2737, respectively, agents used an experienced center regarding the selection of individual or in development as disease-modifying agents in ADPKD). patients, including evaluation of MRIs, patient counseling and R.T. was a member of the Independent Data Monitoring Com- the management of side effects. This algorithm aims to provide mittee for the TEMPO 3:4 study and received grants and/or re- an evidence-based medical guidance consensus. Prescribing muneration from Otsuka, Ipsen, Sanofi-Genzyme, Galapagos An update on the use of tolvaptan for ADPKD 837 and Reata (manufacturers of tolvaptan, lanreotide, venglustat, kidney disease: the TEMPO 4:4 trial. 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