Randomised controlled trial to determine the efficacy and safety of prescribed water intake to prevent kidney failure due to autosomal dominant polycystic kidney disease (PREVENT-ADPKD)

Introduction Maintaining fluid intake sufficient to reduce arginine vasopressin (AVP) secretion has been hypothesised to slow kidney cyst growth in autosomal dominant polycystic kidney disease (ADPKD). However, evidence to support this as a clinical practice recommendation is of poor quality. The aim of the present study is to determine the long-term efficacy and safety of prescribed water intake to prevent the progression of height-adjusted total kidney volume (ht-TKV) in patients with chronic kidney disease (stages 1–3) due to ADPKD. Methods and analysis A multicentre, prospective, parallel-group, open-label, randomised controlled trial will be conducted. Patients with ADPKD (n=180; age ≤65 years, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2) will be randomised (1:1) to either the control (standard treatment+usual fluid intake) or intervention (standard treatment+prescribed fluid intake) group. Participants in the intervention arm will be prescribed an individualised daily fluid intake to reduce urine osmolality to ≤270 mOsmol/kg, and supported with structured clinic and telephonic dietetic review, self-monitoring of urine-specific gravity, short message service text reminders and internet-based tools. All participants will have 6-monthly follow-up visits, and ht-TKV will be measured by MRI at 0, 18 and 36 months. The primary end point is the annual rate of change in ht-TKV as determined by serial renal MRI in control vs intervention groups, from baseline to 3 years. The secondary end points are differences between the two groups in systemic AVP activity, renal disease (eGFR, blood pressure, renal pain), patient adherence, acceptability and safety. Ethics and dissemination The trial was approved by the Human Research Ethics Committee, Western Sydney Local Health District. The results will inform clinicians, patients and policy-makers regarding the long-term safety, efficacy and feasibility of prescribed fluid intake as an approach to reduce kidney cyst growth in patients with ADPKD. Trial registration number ANZCTR12614001216606.

The Authors may wish to consider the following drawbacks: 1. The aim of present study is to compare the long-term efficacy and safety of high water intake compared to usual water consumption on the rate of total kidney volume increase in patients with ADPKD. An economic evaluation versus tolvaptan will be carried out using trial costs and outcomes (Page 25,. However, it would have been much more valuable to assess the efficacy and safety of high water intake compared to tolvaptan on ADPKD progression in the setting of a randomized clinical trial. Indeed, since the benefits of tolvaptan on ADPKD (i.e., slowing the progressive increase in total kidney volume and the decline in renal function) have been ascribed to inhibition of V2-receptor activation and the eventual suppression of cyclic adenosine monophosphate (N Eng J Med 2012;367:2407-18), it is reasonable to expect that a similar favourable effect on the course of ADPKD could be achieved with high fluid intake alone, because this also suppresses vasopressin release and cyclic adenosine monophosphate formation. Actually, considering the adverse effects (in particular hepatic toxicity) and the extremely high cost of tolvaptan, high water intake would be a safer and far cheaper alternative, provided that they are equally effective in slowing ADPKD progression.
2. A limitation of this study is that the sample size was calculated accounting for a drop-out rate of only 15%. The expectation that most of the patients assigned to the intervention group will be actually compliant to a high water intake regimen (about 3-4 L per day) for as long as 36 months sounds quite optimistic. Indeed, in a previous work investigating the potential benefits of water loading on renal graft function preservation in kidney transplant recipients, patients' adherence to the prescribed high fluid intake (4L per day) abated over the 12 month study period (J Ren Nutr 2011;21:499-505). Moreover, in a pilot study in ADPKD patients, in three of the eight patients (i.e., 37.5%) urinary osmolality could not be adequately suppressed during one week of oral water loading (Clin J Am Soc Nephrol 2011;6:192-197). The rational for the anticipated 15% drop-out rate should be explained.
3. At screening visit venous blood samples were collected for DNA analysis (Page 10, lines 11-12). Considering that mutations in the gene coding for polycystin 1 have been associated to more rapid renal disease progression compared to mutation in polycystin 2, I wonder whether ADPKD patients were randomized to usual water consumption or increased water intake according to either PKD1 or PKD2 mutations. A comment on this issue is welcome. 4. Since a high dietary solute load (due to high salt and/or protein intakes) requires a higher fluid intake to maintain urine dilution, the study dietician will provide dietary advice to limit sodium intake to 80-100 mmol/day (i.e., 1.8-2.3 mg/day) in patients randomized to increase water intake (Page 13, lines 1-2). However, the nature of the Western diet and the excess of salt in processed food mean that a careful dietary plan may not be sufficient to achieve and maintain the proposed target of sodium intake in the long-term run. This issue deserves a comment. Moreover, it should be clarified whether 24 h urinary sodium excretion will be monitored to assess actual adherence to low sodium diet. 5. As a secondary end-point of this clinical trial, renal function will be estimated by means of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Page 16, lines 4-5). However, creatinine-based prediction formulas, including CKD-EPI, have been shown to unreliably estimate measured GFR, and failed to predict GFR changes over time in a cohort of adult patients with ADPKD, independent of their baseline kidney function (PLoS One 2012; 7:e32533). This study limitation should be acknowledged.
6. To avoid that bias could be introduced by prior knowledge of the hypothesised role of fluid intake in ADPKD, patients will be educated about the notion that fluid requirement in ADPKD is not known (Page 23, lines 1-7). However, a previous study evaluating the effects of increased water intake on ADPKD progression showed that even before randomisation several patients had already been informed on the potential favourable effect of high water intake on the course of their disease (Nephrol Dial Transplant 2014;29:1710-1719. Thus, it is reasonable to expect that in the present study patients randomized to the usual water intake, but already informed regarding the potential benefits of fluid intake on disease course, will be motivated to drink large amounts of water, eventually reducing the difference in urine osmolality between the two study groups and masking any possible benefit(s) of water intake on ADPKD progression. A comment on this issue is welcome.
Minor points: − In the Introduction it was stated that in ADPKD renal cysts derive from epithelial cells of the distal tubule and collecting duct (Page 5, lines 8-9; Page 5, lines 21-22). However, kidney cysts can also originate from other segments of the nephron, such as proximal tubule (Nat Clin Pract Nephrol 2006;2: 40-55). These sentences should be revised accordingly.
− Based on the Legend of Figure 1, the schema of the PREVENT-ADPKD Trial Design has been adapted from reference #9. However, the cited reference (Nat Med 2003; 9:1323-26) deals with the use of a vasopressin V2-receptor antagonist in mice with a rapidly progressive form of polycystic kidney disease. Proper reference(s) should be quoted.

REVIEWER
Adam E. Mikolajczyk, MD Transplant Hepatology Fellow University of Chicago Medicine Chicago, IL USA REVIEW RETURNED 14-Aug-2017

GENERAL COMMENTS
Rangan and colleagues have crafted a well-designed protocol to study the effects of prescribed water intake on the progression of renal disease in ADPKD. This manuscript does a nice job of providing a detailed description of the study design.
A few comments that should be addressed prior to publication: 1. One of the exclusion criteria listed is "risk of non-compliance with trial procedures". Is this a subjective assessment alone or were some objective measures (e.g. number of no shows to clinic, etc.) considered.
2. "Concomitant conditions or treatments likely to confound endpoint assessments" was also listed as an exclusion criteria. But it is important to list what such entities would preclude involvement in the trial. If there was no pre-defined list of conditions/treatments, it seems that this a potential area of bias for those individuals enrolling patients.
3. This study utilizes standardized quality of life questionnaires, but are metrics specific to side effects of the intervention, such as quality of sleep (because of presumed increase in rate of nocturia) and level of satisfaction with an increased frequency of urination (which may be disruptive when at work or running errands), going to be measured? If so, are they included in the secondary endpoint "patient acceptability"? If not, it still would be helpful to provide a copy of this questionnaire as a supplement to know what items are being assessed. 4. Are the USG assessments randomly occurring or are they scheduled in a predictable manner? This should be clarified. It would be much more powerful to have these assessments occur randomly after the initial two weeks, because otherwise patients may only increase fluid intake on the days that they know their urine will be assessed. If randomly occurring, patients will be more likely to adhere to the prescribed water intake on a daily basis because they will never know when they are going to be assessed. 5. Page 17, line 49, "and a baseline ht-TKV vale of > 600"--the "and" should be removed

VERSION 1 -AUTHOR RESPONSE
Reviewer #1 Comment #1: The aim of present study is to compare the long-term efficacy and safety of high water intake compared to usual water consumption on the rate of total kidney volume increase in patients with ADPKD. An economic evaluation versus tolvaptan will be carried out using trial costs and outcomes (Page 25, lines 18-22). However, it would have been much more valuable to assess the efficacy and safety of high water intake compared to tolvaptan on ADPKD progression in the setting of a randomized clinical trial. Indeed, since the benefits of tolvaptan on ADPKD (i.e., slowing the progressive increase in total kidney volume and the decline in renal function) have been ascribed to inhibition of V2-receptor activation and the eventual suppression of cyclic adenosine monophosphate (N Eng J Med 2012; 367U2407-18), it is reasonable to expect that a similar favourable effect on the course of ADPKD could be achieved with high fluid intake alone, because this also suppresses vasopressin release and cyclic adenosine monophosphate formation. Actually, considering the adverse effects (in particular hepatic toxicity) and the extremely high cost of tolvaptan, high water intake would be a safer and far cheaper alternative, provided that they are equally effective in slowing ADPKD progression.
Authors' Response: We agree with Reviewer #1. The manuscript has been revised to include an extra paragraph to discuss this comment. Please see page 29, paragraph 2 of the Tracked version.
Comment #2: A limitation of this study is that the sample size was calculated accounting for a dropout rate of only 15%. The expectation that most of the patients assigned to the intervention group will be actually compliant to a high water intake regimen (about 3-4 L per day) for as long as 36 months sounds quite optimistic. Indeed, in a previous work investigating the potential benefits of water loading on renal graft function preservation in kidney transplant recipients, patientsʼ adherence to the prescribed high fluid intake (4L per day) abated over the 12 month study period (J Ren Nutr 2011; 21U499-505). Moreover, in a pilot study in ADPKD patients, in three of the eight patients (i.e., 37.5%) urinary osmolality could not be adequately suppressed during one week of oral water loading (Clin J Am Soc Nephrol 2011; 6U192-197). The rational for the anticipated 15% drop-out rate should be explained.
Authors' Response: The estimation of dropouts was based on experience from previous clinical trials in ADPKD. Furthermore, it was suspected that there would be significant interest for participants to remain in this study due to the low risk of adverse events with the intervention; as well as the strong interest and motivation expressed by PKD patients at the study centres, in part due to genetic nature of the disease and the paucity of opportunities for clinical research in PKD in the past. In reality, however, the exact proportion of subjects that dropout and/or withdraw from the intervention (protocol deviation) will not be known until the trial has concluded, and is a secondary outcome measure to assess the intervention's efficacy. The manuscript has been revised to include an extra paragraph to discuss this comment. Please see page 27, paragraph 1 of the Tracked version.
Comment #3: At screening visit venous blood samples were collected for DNA analysis (Page 10, lines 11-12). Considering that mutations in the gene coding for polycystin 1 have been associated to more rapid renal disease progression compared to mutation in polycystin 2, I wonder whether ADPKD patients were randomized to usual water consumption or increased water intake according to either PKD1 or PKD2 mutations. A comment on this issue is welcome.
Authors' Response: Due to time and cost of genetic testing, the effect of PKD mutation type on trial outcomes will be assessed retrospectively. The manuscript has been revised to include an extra sentence to discuss this comment. Please see page 12, paragraph 1 of the Tracked version.
Comment #4: Since a high dietary solute load (due to high salt and/or protein intakes) requires a higher fluid intake to maintain urine dilution, the study dietician will provide dietary advice to limit sodium intake to 80-100 mmol/day (i.e., 1.8-2.3 mg/day) in patients randomized to increase water intake (Page 13, lines 1-2). However, the nature of the Western diet and the excess of salt in processed food mean that a careful dietary plan may not be sufficient to achieve and maintain the proposed target of sodium intake in the long-term run. This issue deserves a comment. Moreover, it should be clarified whether 24 h urinary sodium excretion will be monitored to assess actual adherence to low sodium diet.
Authors' Response: We agree with Reviewer #1. Due to the nature of the western diet, adherence to the trial intervention (both prescribed water intake and limitation of dietary salt and protein restriction) can be difficult even with intensive dietary counselling. Progress results from the 24-hour urine volume, osmolality and sodium will be monitored to assess compliance of Group B participants with the trial intervention. The manuscript has been revised to include an extra sentence to discuss this comment. Please see page 31, paragraph 1 of the Tracked version.
Comment #5: As a secondary end-point of this clinical trial, renal function will be estimated by means of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Page 16, lines 4-5). However, creatinine-based prediction formulas, including CKD-EPI, have been shown to unreliably estimate measured GFR, and failed to predict GFR changes over time in a cohort of adult patients with ADPKD, independent of their baseline kidney function (PLoS One 2012; 7:e32533). This study limitation should be acknowledged.