Autosomal-dominant polycystic kidney disease (ADPKD) is a chronic systemic disease that affects all races and ethnicities. During the past decade, more evidence has emerged regarding optimal ADPKD management. In a Review recently published in AJKD, Sara S. Jdiaa, Reem A. Mustafa, and Alan S.L. Yu went over optimal ways for identifying patients with ADPKD who are at risk of rapid progression, and options to guide therapeutic decisions.

AJKDBlog’s Interviews Editor, Timothy Yau (@Maximal_Change), sat down with authors Sara S. Jdiaa (@JdiaaSara) and Reem A. Mustafa (@Reem_A_Mustafa) to discuss all things ADPKD.

 Dr. Sara Jdiaa is a nephrologist with advanced training in glomerulonephritis, obstetric nephrology, and kidney transplantation from the University of Toronto, Canada. Dr. Jdiaa is a Clinical Assistant Professor of Internal Medicine, University of South Dakota Sanford School of Medicine. She has a particular interest in autosomal dominant polycystic kidney disease (ADPKD). 

Dr. Reem Mustafa is a nephrologist with a master’s degree in public health and a PhD in Health Research Methodology/Clinical Epidemiology. She is a Professor of Internal Medicine/Nephrology, University of Kansas Health System and the Director of Evidence-Based Practice and Impact Center. Dr. Mustafa’s research interest focuses on the application of principles of evidence-based medicine in clinical and public health decision-making with a focus on diagnosis.

AJKD Blog: Thanks for writing such a comprehensive review on an important topic like ADPKD.  We know so much more than we did 10 years ago, and I’d like to start with some of the prognostic advancements we have made.  Can you tell us about prognostic factors like genetic phenotypes and kidney imaging to determine which patients are at highest risk of progressive loss of kidney function?

Drs Mustafa and Jdiaa: There are several prognostic factors available to identify patients with ADPKD who are at high risk for progressive kidney function loss. These include kidney size, the specific genetic mutation, the rate at which kidney function is declining in addition to PKD-related complications such as early hypertension and/or early urologic events (hematuria or cyst infections). To expand on a few of these:

Kidney size/volume – The Consortium for Radiologic Imaging Studies of PKD (CRISP) identified total kidney volume (TKV) as an early marker of eGFR decline. Beyond predicting kidney function loss, TKV is also associated with important patient-centered outcomes, such as kidney pain, hospitalizations, poor quality of life, and low work productivity. TKV can be accurately measured using either computed tomography or abdominal magnetic resonance imaging, which avoids ionizing radiation.  Once measured, TKV is adjusted for height and age using Mayo Imaging Classification (MIC), which adjusts TKV for height and age. Patients classified as MIC 1E, 1D, and a subset of 1C typically have rapidly progressive ADPKD, making them potential candidates for disease-modifying treatment with Tolvaptan.

Genetic studies – Patients with PKD1 mutations generally have worse renal outcomes and earlier kidney disease progression compared to those with PKD2 mutations, with a median age of end-stage kidney disease (ESKD) onset at 54–58 years for PKD1 and 74–79 years for PKD2. Additionally, the type of PKD1 mutation matters—truncating variants are associated with more rapid progression than non-truncating mutations. The predictive value of genetic studies is enhanced when combined with MIC.

Demographic and clinical factors – Male sex, early-onset hypertension, and urologic complications before age of 35 are associated with faster disease progression. The PROPKD score is a useful tool that incorporates clinical and genetic factors to stratify risk; however, it is primarily applicable to patients aged 35 or older. Additionally, genetic testing is not always accessible in resource-limited settings, restricting its widespread use.

While eGFR slope (rate of eGFR decline) serves as an indicator of ADPKD severity, it is considered a late marker of disease progression. To help identify patients at risk for rapid progression, the European Renal Association (ERA) working group has adapted two criteria based on kidney function: (1) a confirmed annual eGFR decline of ≥3 mL/min/1.73 m², based on multiple measurements over ≥4 years and (2) an age-based eGFR threshold, where eGFR is considered low for 40-44 years (<90 mL/min), 45-49 years (<75 mL/min), and 50-55 years (<60 mL/min).

AJKD Blog: Tolvaptan for ADPKD has made a big splash over the past few years.  Before we get into the data, can you tell us mechanistically how it works to preserve GFR and impact cyst growth?

Drs Mustafa and Jdiaa: In ADPKD, arginine vasopressin (AVP) stimulates intracellular cyclic adenosine monophosphate (cAMP) in renal epithelial cells, which in turn promotes epithelial cell proliferation, chloride-dependent fluid secretion, and cyst expansion through extracellular signal-regulated kinase (ERK) signaling.

Tolvaptan is a selective vasopressin V2 receptor antagonist which reduces intracellular cAMP levels in cyst epithelial cells, thereby inhibiting these pathological processes. This leads to slower cyst growth and preservation of kidney function over time.

AJKD Blog: Now looking into the data for tolvaptan, what do some of the large trials tell us with regards to how it slows cyst growth, GFR compared to control, and in which patients should we consider using it?

Drs Mustafa and Jdiaa: Tolvaptan has been shown to slow the progression of ADPKD by reducing both the rate of eGFR decline and cyst growth. While Tolvaptan decreases TKV growth by an average of 2.7% per year, its impact on kidney volume is greatest in the first year and wanes over time. The pivotal TEMPO 3:4 (Tolvaptan Efficacy and Safety in the Management of ADPKD and its Outcomes) and REPRISE (Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy in ADPKD) trials demonstrated that tolvaptan slows eGFR decline by approximately 1 mL/min/1.73 m² annually, a benefit comparable to other renoprotective therapies, such as angiotensin receptor blockers in diabetic nephropathy and SGLT2 inhibitors in chronic kidney disease. Although the long-term renoprotective effect of tolvaptan is not fully demonstrated in long-term studies, it could potentially delay the need for renal replacement therapy for several years if the benefits are sustained.

Current guidelines recommend tolvaptan for patients under 55 years old with an eGFR of ≥25 mL/min/1.73 m² who are at high risk of rapid disease progression. Indicators of rapid progression include MIC 1C-1E, a high-risk PROPKD score (>6), an annual eGFR decline of ≥3 mL/min/1.73 m² over ≥4y, the above-mentioned age-based eGFR thresholds, and kidney length >16.5 cm in patients younger than 45 years.

Table 1 from Jdiaa et al,© National Kidney Foundation

The benefit of tolvaptan in patients over 55 years old remains uncertain. While the REPRISE trial subgroup analysis did not show a significant benefit in this population, a pooled analysis suggested that those with CKD stage 3/4 and a confirmed annual eGFR decline of ≥3 mL/min/1.73 m² may still experience a meaningful reduction in kidney function loss with tolvaptan. Shared decision-making considering individual factors is advised in this population.

AJKD Blog: One of the more challenging aspects of ADPKD management with tolvaptan is how to monitor for adverse events, and how to determine its efficacy.  Can you tell us what routine labs need to be checked while on tolvaptan?  How do we determine if it is working, is it an indefinite medication, and if not, at what point should it be discontinued?

Drs Mustafa and Jdiaa: Routine laboratory monitoring is essential for patients on tolvaptan to ensure both efficacy and safety. Liver function tests (LFTs), including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin, should be monitored frequently—every two weeks in the first month, monthly from months two to eighteen, and then every three months thereafter. This is due to the risk of drug-induced liver injury, which was observed in 4-5% of participants in tolvaptan clinical trials including TEMPO 3:4 and REPRISE. If LFTs rise to more than three times the upper limit of normal or if there are signs of liver failure, tolvaptan should be permanently discontinued. However, if LFTs elevations remain below this threshold and liver function stabilizes or normalizes within 48–72 hours of holding tolvaptan, rechallenge with a lower dose under close monitoring can be considered.

Beyond liver function, serum sodium levels should be checked regularly due to tolvaptan’s aquaretic effects, which can lead to hypernatremia if adequate oral hydration is not maintained throughout the day to replace urinary losses.  Renal function tests, including serum creatinine and eGFR, should also be monitored to track disease progression and assess treatment efficacy.

Currently, there are no established guidelines on the best method to monitor treatment response to tolvaptan in ADPKD. The role of follow-up imaging and the ideal frequency for assessing kidney volume changes remains uncertain. While treatment efficacy is typically inferred through slower eGFR decline, no standardized monitoring protocol exists. Similarly, the optimal duration of tolvaptan therapy has not been definitively determined. However, given its role in slowing disease progression, it is generally continued until advanced CKD develops and the patient nears the need for renal replacement therapy.

AJKD Blog: Moving now to BP control, what is the goal recommended BP for patients with ADPKD, what are the first line agents, and what are the trials that support this recommendation?

Drs Mustafa and Jdiaa: The recommended BP target in ADPKD depends on age and kidney function. For patients younger than 50 years with an eGFR >60 mL/min, a goal BP of ≤110/75 mm Hg, measured by home BP monitoring, is advised. This recommendation is based on HALT-PKD Study, which demonstrated that intensive BP control slowed TKV growth, although it did not significantly impact eGFR decline when compared to standard BP control 120-130/70-80 mmHg.

For older patients or those with eGFR <60 mL/min/1.73 m², a specific ADPKD-targeted BP goal has not been established, but applying the SPRINT trial recommendation of a systolic BP <120 mm Hg using standardized office measurements is suggested, keeping in mind that patients with ADPKD were excluded from the SPRINT trial. Blood pressure control in ADPKD is also helpful for preventing intracranial aneurysm growth and rupture, reducing left ventricular mass index and decreasing albuminuria.

The first-line antihypertensive agents in ADPKD are angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), as hypertension in ADPKD is largely driven by cyst-induced renal ischemia and activation of the renin-angiotensin system. Both HALT-PKD A and HALT-PKD B trials showed no added benefit of combination therapy of ACE inhibitor and ARB on kidney function decline or total kidney volume increase when compared to ACEi monotherapy.

AJKD Blog: The new kids on the block for GFR preservation are the SGLT2-inhibitors. Can you speak about their use in ADPKD?

Drs Mustafa and Jdiaa: SGLT2 inhibitors are a cornerstone in preserving kidney function in patients with chronic kidney disease; however, their role in ADPKD remains uncertain. Major clinical trials of SGLT2 inhibitors have excluded patients with ADPKD, so there is currently no direct evidence supporting their use in this population.

A key concern is that SGLT2 inhibitors promote osmotic diuresis, which could stimulate vasopressin release and potentially exacerbate cyst growth, rather than slowing disease progression. That said, ongoing studies are recruiting to explore their safety and efficacy in ADPKD. Until more data become available, their use in this population remains investigational.

AJKD Blog: Closing question – what is in the future for ADPKD treatments?  Some have not panned out (everolimus comes to mind), but are there any promising new treatments for this important disease?

Drs Mustafa and Jdiaa: Several promising therapies are currently being investigated for ADPKD, including gene-targeted and molecular approaches aimed at slowing disease progression. RGLS8429, a next-generation oligonucleotide inhibitor of miR-17, is currently in phase 1B trials. This micro-RNA represses PKD1 and PKD2 mRNA, and preclinical studies suggest that inhibiting miR-17 may help increase polycystin expression, potentially reducing cyst growth and slowing disease progression. Another emerging therapy is VX-407, a small-molecule corrector of PKD1 variants, which has recently entered first-in-human trials, offering hope for a mutation-targeted approach to ADPKD treatment.

To view Jdiaa et al (Open Access), please visit AJKD.org:
Title: Treatment of Autosomal-Dominant Polycystic Kidney Disease
Authors: Sara S. Jdiaa, Reem A. Mustafa, and Alan S.L. Yu
DOI:  10.1053/j.ajkd.2024.08.008

Review articles cover clinical, translational, or basic science topics of interest to practitioners. Reviews published in the last two years are freely available.