Polycystic kidney disease is one of the most recognizable and consequential inherited disorders affecting the kidneys. Unlike many kidney diseases that develop silently over decades before diagnosis, this condition often announces itself through a combination of family history, progressive abdominal discomfort, and the gradual but relentless expansion of fluid-filled cysts within kidney tissue. For patients, it can mean decades of watchful waiting, careful management, and — increasingly — access to treatments that can genuinely slow the disease course. For the nephrology community, it represents one of the most scientifically rich areas of research, linking molecular genetics, cell biology, imaging science, and clinical pharmacology into a coherent and evolving story of discovery and therapeutic progress. The International Society of Nephrology has been a central part of that story, facilitating global research collaboration, supporting clinical guidelines, and ensuring that advances in science translate into better outcomes for patients around the world.
Understanding Polycystic Kidney Disease: The Basics
Autosomal dominant polycystic kidney disease — referred to in clinical and scientific literature as ADPKD — is the most prevalent hereditary kidney disease in the world. Estimates suggest it affects approximately 1 in 400 to 1 in 1,000 individuals, making it a significant cause of kidney failure globally. Unlike some inherited conditions that are rare and confined to specific populations, ADPKD is found across all ethnicities and geographic regions, and its prevalence means that nephrologists everywhere will encounter patients with this diagnosis throughout their careers.
The condition is characterised by the bilateral development of multiple fluid-filled cysts within both kidneys. Over time, these cysts grow in number and size, progressively replacing normal functional kidney tissue and causing the kidneys themselves to enlarge — sometimes dramatically. A healthy adult kidney weighs roughly 150 grams; in advanced ADPKD, individual kidneys may weigh several kilograms. This physical transformation correlates with a gradual decline in kidney function, and many patients eventually progress to end-stage kidney disease, requiring dialysis or kidney transplantation.
Beyond the kidneys, ADPKD is a systemic disease. Cysts can also develop in the liver — a common extrarenal manifestation — and patients face elevated risks of intracranial aneurysms, cardiac valve abnormalities, and hypertension, which itself accelerates kidney function loss. Understanding and managing ADPKD therefore requires attention to the whole patient, not just their kidney function numbers.
The Molecular Foundation: PKD1, PKD2, and the Polycystins
The genetic basis of ADPKD was established through landmark positional cloning studies in the 1990s. The identification of the PKD1 gene, published in the journal Cell in 1994, and the subsequent identification of PKD2, published in Nature Genetics in 1996, provided the molecular keys to understanding how the disease begins. These discoveries revealed that ADPKD is caused by mutations in genes encoding two related proteins: polycystin-1 (PC1) and polycystin-2 (PC2).
Polycystin-1 is a large transmembrane protein expressed on the surface of kidney tubular cells, particularly within the primary cilium — a tiny antenna-like structure that protrudes from the cell surface and functions as a sensor for mechanical and chemical signals in the tubular environment. Polycystin-2 is an ion channel that physically interacts with polycystin-1 and is involved in regulating calcium signalling within the cell. Together, these proteins form a functional complex that plays a critical role in controlling tubular cell growth, differentiation, and fluid secretion.
When PKD1 or PKD2 is mutated, this regulatory complex malfunctions. The result is a cascade of disordered cellular behaviour: tubular epithelial cells begin to proliferate abnormally, fluid is secreted into nascent cysts rather than being reabsorbed, and the cysts expand over time. Several downstream signalling pathways are implicated in driving this process, including the mTOR (mechanistic target of rapamycin) pathway, which regulates cell growth; the cAMP (cyclic adenosine monophosphate) pathway, which drives fluid secretion; and the MAPK/ERK pathway, which promotes cell proliferation. These pathways have become targets for therapeutic intervention, as discussed below.
Approximately 85% of ADPKD cases are caused by PKD1 mutations, and the remaining 15% by PKD2 mutations. PKD1-associated disease tends to be more severe, with earlier progression to kidney failure — on average in the fifth decade of life — compared to PKD2, where kidney failure may not occur until the sixth or seventh decade. This genotype-phenotype correlation has important implications for how individual patients are counselled and managed.
Assessing Disease Severity: The Role of Total Kidney Volume
One of the challenges in managing ADPKD is that conventional measures of kidney function — most importantly, the estimated glomerular filtration rate (eGFR) — remain relatively preserved for many years even as the disease progresses. This is because the kidneys have substantial functional reserve; cysts can cause considerable structural damage before eGFR begins to fall measurably. By the time significant eGFR decline is detectable, substantial and irreversible kidney damage has already occurred.
This limitation spurred the development of imaging-based biomarkers capable of detecting disease progression earlier. Total kidney volume (TKV) — the combined volume of both kidneys as measured by imaging — emerged as the most powerful and validated surrogate marker of disease activity in ADPKD. Because cyst growth drives kidney enlargement, TKV serves as a direct measure of the underlying pathological process.
The Mayo Clinic imaging classification system, described by Irazabal and colleagues in the Journal of the American Society of Nephrology in 2015, formalised the use of height-adjusted TKV and MRI-based growth rate calculations to stratify patients according to their risk of rapid progression. Under this system, patients are classified into different imaging classes — from 1A (least severe) to 1E (most severe) — based on the ratio of height-adjusted TKV to age. Patients in classes 1C, 1D, and 1E are considered to have rapidly progressive disease and are the primary candidates for disease-modifying therapy.
The ISN (International Society of Nephrology) has played an important role in promoting the adoption of TKV measurement as the standard imaging biomarker in ADPKD through its support of clinical practice frameworks and international guideline initiatives. Ensuring consistent application of these tools across different healthcare settings and countries remains an ongoing priority for the global nephrology community.
Key Imaging and Clinical Parameters in ADPKD Assessment
| Parameter | Method | Clinical Significance | Limitations |
|---|---|---|---|
| Total Kidney Volume (TKV) | MRI or CT imaging | Primary imaging biomarker; reflects cyst burden and disease activity | Requires imaging access; not universally available |
| Height-adjusted TKV (htTKV) | TKV divided by patient height | Normalises for body size; used in Mayo classification | Does not account for sex-based differences in kidney size |
| eGFR (estimated glomerular filtration rate) | Serum creatinine-based calculation | Standard measure of kidney function; guides CKD staging | Preserved for many years despite significant cyst growth; poor early marker |
| Mayo Imaging Class | htTKV plotted against age | Stratifies patients into rapid vs. typical progressors; informs treatment eligibility | Requires consistent imaging protocols across centres |
| Genotype (PKD1 vs. PKD2) | Genetic testing | PKD1 mutations associated with more severe and earlier disease | Genotyping not routinely performed in all clinical settings |
Tolvaptan: A Disease-Modifying Therapy for ADPKD
The identification of cAMP-driven fluid secretion as a key driver of cyst expansion provided a compelling rationale for targeting the vasopressin V2 receptor as a therapeutic strategy. Vasopressin, released from the pituitary gland in response to dehydration and other stimuli, acts on the V2 receptor in kidney tubular cells to increase cAMP levels, thereby promoting both tubular water reabsorption and, in cystic cells, fluid secretion into cysts. Blocking this receptor with an antagonist — a V2 receptor blocker — should theoretically reduce cAMP levels within cystic cells and slow cyst growth.
Tolvaptan, an oral vasopressin V2 receptor antagonist, was tested in the landmark TEMPO 3:4 trial, published in the New England Journal of Medicine in 2012. This phase 3 randomised controlled trial enrolled 1,445 patients with ADPKD and followed them for three years. The results were striking: patients treated with tolvaptan showed a significantly slower rate of TKV growth — approximately 2.8% per year compared to 5.5% per year in the placebo group — and a slower annual rate of eGFR decline. These findings established tolvaptan as the first disease-modifying therapy for ADPKD.
The subsequent REPRISE trial, also published in the New England Journal of Medicine in 2017, extended the evidence base by studying tolvaptan in patients with more advanced chronic kidney disease — specifically those with an eGFR between 25 and 65 mL/min/1.73 m². This population was not well represented in TEMPO 3:4, and there were theoretical concerns that a drug promoting aquaresis (water excretion) might be harmful in patients with reduced kidney function. REPRISE demonstrated that tolvaptan continued to attenuate eGFR decline in this group, supporting its use across a broader range of disease stages and contributing to regulatory approvals in multiple jurisdictions.
Tolvaptan: Benefits and Risks at a Glance
- Mechanism: Vasopressin V2 receptor antagonism, reducing intracellular cAMP and thereby slowing cyst fluid secretion and cell proliferation.
- Primary benefit: Slowed TKV growth rate and attenuated annual eGFR decline in patients with rapidly progressive ADPKD.
- Key trials: TEMPO 3:4 (early-stage ADPKD) and REPRISE (more advanced CKD with eGFR 25–65 mL/min/1.73 m²).
- Side effects: Aquaretic symptoms (polyuria, polydipsia, nocturia) are common; hepatotoxicity is a serious but uncommon risk requiring monitoring.
- Monitoring requirement: Monthly liver function tests are mandatory due to the hepatotoxicity signal identified in TEMPO 3:4 and subsequent post-marketing surveillance.
- Patient selection: Recommended primarily for patients with rapidly progressive disease as defined by Mayo imaging class or other validated criteria.
The hepatotoxicity signal identified during the TEMPO 3:4 trial prompted significant regulatory attention. Both the FDA in the United States and the EMA in Europe introduced risk communication measures, including mandatory liver function monitoring at monthly intervals during treatment. While serious hepatotoxicity remains uncommon, its potential severity underscores the importance of careful patient selection and ongoing monitoring. The risk-benefit assessment supporting tolvaptan use in rapidly progressive ADPKD is addressed in detail in the 2023 KDIGO ADPKD Practice Points document — a guidance framework developed in alignment with the International Society of Nephrology’s standards for evidence-based practice.
Other Therapeutic Approaches: mTOR Inhibitors and Somatostatin Analogues
Given the multiple signalling pathways implicated in ADPKD pathogenesis, tolvaptan was not the only compound to reach late-stage clinical evaluation. Two additional therapeutic strategies — mTOR inhibition and somatostatin analogue therapy — generated substantial scientific interest and moved into phase 3 trials.
mTOR Inhibitors: A Promising Hypothesis That Did Not Translate Clinically
The mTOR pathway is a master regulator of cell growth and proliferation, and preclinical studies in animal models of polycystic kidney disease demonstrated impressive TKV-slowing effects with mTOR inhibitors. This prompted two large phase 3 trials: one evaluating everolimus (Serra et al., New England Journal of Medicine, 2010) and another evaluating sirolimus (Walz et al., New England Journal of Medicine, 2010). Both trials, however, failed to demonstrate clinically meaningful slowing of TKV growth in human ADPKD patients, despite the encouraging preclinical data.
Several explanations have been proposed for this translational gap. Species differences in the degree of mTOR pathway activation in cystic disease, differences in drug exposure and target engagement, and the complex interplay between mTOR and compensatory signalling pathways may all have contributed to the discrepancy between animal and human results. Additionally, the side effect profiles of mTOR inhibitors — including immunosuppression, impaired wound healing, and metabolic disturbances — make them less attractive in a non-transplant setting. These trials served as an important reminder that preclinical efficacy in animal models does not guarantee clinical benefit in human patients with ADPKD.
Somatostatin Analogues: An Alternative Approach Under Investigation
Somatostatin analogues, including octreotide and lanreotide, work through a different mechanism: by reducing intracellular cAMP levels via somatostatin receptor signalling, they can theoretically slow cyst growth in a manner conceptually similar to — but mechanistically distinct from — vasopressin V2 receptor blockade. Unlike tolvaptan, somatostatin analogues also reduce hepatic cyst growth, making them potentially attractive in patients with significant liver involvement alongside kidney disease.
The DIPAK-1 trial, published in JAMA Internal Medicine in 2016, demonstrated that lanreotide significantly slowed TKV growth over 2.5 years compared to standard care. These results established somatostatin analogues as a viable alternative therapeutic approach, particularly in patients who cannot tolerate tolvaptan, in those with predominantly hepatic cyst burden, or in clinical contexts where tolvaptan is not yet available or approved. Further research is ongoing to better define which patients benefit most from somatostatin analogue therapy and how it compares head-to-head with tolvaptan in different disease phenotypes.
The ISN’s Role in Advancing ADPKD Research and Care
The International Society of Nephrology has been an active participant in the global effort to improve outcomes for patients with ADPKD. Through its engagement with KDIGO (Kidney Disease: Improving Global Outcomes) work groups — an initiative ISN has long supported — and through its flagship journal, Kidney International, which has published extensively on ADPKD pathophysiology and treatment, ISN has helped shape the scientific and clinical landscape surrounding this disease.
The 2023 KDIGO ADPKD Practice Points document represents one of the most recent and comprehensive frameworks for clinical decision-making in this area, addressing patient stratification, TKV measurement protocols, tolvaptan eligibility and safety monitoring, and the place of somatostatin analogues in the therapeutic landscape. These practice points reflect the collaborative international spirit that
defines ISN’s approach: bringing together expertise from across the world to produce guidance that is evidence-based, clinically practical, and applicable across diverse healthcare settings.
Beyond guidelines, ISN has supported international collaboration on disease monitoring, helped disseminate best practices for TKV measurement, and facilitated educational initiatives to ensure that both specialist nephrologists and generalist practitioners have access to the latest knowledge about ADPKD management. In low- and middle-income countries, where access to advanced imaging and newer therapies may be limited, these educational efforts are particularly valuable.
The Road Ahead: Emerging Research Directions
The therapeutic landscape for ADPKD continues to evolve. Researchers are exploring several promising avenues that may complement or extend the benefit achieved with tolvaptan and somatostatin analogues:
- Combination therapy: Whether combining agents with complementary mechanisms — for example, tolvaptan and a somatostatin analogue — could produce additive or synergistic benefits is an active area of investigation.
- Metabolic reprogramming: ADPKD cystic cells show altered metabolic behaviour, and targeting metabolic pathways — including glucose metabolism and mitochondrial function — is being explored in preclinical and early clinical research.
- Genetic and cellular therapies: Advances in gene editing and RNA-targeted therapies raise the possibility of addressing the root genetic cause of ADPKD, although significant translational challenges remain before such approaches could enter routine clinical practice.
- Biomarker development: Beyond TKV, there is active research into urinary, blood, and genetic biomarkers that could provide earlier and more personalised assessments of disease activity and treatment response.
- Precision medicine: Integrating genotype, imaging data, and emerging biomarkers to better predict individual patient trajectories and tailor therapy accordingly is a key goal for the next phase of ADPKD research.
The ISN (International Society of Nephrology) remains committed to supporting these research directions through its networks, publications, and policy engagement, ensuring that scientific advances are translated into improved patient care as rapidly and equitably as possible.
Conclusion
Autosomal dominant polycystic kidney disease represents both a major clinical challenge and a field of remarkable scientific progress. From the identification of PKD1 and PKD2 in the 1990s, to the validation of total kidney volume as a disease biomarker, to the approval of the first disease-modifying therapy in tolvaptan, the trajectory of ADPKD research tells a story of sustained scientific effort yielding real clinical benefit. The negative results with mTOR inhibitors serve as a salutary reminder of the complexity of translating biological insights into effective therapies, while the positive data with somatostatin analogues demonstrate that multiple pathways remain open for therapeutic exploitation. Throughout this journey, the International Society of Nephrology has served as a vital connective tissue — linking researchers across continents, supporting the development of evidence-based guidelines, and advocating for patients living with this lifelong condition. As the field continues to advance, ISN will remain central to ensuring that the next generation of discoveries reaches patients not just in well-resourced settings, but everywhere kidney disease is encountered.