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4. International ADTKD Summit 
Comprehensive update on research

Here you will find a report on the scientific program of the 4th International ADTKD Summit, which took place on April 4, 2025. Top-scientists from different countries gave an overview of the current state of research on this rare kidney disease. The summit was organized by the Rare Kidney Disease Foundation, the US-American patient organization for ADTKD.

At the beginning of the event, those affected reported on their experiences with ADTKD. They gave an insight into the burden of the disease and how families deal with it. These emotional stories emphasized how important it is to develop a therapy for ADTKD. If you would like to find out more, we recommend that you watch the recording of the video.

CLINICAL AND GENETIC SPECTRA of ADTKD  
Holly Mabillard, Newcastle, GB

Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) is characterized by interstitial kidney fibrosis, tubular damage, a typically bland urinalysis (with little or no protein or blood), and progressive kidney dysfunction. It ranks among the three most prevalent inherited kidney diseases—alongside Alport syndrome and autosomal dominant polycystic kidney disease (ADPKD)—and accounts for approximately 5% of all monogenic chronic kidney disease (CKD) cases. Historically, a lack of consistent nomenclature (e.g., medullary cystic kidney disease, familial juvenile hyperuricemic nephropathy) has hindered recognition and diagnosis.


The most common subtypes of ADTKD are caused by mutations in the UMOD and MUC1 genes. These mutations lead to the toxic intracellular accumulation of misfolded proteins  (uromodulin and mucin-1), causing endoplasmic reticulum stress and subsequent fibrosis. Less common subtypes involve other genes such as REN, HNF1B, and SEC61A1, and often include extra-renal symptoms.


Due to its non-specific clinical presentation, ADTKD often goes undiagnosed. Many patients are only identified after a family member is tested or following abnormal blood test results. Classic features like adolescent-onset gout are hallmark traits mainly for UMOD  mutations, but not universal. Kidney cysts may appear, but typically don’t enlarge the kidneys. Within families, disease expression can vary significantly—even among siblings.


This individual variability is influenced by several factors:

  • Even with the same primary mutation, modifier genes may alter the severity and speed of disease progression.
  • Environmental influences such as diet, lifestyle, and exposure to toxins can impact kidney stress and damage.
  • Epigenetic factors may regulate how strongly a mutation affects protein expression and cell stress responses, further contributing to diverse outcomes.


Diagnosis relies heavily on genetic testing, with next-generation sequencing (NGS) being standard. However, detecting MUC1 mutations is particularly challenging and requires specialized techniques such as VNtyper or immunohistochemistry. Importantly, a negative genetic result doesn’t rule out ADTKD; unknown genetic variants (ADTKD-NOS) may be involved.


The speaker addressed several common misconceptions—such as the belief that testing is unnecessary due to lack of treatment—emphasizing the importance of diagnosis for research, counseling, and access to clinical trials. In the UK, preimplantation genetic diagnosis (PGD) is accessible and discussed routinely with affected families.

Epidemiologically, ADTKD is mostly identified in Europe and North America, likely reflecting diagnostic access rather than true distribution. Notably, a single UMOD mutation is responsible for over half the cases in the UK, providing a unique opportunity for focused research.


The current research agenda includes exploring genotype-phenotype correlations, genetic modifiers, disease biomarkers, mechanisms of protein misfolding and stress responses, and therapeutic strategies. ADTKD serves as a valuable model for studying kidney fibrosis, with potential implications for broader kidney disease treatments.

ADVANCES IN GENEIC TESTING FOR ADTKD
Guillaume Dorval, Paris, FR

ADTKD is a genetically heterogeneous condition lacking a specific clinical phenotype, which makes its diagnosis particularly challenging. The identification of pathogenic variants in specific genes—most notably MUC1, UMOD, REN, HNF1B, and SEC61A1—is essential for confirming ADTKD. However, MUC1 presents a unique diagnostic challenge due to its complex genetic structure, especially within the Variable Number Tandem Repeat (VNTR) region, which contains high GC content and extensive sequence homology. These features hinder conventional sequencing technologies, leading to misalignment of reads and frequent failure to detect mutations.

 

This context motivated the development of VNTyper, a novel bioinformatics tool designed to address the limitations of standard short-read sequencing in detecting MUC1 mutations. VNTyper was developed by Hassan Saei and colleagues to enable unsupervised analysis of the MUC1 gene using existing short-read data, eliminating the need for clinicians to pre-specify MUC1 as a target.

 

VNTyper works by reconstructing the VNTR region sequence from patient data, then comparing it to known VNTR structures to identify deviations that suggest pathogenic variants. This method allowed the research team to re-identify known mutations in 96 patients and discover 13 new ADTKD cases, including patients who were not initially suspected to have MUC1-related disease. This breakthrough demonstrates that VNTyper expands diagnostic capabilities beyond clinical expectations and enables detection of MUC1 mutations in atypical phenotypes.

 

In further validation, VNTyper was used to analyze large cohorts and identified 33 new index cases, some of which had no family history or were initially misdiagnosed. Importantly, VNTyper uncovered novel MUC1 variants beyond the commonly known DupC mutation, enhancing the genetic spectrum of known ADTKD-causing mutations.

 

Despite its utility, VNTyper’s sensitivity is dependent on sequencing coverage and technology, with reduced accuracy in low-read-depth samples. It is not a replacement  for long-read sequencing, which remains the gold standard for MUC1 analysis. However, VNTyper fills a critical gap by enabling large-scale, accessible, and unsupervised screening from commonly available exome or genome data.

GENETIC TESTING IN CLINICAL PRACTICE
Hila Milo Rasouly, Columbia, USA

This presentation offered a comprehensive review of the integration of genetic testing into nephrology practice, focusing on the essential questions of why, when, and how such evaluations should be conducted.

 

Why Genetic Testing?

Several compelling reasons were outlined for incorporating genetic testing in the management of kidney disease. These include:

  • clarification of disease etiology, prognosis determination, optimization of treatment plans,
  • identification of eligibility for clinical trials
  • support reproductive planning, cascade testing for family members, and connection to relevant patient communities.  may conclude prolonged diagnostic journeys, offering patients and families clarity after years of uncertainty.


One of the core messages emphasized was that clinicians should not act as barriers to genetic testing. Even when unfamiliar with the details of genetic evaluation, providers should recognize potential candidates and refer them appropriately.

 

Clinical Impacts and Resources

Genetic findings can influence transplantation decisions, particularly when family members are considered as donors. They may also open doors to clinical trials or experimental therapies under development. Resources like clinicaltrials.gov, reporter.nih.gov, and Orphanet were recommended as tools to track ongoing studies and research.

 

When to Refer for Genetic Evaluation

Although patient-initiated requests are valid, providers should proactively suggest evaluation in the presence of certain “red flags”. These include family history of kidney disease, atypical clinical presentations, extra-renal symptoms (e.g., gout), early onset  of disease, unknown etiology, or suspicion of a specific genetic condition. Referral is particularly crucial when the treating nephrologist lacks the confidence or resources to manage genetic testing directly.

 

Practical Considerations for Clinicians

Clinicians are not required to become genetic specialists. Instead, they can refer patients to genetic counselors, geneticists, or specialized nephrologists. For those interested, further training and subspecialty programs in nephrogenetics are available. Even if a nephrologist decides to order testing, informed consent  is a critical component. Patients should understand the purpose, potential results, implications for themselves and family members, and the possibility of uncertain or negative findings. In complex cases—such as ADTKD with MUC1 variants—specialist involvement is especially warranted due to limitations of standard testing panels.

 

Patient History and Family Pedigree

The medical and family history are vital to assessing the likelihood of a genetic condition. Key elements include the age of onset, progression rate, presence of non-kidney-related symptoms, and a detailed three-generation family pedigree. Providers were advised to act as detectives—systematically and sensitively probing for patterns of disease and unexplained health events in relatives.

 

Genetic Counseling and Referral Tools

Genetic counseling is a central component, helping patients navigate decisions with appropriate information and support. The speaker recommended the NSGC's “Find a Genetic Counselor” tool for locating nephrology-focused counselors in the U.S., and Orphanet and ERKNet entifying rare disease expertise across Europe and beyond. 

SEARCHING OF BIOMARKERS in ADTKD

Greg Papagregoriou, Cyprus, ZY; Anthony Bleyer, Wake Forest, USA

The biobank.cy Center of Excellence at the University of Cyprus has been at the forefront of research into ADTKD, focusing particularly on the MUC1 variant (previously known as MCKD1). Under the leadership of Professor Constantinos Deltas and Dr. Christophoros Stavrou, this effort has grown into a robust translational research program combining longitudinal clinical data, biobanking, and advanced biomarker discovery.

 

One of the most striking epidemiological findings is the high prevalence of the MUC1 mutation in the western Cypriot district of Paphos, where over 160 individuals have tested positive for the pathogenic “seed insertion” mutation, out of more than 400 tested. This corresponds to a frequency of approximately 1 in every 580 individuals—a significant concentration for a rare genetic disease. 

 

The core strategy of the team is to develop biomarkers that are:

  • robust and widely accessible;
  • multi-parametric, reflecting the complex clinical manifestations of the disease;
  • biologically relevant and disease-specific, to enable targeted clinical trials.

 

The foundation of this research is a longitudinal observational study that has been ongoing for over eight years. This study tracks the natural history of ADTKD in 46 affected individuals and 29 genetically related controls from the same region, effectively controlling for environmental variables. The biobank holds serial biological samples (urine, plasma, and serum) which are used for retrospective biomarker analyses, especially focusing on urinary extracellular vesicles (uEVs). These nano-sized vesicles are promising as a non-invasive "liquid biopsy" tool, potentially reflecting intra-renal events without the need for kidney biopsy.

 

A major challenge in rare disease research like ADTKD is patient heterogeneity. The team uses machine learning models to classify patients based on their disease progression patterns, enabling better-defined cohorts for future trials. By aggregating 40 years’ worth of data from 130 patients and applying Euclidean distance-based clustering, researchers have delineated subgroups with distinct progression rates. These insights are key to developing predictive tools and defining clinical trial endpoints.

 

Among the parameters used in modeling are eGFR, urea, fractional excretion of magnesium, and specific proteins such as C53. The team also applies dimension reduction techniques to enable forecasting of disease trajectories, which could eventually reduce the duration and cost of clinical trials by providing early surrogate endpoints.

 

Multi-omics approaches applied to uEVs—covering proteomics, transcriptomics, and metabolomics—enable a personalized medicine approach, identifying individual disease signatures and potential druggable targets. These data support the development of targeted biomarker assays. A prior biomarker trial using Vitamin D—identified as a modulator of wild-type and mutant forms of MUC1—validated a mass spectrometry-based assay (IMRM) for peptide detection in urine.

 

The research team’s integration into European efforts, such as the European registry for ADTKD, underscores the collaborative and forward-looking nature of their work. The emergence of BRD4780 and other compounds as potential therapeutics  further highlights the need for robust, real-time biomarkers, which the biobank.cy team is actively striving to deliver.

 

This integrated approach—spanning observational study, biobanking, bioinformatics, and clinical translation—represents a model of excellence in rare disease research.

 

The urgent need for reliable biomarkers in this field remains a central challenge, impeding progress in therapeutic development. Unlike diabetic nephropathy, where proteinuria serves as a robust and dynamic biomarker, ADTKD currently lacks equivalent indicators, limiting the ability to track disease progression or evaluate treatment efficacy effectively.

 

A biomarker is defined as a measurable indicator of a biological state, which may be predictive/prognostic, diagnostic, or a marker of disease activity. Several illustrative cases were presented, including the Rampoldi score, which uses Western blotting of UMOD mutations to correlate intracellular processing defects with clinical severity and progression to kidney failure. Although this score offers predictive value, it is not modifiable and therefore less useful for treatment monitoring.

 

In ADPKD, total kidney volume serves as a meaningful prognostic marker correlated with GFR decline, an area where Sorin and C-Path have contributed significantly. Such intermediate markers, which can reflect treatment impact (e.g., with tolvaptan), are urgently needed in ADTKD. Markers of disease activity—such as proteinuria or sedimentation rate in other renal or inflammatory diseases—remain elusive in ADTKD. The analogy of serum creatinine as a fuel gauge (measuring cumulative damage) versus a speedometer (measuring current disease activity) was used to highlight the need for more dynamic biomarkers.

 

Challenges in biomarker discovery in ADTKD are substantial. The rarity of the disease precludes large, long-term cohort studies. Disease progression is slow and nonlinear, particularly frustrating for researchers attempting to use eGFR decline (~2 ml/min/year) as a meaningful endpoint. GFR variability due to hydration status, dietary influences, and short-term fluctuation further complicate biomarker reliability.

 

Biomarker utility is highly context-dependent. For example:

  • A drug reducing total UMOD production could be tracked via urine/plasma UMOD.
  • Targeting mutant UMOD production is harder and still under investigation.
  • A drug impacting tubulointerstitial fibrosis, a shared downstream pathology, would necessitate imaging or biopsy-based endpoints.

 

The same applies to MUC1, which differs from UMOD in that it is not cleaved but retained in exosomes. Measuring mutant MUC1 is technically challenging and complicated by its expression in multiple tissues. Emerging strategies, including salivary or sebaceous gland biopsies, may provide more accessible surrogate markers.

 

Previous biomarker studies have often lost statistical significance when adjusted for urinary protein or baseline kidney function. While many candidates have been tested at Wake Forest—including KIM-1, NGAL, TNF receptors, DKK3, MCP-1—none has demonstrated sufficient  predictive   or dynamic utility in ADTKD. Imaging, though promising, is limited by the lack of historical data and complex interpretation of regional kidney changes over time. Biopsy studies are hampered by sampling error and the absence of robust longitudinal cohorts, though new collaborative efforts are underway.


The OPTIMUM study, initiated in September 2024, aims to accelerate biomarker discovery through a combination of patient-led longitudinal data, ultrasound, and kidney elastography. The study also leverages a well-characterized biobank of 150 patients with comprehensive plasma and urine collections. Collaborations are actively encouraged for validating new candidate markers.

 

Despite strong efforts, a reliable biomarker for disease activity in ADTKD remains unavailable. Continued collaboration, open sharing of samples, and unbiased omics approaches offer the best path forward. Researchers with novel hypotheses or biomarker candidates are warmly invited to contribute to this shared endeavor.

TARGETING TMED CARGO RECEPTORS in ADTKD-UMOD
Silvana Bazua Valenti, Broad Institute, USA

ADTKD-UMOD is caused by mutations in the UMOD gene, which lead to the production of a misfolded form of the uromodulin protein. This misfolded protein becomes trapped inside kidney cells, particularly in the endoplasmic reticulum (ER), instead of being transported to the cell surface and secreted into the urine. The accumulation of the misfolded protein induces ER stress, promotes inflammation and fibrosis, and contributes to progressive kidney damage.

 

Recent research has identified TMED cargo receptors, specifically TMED2 and TMED9, as key mediators in the intracellular retention of mutant UMOD. In a mouse model of ADTKD-UMOD, the use of a small molecule compound, BRD4780, was found to release the mutant protein from these intracellular compartments. This led to reduced accumulation of UMOD within the cells and restored its correct localization at the apical membrane of the kidney tubules.

 

Further analysis revealed that BRD4780 facilitated the trafficking of the misfolded protein toward degradation pathways and increased its secretion into the urine. Importantly, treatment with BRD4780 significantly reduced markers of inflammation and fibrosis in the kidney tissue of affected mice.

 

To assess human relevance, kidney organoids  derived from ADTKD-UMOD patients were used. These organoids replicated the protein misfolding and retention seen in vivo. Upon treatment with BRD4780, the correct localization of uromodulin was restored, supporting the translational potential of this therapeutic approach.

 

These findings highlight TMED cargo receptors as promising drug targets for addressing the root cause of ADTKD-UMOD. By correcting the underlying protein trafficking defect rather than only managing downstream effects, this strategy may offer a path toward disease-modifying treatments. Ongoing work focuses on developing cell-based models and urinary biomarkers to further assess therapeutic responses and support future clinical translation.

THERAPIES ON THE HORIZON
Anna Greka, Broad Institute, USA

Dr. Greka and her team, working at the intersection of human genetics and therapeutic development, have made substantial progress in understanding and targeting the root causes of ADTKD, particularly those involving MUC1 and UMOD gene mutations. The research strategy starts by identifying the genetic mutation, then unravels how the faulty gene causes disease at the cellular level, ultimately aiming to correct the dysfunction through targeted therapies.

 

Over the past several years, the team has used scalable technologies, including human cell models and organoids, to map disease mechanisms and test potential interventions. A key breakthrough was the identification of a small molecule tool compound—BRD4780—that promotes the degradation of mutant MUC1 and UMOD proteins. While not a drug itself, this tool illuminated a pathway for developing actual treatments.

 

One such treatment, developed based on this research, was in preparation for clinical trials  but encountered unexpected toxicity late in the process. While this setback was disappointing, it provided valuable data and reinforced the team’s commitment to safety and thorough investigation. Efforts are now underway to develop a new, safer version of the compound, with phase 1 clinical trials anticipated around 2027, pending successful preclinical results.

 

Importantly, this mechanism involving the TMED family of proteins appears relevant not only to kidney diseases but also to other genetic conditions involving misfolded proteins—including some forms of Alzheimer’s disease, retinitis pigmentosa, and liver and lung disorders. This broader applicability could increase interest and investment from pharmaceutical partners and accelerate drug development.

 

The research team is also exploring next-generation therapeutic strategies, including antisense oligonucleotides, siRNA therapies, and gene-editing approaches. While these are longer-term efforts—especially gene therapy, which may take a decade or more—they represent potential "one-and-done" solutions to curing genetic kidney diseases.

 

To support and expand these efforts, Dr. Greta and colleagues have launched the Ladders to Cures Accelerator at the Broad Institute. This initiative aims to speed up the path from discovery to therapy  across all rare genetic diseases, with a special focus on those affecting children.

 

Patients and families are encouraged to join registries. Being counted helps researchers plan clinical trials accordingly—potentially enabling international access to new treatments once trials begin.

 

The video recording of the second day (patient day) can be found here: