2021 Poster summaries

Liudmila Cebotaru

Johns Hopkins University

Murali K. Yanda and Vartika Tomar

A new therapeutic approach for the treatment of ADPKD and ARPKD

We’ve developed a new way of reducing cyst growth and preserving kidney and liver function in both AD- and ARPKD, using CFTR modulators such as VX-809, already approved by the FDA to treat patients with Cystic Fibrosis.  In both rapid onset and slowly progressing mouse models of ADPKD, VX-809 reduced cyst growth, improved renal function and reduced proliferation.  We found in cell models that treatment with VX-809 of both kidney cysts in ADPKD and liver cysts in ARPKD caused CFTR’s colocalization to change from its cystic location consistent with secretion to a basolateral location consistent with fluid absorption.  In the cell models of AD- and ARPKD, trafficking, degradative and signaling pathways were altered fueling cyst growth; and restored toward normal by VX-809.  Thus, VX-809 and potentially other CFTR modulators could be powerful treatment options to reduce cyst growth and restore renal function in both AD- and ARPKD.

Arlene Chapman

University of Chicago

Gerald B. Appel | Columbia University College of Physicians and Surgeons

Geoffrey A. Block | US Renal Care, Inc

Melanie Chin, Angie Goldsberry, Colin J. Meyer, and Megan O’Grady | Reata Pharmaceuticals Inc.

Arnold L. Silva | Boise Kidney & Hypertension Institute

Vladimir Tesar | Charles University

Pablo E. Pergola | Renal Associates

Trial Design for Phase 3 FALCON: Evaluation of the Safety, Tolerability, and Efficacy of Bardoxolone Methyl in Patients with ADPKD

Bardoxolone methyl (Bard), an Nrf2 activator, improved kidney function (eGFR) in previous clinical trials that enrolled over 3,000 patients with various forms of chronic kidney disease. A Phase 2 study showed Bard increased mean eGFR by 9.3 ± 1.4 mL/min/1.73 m2 in subjects with ADPKD after 12 weeks of treatment in a patient population with a historical eGFR decline of ~4.8 mL/min/1.73 m2 annually. Additionally, Bard was well-tolerated with no patients reporting serious adverse events. As a result, a Phase 3 trial (FALCON; NCT03918447) was designed to further assess the safety, tolerability, and efficacy of Bard on rate of decline in eGFR in subjects with ADPKD. FALCON is enrolling 550 subjects with ADPKD, aged 18 to 70 years, eGFR ≥ 30 ≤ 90 mL/min/1.73 m2, and UACR ≤ 2500 mg/g. Enrolled subjects will continue treatment until Week 100 and will be followed for an additional 4 weeks off study drug.

Maroun Chedid

Mayo Clinic

Fouad T. Chebib and Christian Hanna

Ruptured Intracranial Aneurysm as the Initial Presentation of ADPKD in a Pediatric Patient

Brain aneurysms (ICA) are dilatation of the brain vessels that are prone to rupture, leading to bleeding within the brain and a mortality rate up to 50%. ICA occur more frequently in patients with ADPKD than in the general population with an average age of 39 years at rupture. Risk factors for ICA rupture in ADPKD include a family history of brain bleeding or aneurysm. Almost all cases of ruptured ICA have been reported in adult patients, and it is extremely rare in pediatrics. Here, we report a case of a 9-year-old boy who presented with a ruptured ICA preceding his ADPKD diagnosis. Although he has a strong family history of ADPKD, there was no history of ICA or bleeding. This report is important to raise awareness that ICA rupture can occur in children with ADPKD with a negative family history of ICA.

Eun Ji Chung

University of Southern California

Oral delivery of drug-loaded nanoparticles for ADPKD therapy

Autosomal dominant polycystic kidney disease is the most commonly inherited disorder worldwide, but has limited treatment options. Although tolvaptan has been approved by the FDA to slow cystogenesis, tolvaptan causes adverse side effects that limits its widespread use. Here we describe the development of multifunctional nanotherapeutics that can be orally taken, home directly to diseased kidneys, and simultaneously deliver drugs to stop the formation and expansion of renal cysts. This is the first study to apply nanomedicine and its benefits to inhibit polycystic kidney disease.
Xiangqin Cui

Emory University

Xiangqin Cui and Jiawei Meng | Emory University

Christine L. Jasien | Department of Veterans Affairs Medical Center

Julia W. Gallini | Foundation for Atlanta Veterans Education and Research

Michal Mrug | University of Alabama at Birmingham

ADPKD patients and COVID-19 severe illness risk

We examined how ADPKD patients fair in comparison with patients with other cystic kidney disease or cystic liver disease after being tested COVID-19 positive in the VA health system. Our results from 318 ADPKD patients that were confirmed COVID-19 positive showed that ADPKD is not an independent contributor to severe COVID-19 illness outcomes (hospitalization, ICU admission, ventilator requirement, and mortality). However, ADPKD is significantly associated with increased risk for new post-COVID-19 dialysis incidences.

Angélique Dachy 

KU Leuven

S. De Rechter and D. Mekahli on behalf the ADPedKD consortium | KU Leuven

L.M. Guay-Woodford | Children’s National Health System

A.J. Mallet | Royal Brisbane and Women’s Hospital

T. Harris | PKD International

D. Bockenhauer | UCL Centre for Nephrology

F.  Schaefer | Heidelberg University Medical Centre

M.C. Liebau | University Hospital of Cologne

ADPedKD: A global online platform to explore the childhood phenotype of ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and the 4th common cause for renal replacement therapy worldwide. ADPKD is characterized by the development of multiple renal cysts in both kidneys progressively leading to end-stage kidney disease by the age of 60 years. If ADPKD has been historically considered as an “adult-onset” disease, it is now recognized that the adult expression of the disease is only the tip of the iceberg, while cyst formation already begins in utero and a significant proportion of children displayed symptoms during childhood.

The ADPedKD Registry is a secured international worldwide web-based database that includes longitudinal data from young ADPKD patients (≤19 years). The aim of this registry is to give insights in the pediatric manifestations of the disease. Hereby, we report some data from the ADPedKD registry focusing on the basic’s characteristics of patients, reason for diagnosis and main clinical manifestations.

Sorin Fedeles

Yale University


Matteus Krappitz, Ke Dong, Tobias Staudner, Parisa Westergengling, David Ruemmele, Tillman Hollmann, Thuy Anh Nguyen, Yiqiang Cai, Anna-Rachel Gallagher, Stefan Somlo, and Sorin Fedeles | Yale School of Medicine

Enhanced protein folding via XBP1 activation in vivo can rescue polycystic kidney disease due to a missense PC1 mutation

Polycystic kidney and liver diseases belong to a family of genetic fibrocystic disorders that primarily affect the kidney and liver. In previous work, we have shown that XBP1 (a critical component of the unfolded protein response) and SEC63 (one of the Autosomal Dominant Polycystic Liver Disease, ADPLD, genes) interact genetically to control the severity of the polycystic phenotype in a polycystin-1-dependent (encoded by Pkd1, one of the two ADPKD genes) manner.
In the current project we have examined the impact of XBP1 on the progression of cystic disease due to Pkd1 missense mutations. We have found that activation of XBP1 in vitro and in vivo leads to improved PC1 biogenesis and decreased severity of cystic disease. Our study sheds light on a potentially important approach to tackle polycystic kidney disease in a mutation specific fashion and may form the basis of future personalized interventions for ADPKD patients.

Franziska Grundmann

University of Cologne

Christoph Lindemann, Simon Oehm, Polina Todorova, Konstantin Steinke, Thomas Benzing , and Roman-Ulrich Müller | University of Cologne

Thomas Weimbs and Sebastian Strubl | University of California Santa Barbara

Uwe Korst | PKD Familiaere Zystennieren e.V.

KETO-ADPKD – a controlled, randomized, open-label clinical trial on the feasibility of ketogenic interventions in ADPKD

Basic research results have shown, that food restriction and carbohydrate depletion ameliorates cyst growth in animal models of autosomal dominant polycystic kidney disease (ADPKD) by promoting a metabolic state called „ketosis“. During ketosis the body uses fat as an energy source instead of sugar. Using this strategy to inhibit disease progression in humans is a promising new approach. The randomized, controlled KETO-ADPKD trial pursues this innovative idea and examines two different nutritional interventions (3-day water fasting vs. ketogenic diet) to induce ketosis in comparison to a control group. The primary aim of the study is to answer whether these diets are generally acceptable to ADPKD patients in everyday life and to ascertain safety. Besides, the impact of ketosis on kidney volume is examined using serial kidney volumetry. The resulting findings will be the basis for future multicenter trials that will examine the efficacy of ketosis in ADPKD.
Tess Harris

PKD Charity UK

James Lind | Alliance

Top 10 ADPKD Research Priorities in the UK

In 2019–2020, the PKD Charity UK asked ADPKD patients, their family members/carers and healthcare professionals to identify and rank their Top 10 research priorities. We started with a list of 117 unanswered questions about ADPKD treatment, care and management which we summarised into 35 for a survey. The top 17 ranked questions from the survey were debated in an online workshop to arrive at a Top 10. The Top 10 questions reflect the varied physical, psychological and practical challenges faced by people living with ADPKD, and the gaps in knowledge and healthcare. We are encouraging researchers and funding bodies to use our Top 10 list to inform their research proposals and grant awards, respectively. By doing so, they can ensure their research is shaping a future that those affected by and treating ADPKD hope to see.
Sonu Kashyap

Mayo Clinic

Kyaw Z. Hein, Jorgo Lika, Gina M Warner and Eduardo N. Chini

Dietary methionine restriction improves cystic disease in ADPKD

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the fourth leading cause of end stage renal disease. Although tolvaptan has been recently approved by FDA for ADPKD, but several adverse effects of this drug make it unsuitable for many patients. Therefore, development of novel therapies against this cystic disease is of great importance. Nutritional manipulations studies involving a decrease in food intake or time restricted feeding have shown beneficial effects in animal models of PKD. Despite the fact that these nutritional manipulations are effective treatments, they do have many limitations. In the present study, we show that dietary restriction of methionine has beneficial effects in animal model of PKD. Thus, dietary interventions involving MR have great potential as an alternative nutritional therapeutic strategy against this cystic disease.

Nancy K. Kleene

University of Cincinnati

Fouad T. Chebib and Grace Nelson | Mayo Clinic

Steve J. Kleene | University of Cincinnati

The Therapeutic Potential of a PC2 Activator in Polycystic Kidney Disease

One of the first defects that leads to the formation of cysts in polycystic kidney disease (PKD) is an abnormally low level of calcium inside the kidney cells. In healthy individuals, polycystin-2 (PC2) allows calcium entry into kidney cells, and about 85% of PKD cases do not involve defects in PC2. A novel, PKD specific approach to restoring cellular calcium would be to identify a drug that activates PC2. We have found such a drug: pregnenolone sulfate. The drug raises the calcium level in cultured kidney cells from mice and humans. The drug reduces cysts in an assay using cultured kidney cells from mice, and it reduces cysts in an assay using cultured, whole kidneys from mice. We are confirming these studies, extending them to other models of PKD, and exploring the drug’s mechanism of action.

Edmund Lee

Regulus Therapeutics Inc.

Tania Valencia, Jessica Mastroianni, Garth Kinberger, Firuz Shakoori, Tate Owen, Steven Neben, Karl Cremer, Rekha Garg and Denis Drygin | Regulus Therapeutics Inc.

Andrea Flaten and Vishal Patel | University of Texas Southwestern Medical Center

Wendi Lea and Christopher Ward | University of Kansas Medical Center

Preclinical Evaluation and Results from the First Cohort of Phase 1b Clinical Trial of RGLS4326 for the Treatment of Patients with ADPKD

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either PKD1 or PKD2 genes, which results in kidney cyst formation. Here we report the evaluation of RGLS4326, a novel investigational drug identified to inhibit a target called miR-17, and to slow down kidney cyst growth. We have shown that miR-17 is overproduced in kidneys of ADPKD patients and causes decreased levels of PC1 and PC2 (proteins encoded by PKD1 and PKD2). In studies in animals with PKD, RGLS4326 increased levels of PC1 and PC2, reduced kidney injury marker uNGAL, and inhibited kidney cyst growth. In an ongoing Phase 1b study in patients with ADPKD, four doses of subcutaneous (s.c.) injections every other week of RGLS4326 in the first cohort was well tolerated and showed increases in urinary PC1 and PC2 levels. The study is continuing to enroll ADPKD patients in additional cohorts to evaluate different doses of RGLS4326.

Kristin Leonberg

Sanofi Genzyme

Manish Maski and Ali Hariri

ADPKD Patient Perspectives on Diagnosis and Management

Patients with ADPKD experience symptoms from the disease, but also a variety of challenges in their interactions with the healthcare system and their families. Interviews were conducted in the US, UK, France, Germany, Japan, and Brazil to better understand the patient experience. 68 participants completed the interviews. Enlarged kidney cysts were usually experienced as pain (flank, abdominal, and/or back; chronic and/or acute) and fatigue that worsens as kidney function declines. Patients felt their degree of pain is not always appreciated by health care providers. Depression and anxiety often developed as patients faced a progressive decline in health and kidney function, coupled with unknown timeline to end-stage kidney disease. Most said their nephrologists did not discuss whether they are “rapid progressors,” nor did they offer a predicted timeline of kidney function decline. Patients had many concerns around family planning, pregnancy, and their ability to provide family care over time. Physicians rarely shared information on therapeutic developments and/or clinical trials.
Jared Lutsic

Mayo Clinic

Ali Tug, Alexis Adrian, Yahya Alsawaf, Ivan Vuckovic, Slobodan Macura, Peter C. Harris, Vicente E. Torres and Maria V Irazabal | Mayo Clinic

The Nuclear Factor (Erythroid-Derived 2)-Like 2 (NRF2) response evolves as the disease progresses in ADPKD

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a devastating genetic disorder that causes numerous cysts in the kidneys and remains a leading cause of renal failure among adults worldwide. However, a complete understanding of the different cellular changes at each stage of the disease is still missing. A better understanding of the cellular mechanisms associated with renal damage at each stage of the disease is likely to have important clinical implications by identifying novel early biomarkers and highlighting additional processes that could be a target for therapeutic intervention.
Chuck Madsen

Mayo Clinic

Neil Shusterman, John Castellana,
Lorenzo Pellegrini | Palladio Biosciences, Inc

A Phase 3 Program of the Novel Vasopressin V2 Receptor Antagonist Lixivaptan in Patients with ADPKD

Additional treatments for ADPKD patients to slow the progression of kidney function decline are needed. Tolvaptan, the only approved therapy, is associated with liver side effects in some patients. Lixivaptan, which works through the same mechanism as tolvaptan, has been shown in models to be potentially safer for the liver. We present here the planned Phase 3 clinical trial to show the efficacy and safety of lixivaptan. In this trial, after increasing the dose to the highest tolerated level, participants will be randomized in a ratio of 2 to 1 to receive double-blind treatment with lixivaptan or placebo for 1 year. After the first year, all participants will receive lixivaptan for the second year. The change in estimated glomerular filtration rate is the main efficacy endpoint and the increase in liver enzyme levels is the main safety endpoint. The trial is planned to start in early 2021.

Robin Maser

University of Kansas Medical Center

Brenda Magenheimer and
Ericka Nevarez Munoz

Understanding Polycystin-1 G protein-coupled receptor function for therapeutic targeting

Polycystin-1, product of the PKD1 gene, functions as an atypical G protein-coupled receptor (GPCR). Typical GPCRs bind a specific ligand, which activates G protein signaling to alter the function/properties of the cell. Polycystin-1 resembles Adhesion GPCRs that undergo an unusual, self-catalyzed cleavage resulting in N-terminal (NTF) and C-terminal (CTF) fragments. The NTF and cell membrane-embedded CTF subunits typically remain associated. Recent studies demonstrate that removal of the NTF allows activation of signaling by the CTF. Further analyses show the short sequence region at the beginning of the CTF – the stalk – becomes exposed upon removal of the NTF and subsequently ‘bends backwards’ to bind to the remainder of the CTF, resulting in activation of G protein signaling by the Adhesion GPCR. The CTF stalk is therefore a ‘tethered peptide ligand’. We reveal polycystin-1 signaling is also activated by its stalk and propose this mechanism as a new therapeutic target.
Laura Onuchic

Yale University

Valeria Padovano, Giorgia Schena, Nikolay Gresko, Vanathy Rajendran, Ke Dong, Stefan Somlo, and Michael Caplan

The C-terminal tail of polycystin-1 is sufficient to rescue the cystic phenotype in a mitochondrial enzyme-dependent fashion

About 80-85% of Autosomal Dominant Polycystic Kidney Disease (ADPKD) cases are caused by genetic mutations in the PKD1 gene, leading to production of defective Polycystin-1 (PC1) protein. PC1 is a large transmembrane protein that undergoes cleavage at its N and C-terminal domains. Cleavage at the C-terminal domain leads to the generation of PC1 C-terminal tail fragments (PC1-CTT) of approximately 17 and 34kD that are capable of translocating to the mitochondria and nucleus.

In this study we aimed to assess the effects of re-expressing the PC1-CTT in an inducible PC1 KO ADPKD mouse model. To this purpose, we first generated a BAC transgenic mouse model expressing a Flox-Stop 2HA-PC1-CTT inserted in the Rosa26 locus and crossed it with the inducible Pax8rtTA; TetO-Cre; Pkd1fl/fl ADPKD mouse model. Induction of this second-generation mouse model (PC1-CTT; Pax8rtTA; TetO-Cre; Pkd1fl/fl on the C57BL6N mouse strain background) with oral doxycycline from P28-P42 leads to re-expression of PC1-CTT in an ADPKD animal model that lacks full-length PC1. We show that expression of the PC1-CTT in this background produces dramatic effects on the cystic phenotype: PC1 KO mice that re-express PC1-CTT present a 2.5-fold decrease in kidney weight/body weight ratio (5.1% versus 13.1%, p=0.0006) and a 3.5-fold decrease in BUN (32.7mg/dL versus 109.9mg/dL, p=0.004) when compared to PC1 KO only mice.

Furthermore, we show that the BUN levels observed in these PC1-CTT expressing ADPKD mice are not significantly different from the levels observed in healthy wild-type (WT) control mice. Additionally, we show that this rescue of renal phenotype is related to a protein interaction between the PC1-CTT and the enzyme Nicotinamide Nucleotide Transhydrogenase (NNT). NNT is a mitochondrial detoxifying enzyme that is capable of modulating intracellular Redox homeostasis by using the mitochondrial proton gradient to catalyze the following reaction: NADH+NADP+<-> NAD++NADPH. We initially identified an interaction between full-length PC1 and NNT through mass spectrometry analysis and the interaction between PC1-CTT and NNT was confirmed by coimmunoprecipitation. We assessed the relevance of this protein interaction in terms of disease progression by crossing the same PC1-CTT; Pax8rtTA; TetO-Cre; Pkd1fl/fl mice with NNT-mutant C57BL6J mice, that differ from C57BL6N because of a deletion on the NNT gene resulting in the complete lack of NNT protein. We show that these animals do not exhibit an improved cystic phenotype as a consequence of PC1-CTT expression.

Moreover, we assess the degree of Redox imbalance between NAD+/NADH in in vitro and in animal ADPKD models and show that these PC1 KO models exhibit a 50% decrease in the NAD+/NADH ratio as compared to WT models. Furthermore, while the presence of functioning NNT is associated with increased NAD+/NADH in WT C57BL6N compared to C57BL6J, the presence of this protein and the consequent Redox modulation is not sufficient to rescue disease phenotype in the absence of PC1-CTT re-expression in the PC1 KO mice.

Finally, we conclude that the significant improvement in phenotype and the small size of the PC1-CTT protein fragment and its corresponding genetic sequence could potentially open the door for effective gene therapy for ADPKD.

Venkata Vivek Reddy Palicharla

UT Southwestern Medical Center

Saikat Mukhopadhyay

Mechanisms of Tulp3 mediated ciliary trafficking of cystogenic cargoes and therapeutic implications

Polycystic Kidney Disease (PKD) is characterized by the presence of multiple large cysts in kidneys. These cysts result in an abnormal increase in the size of the kidneys, ultimately leading to kidney failure. PKD is a potentially fatal disease affecting more than 600,000 Americans and over 12 million people worldwide. No efficient drugs are available to treat PKD. Therefore, it is important to do more research on PKD to develop better treatment strategies. The first step in this process is to understand how kidney cysts are formed. Cells in kidneys have small appendages called primary cilia which are involved in sensing the environment and regulating multiple cellular functions. Earlier research has implicated the involvement of cilia in PKD pathogenesis. Through our research, we aim to understand how protein transport into and out of the cilia regulates cyst formation and test if any of these processes can be of therapeutic potential.
Feng Qian

University of Maryland School of Medicine

Rebecca Walker, Qin Yao, Hangxue Xu, Patricia Outeda-Garcia, and Terry Watnick

Pkd1-Pkhd1 interaction during embryonic development via a mitochondria-dependent mechanism

PKD occurs in autosomal dominant ADPKD or recessive ARPKD forms, caused by mutations mainly in PKD1 (PC1) or PKHD1 (FC) respectively. PC1 cleavage at the GPS motif is required for its full biological function and is frequently disrupted by PKD1 mutations. Pkhd1 mutations in mice result in negligible renal disease, contrarily to what happens in ARPKD. To better understand the molecular mechanism of PKD pathogenesis, we performed genetic studies using a Pkd1 GPS-cleavage mutant and Pkhd1 mutant mice to test for their interaction and the role of PC1 cleavage. We found that Pkhd1 inactivation triggers severe early-onset renal and pancreatic cystogenesis in the absence of PC1 cleavage during embryonic development. This interaction operates for uncleaved PC1 and involves FC’s C-terminal region. We suggest that Pkhd1 mutation may confer a strong procystic state that significantly contributes to early-onset PKD through its C-terminal region by a mitochondria-dependent mechanism.
Harini Ramalingam

University of Texas Southwestern Medical Center

Patricia Cobo-Stark, Andrea Flaten, Chun-Mien Chang, Sachin Hajarnis, Ashwani Kumar, Mohammed Kanchwala, and Chao Xing, and Vishal Patel | UT Southwestern Medical Center

Sonu Kashyap, Kyaw Zaw Hein, Jorgo Lika, Gina M Warner, Jair M. Espindola-Netto, and Eduardo N. Chini | Mayo Clinic

A methionine-Mettl3-N6-methyladenosine axis promotes polycystic kidney disease

Autosomal Polycystic Kidney Disease (ADPKD) is a genetic disorder characterized by the growth of numerous cysts in the kidney. Currently, ADPKD is a leading cause of renal failure. Yet, we are at a paucity of successful therapeutic options.

Here, we have identified that a novel biochemical pathway called m6A-RNA methylation, is elevated in mouse and human ADPKD. The driver of this pathway, an enzyme named Mettl3 is also elevated, surprisingly, from a very early time point. Genetic hyper-activation of Mettl3 promotes cysts. Importantly, removing Mettl3 slows ADPKD and prolongs survival of ADPKD mice. The amino acid methionine is essential for Mettl3 activity. Interestingly, methionine is also increased in PKD and activates Mettl3. Importantly, methionine restriction in mouse diet slows their ADPKD progression. Finally, methionine restriction causes Mettl3 mediated inhibition of c-Myc and cAMP pathogenic signaling.

In conclusion, the methionine/Mettl3 pathway is an Achilles’ heel in ADPKD.

Takamitsu Saigusa

University of Alabama at Birmingham

Jifeng Huang, Jung-Shan Hsu, and Shinobu Yamaguchi

The role of animal vs plant based protein in immune response and cyst progression

This study demonstrates that consuming a high animal protein diet increases immune response in the kidney and accelerates cyst growth in PKD mice. Either consumption of a low protein diet or a high plant based diet mitigates both the immune response and cyst growth, indicating specific protein content plays a role in immune response and the rate of cyst growth.
Neil Shusterman

Palladio Biosciences

Lorenzo Pellegrini | Palladio Biosciences

Marie C. Hogan | Mayo Clinic

The Use of Lixivaptan in a Patient with ADPKD Who Previously Experienced Liver Toxicity with Tolvaptan

Tolvaptan is the only approved pharmacologic therapy for the treatment of ADPKD patients; however, it is associated with potentially serious liver side effects. Lixivaptan is a treatment under investigation for ADPKD patients similar to tolvaptan but thought to have less liver side effects based on models used to predict the liver side effects of drugs. We successfully treated a patient with ADPKD for 14 months with lixivaptan who no longer could take tolvaptan because of liver side effects. During that time there were no changes in liver chemistry tests. We are now studying lixivaptan in a larger study (PA-ADPKD-303: The ALERT Study; NCT04152837) of similar ADPKD patients who had to discontinue tolvaptan because of liver side effects.

Cortney Steele

University of Colorado Anschutz Medical Campus

Kristen Nowak, Victoria Catenacci, Wei Wang, Zhiying You, Kristen Bing, Marsha Miller, Berenice Gitomer, and Michel Chonchol | University of Colorado Anschutz Medical Campus

Timothy L Kline and Bhavya Poudyal | Mayo Clinic

Weight Loss to Slow Cyst Growth in ADPKD

We performed a one-year dietary feasibility study in 28 adults with ADPKD who were overweight or obese. Participants completed a behavioral weight loss intervention based on either daily caloric restriction (DCR, reducing calorie intake per day) or intermittent fasting (severely reducing calorie intake three days per week). Both had clinically significant weight loss, but it was greater in the DCR group at one-year. The DCR group also had better dietary tolerability and adherence. As compared to historic data, kidney growth as measured by magnetic resonance imaging (MRI) was slower than expected in both groups. Kidney growth was strongly related to change in weight and change in abdominal fat measured by MRI (i.e., those who lost the most weight and abdominal fat had the slowest growth of their kidneys). These results will be used to design a longer and larger trial looking specifically at kidney growth with DCR.

Sebastian Strubl

University of California, Santa Barbara

Sebastian Strubl, Jacob A. Torres, Jazmine Haratani, Morgan Decker, Sabrina Vuong, Amrit Kaur Bhandal, Nils Methot, Rhianna Haynie-Cion, and Thomas Weimbs | University of California Santa Barbara

Simon Oehm, Franziska Meyer, Florian Siedek, Roman-Ulrich Müller, and Franziska Grundmann | University of Cologne

Ketogenic Dietary Interventions in ADPKD- Feasibility, Safety and Effects: A Clinical Case Series Study

Our laboratory recently showed that nutritional ketosis induced by ketogenic dietary interventions (KDIs) slows disease progression in PKD animal models. This clinical case series study represents the first step to translate those findings into the human setting. Data of 131 PKD patients who have tried KDIs outside clinical trials suggest that KDIs are feasible and safe for PKD patients. PKD patients seem to benefit from KDIs as the majority reported improvements in overall well-being, PKD-associated health issues, weight, and hypertension. Thus, this study suggests that KDIs may indeed be beneficial in PKD patients. Prospective clinical trials are warranted to confirm these results and assess safety and efficacy of KDIs in PKD.
Caroline R Sussman

Mayo Clinic

Heather L. Holmes,
Mohamed Addani,
Deema Anaam,
Diana Alzamareh,
Kevin L. Webb,
Harrison C. Gottlich,
Abdalla Modawi,
Nicole Ho,
Najma Mohamed,
Ella Rasmussen,
Kaleb Soehl,
Slobodan Macura,
Timothy Kline,
Michael F. Romero and
Vicente E. Torres

Examination of collagen as a quantifiable biomarker for research on early stage PKD

Kidney cells, like most cells, are supported by an extensive network of extracellular proteins called the extracellular matrix, much like bricks in a wall are held together by mortar. The major extracellular matrix protein is Collagen, and its increase is a hallmark of the fibrosis (scarring) that occurs with renal cyst development. Methods commonly used for detecting Collagen changes are relatively insensitive, making it unclear whether these changes precede cyst formation, as some studies suggest. If this is true, Collagen changes could be used as pre-cystic marker of PKD disease progression. This study examined a zebrafish model of PKD with a pkd2 mutation and showed that Collagen changes in the kidney occurred in the absence of cysts. Two different methods of quantifying Collagen characteristics were validated in cystic mouse Pkd1 mutant and patient samples, thereby showing promise for future studies allowing more sensitive evaluation of pre-cystic Collagen changes.
Jacob Torres

University California Santa Barbara

David Asplund, Tselmeg Amarlkhagva, Shagun Agrawal,
Bradley Kroes, and Thomas Weimbs

A combination of BHB and citrate ameliorates disease progression in a rodent model of PKD

Recently, our lab reported that dietary interventions to induce ketosis ameliorate disease progression in PKD animal models, and that this effect involves the natural ketone beta-hydroxybutyrate (BHB). Additionally, we have recently shown that renal microcrystals exacerbate disease progression in PKD models. Crystal burden can be minimized by administering citrate. We now show that a combination of citrate and BHB effectively inhibits PKD progression. These two compounds act on separate mechanisms to control disease progression and the combination of the two display synergistic effects on preventing cyst formation and cyst growth in young rats. In adult rats, the combination treatment leads to a partial reversal of existing renal cystic disease. This synergistic effect enables treatment with lower doses of citrate and BHB while maintaining the full beneficial effect. Both, citrate and BHB, are dietary supplements with minimal side effects. Our results suggest a highly feasible strategy for supporting kidney health in PKD.

Christopher J Ward

University of Kansas Medical Center

Wendy A lea

A high throughput urine based method for diagnosing and following polycystic kidney disease

Polycystic kidney disease is a genetic disease that results in renal failure, however, there are effective treatments that slow the development of the disease, for example, Tolvaptan (Samsca). It is best that treatment is applied early in the disease process before there is significant renal damage. This can be achieved if the mutation in a pedigree is known but unfortunately, this is often not the case as mutation detection in the PKD1 gene is technically difficult. We are developing a urine based test that can be used to diagnose the disease in an affected family and perhaps monitor the disease while it is being treated.
Owen M. Woodward

University of Maryland School of Medicine

Eryn E. Dixon, Victoria L. Halperin Kuhns, Owen M. Woodward, and Terry J. Watnick | University of Maryland School of Medicine

Paul A. Welling | Johns Hopkins University School of Medicine

Mechanisms of cystogenesis in ADPKD

We have developed a new 3D tubuloid model system for studying morphological, protein, and gene expressions changes that occur after acute loss of polycystins in an effort to better understand the initiating steps of cystogenesis. We found inactivation of the Pkd2 gene and loss of the PC2 protein causes the tubuloids to changes shape to a more cystic morphology and these morphological changes correlate with a distinct set of genes differentially regulated, with many of these genes associated with functions in the cell junctions and matrix interactions.

Oral presentation summaries

Hear the presentations during the Research session breakout on Saturday, June 26 at 2:45 p.m.

Alexandra Hayward

The University of Chicago

Rita McGill, Milda Saunders, and Arlene Chapman | UChicago Medicine

Oral presentation summary

Polycystic kidney disease (PKD) is the most common inherited kidney disease with renal failure occurring in the sixth decade. Preemptive planning for kidney transplantation and home dialysis is possible. We postulated that advance awareness of kidney disease mitigated racial disparities in kidney care. We investigated the impact of race, ethnicity, sex, and socioeconomic status on age at kidney failure and access to kidney transplantation in the US. We found that African American and Hispanic patients reached kidney failure 2.3 and 4.4 years earlier than Caucasian patients, respectively. We also found that African American and Hispanic patients were 68% and 54% less likely to receive a preemptive kidney transplant than Caucasian patients, respectively. Private insurance, employment status, geography, and sex significantly affected PKD outcomes in the US. Further work is needed to clarify why these disparities exist and what can be done to fix them.
Harrison Kim

The University of Alabama at Birmingham

Alan C. Yu | Kansas University Medical Center

Arlene B. Chapman | University of Chicago

Vicente E. Torres and Peter C. Harris | Mayo Clinic

Frederic F. Rahbari-Oskoui | Emory University

Kyong Tae Bae and Douglas P. Landsittel | University of Pittsburgh

William M. Bennett | Legacy Good Samaritan Hospital

Michal Mrug | University of Alabama at Birmingham

Oral presentation summary

Total kidney volume has been used as an indicator of autosomal dominant polycystic kidney disease (ADPKD) severity. However, its accuracy in predicting ADPKD activity may be suboptimal in the early stage of the disease. Also, since total kidney volume increases relatively slowly over time, it may take several years to determine whether ADPKD is favorably responding to therapy. Therefore, we sought an alternative to monitor the early activity of ADPKD. We tracked the changes in volumes of individual kidney cysts over time and noted that these changes are variable over time. We have developed new computer software to monitor these changes. We suggest that the pattern of individual cyst-volume change may serve as a better indicator of early ADPKD activity. We have demonstrated the feasibility of this approach with a small group of ADPKD patients.
Cynthia Sieben

Mayo Clinic

Elizabeth K. Dillinger, Vladimir G. Gainullin,, Christina M. Heyer, Michael R. Hinten, Ka Thao, Ines Sturmlechner, and Peter C. Harris

Oral presentation summary

Comparative PKD1 and PKD2 missense variant profiling aids molecular diagnoses across the ADPKD phenotypic spectrum and reveals common pathomechanisms
Autosomal dominant polycystic disease (ADPKD) patients develop fluid-filled kidney cysts, which continually expand, often leading to kidney failure. Disease severity varies widely, from mild cystic kidney disease into old age without renal failure, to severe cystic disease and neonatal death. Typical ADPKD impacts adults, and results from inheritance of one pathogenic variant in the PKD1 or PKD2 genes. Whereas, rarer, severe forms, typically result from inheritance of two pathogenic variants (one from each parent). Given the vast number of pathogenic variants causing ADPKD, and the volume of data obtained from global sequencing approaches, determining the effect/significance of specific variants is difficult. Here, we developed a human kidney cell screening method to assess the damaging effect of PKD1 and PKD2 variants. This analysis can improve molecular diagnoses and prognostics, and aid in determining which features/functions of the PKD1 and PKD2 genes are perturbed, potentially allowing for the development of targeted therapies.

Page last reviewed May 2021

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