Autosomal Dominant Polycystic Kidney Disease Patient Research Articles

Global analysis of urinary extracellular vesicle small RNAs in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent monogenic renal disease progressing to end-stage renal disease. There is a pressing need for the identification of early ADPKD biomarkers to enable timely intervention and the development of effective therapeutic approaches. Here, we profiled human urinary extracellular vesicles small RNAs by small RNA sequencing in patients with ADPKD and compared their differential expression considering healthy control individuals to identify dysregulated small RNAs and analyze downstream interaction to gain insight about molecular pathophysiology. This is a cross-sectional study where urine samples were collected from a total of 23 PKD1-ADPKD patients and 28 healthy individuals. Urinary extracellular vesicles were purified, and small RNA was isolated and sequenced. Differentially expressed Small RNA were identified and functional enrichment analysis of the critical miRNAs was performed to identify driver genes and affected pathways. miR-320b, miR-320c, miR-146a-5p, miR-199b-3p, miR-671-5p, miR-1246, miR-8485, miR-3656, has_piR_020497, has_piR_020496 and has_piR_016271 were significantly upregulated in ADPKD patient urine extracellular vesicles and miRNA-29c was significantly downregulated. Five 'driver' target genes (FBRS, EDC3, FMNL3, CTNNBIP1 and KMT2A) were identified. The findings of the present study make significant contributions to the understanding of ADPKD pathogenesis and to the identification of novel biomarkers and potential drug targets aimed at slowing disease progression in ADPKD.

Heterozygosity of ALG9 in Association with Autosomal Dominant Polycystic Liver Disease.

α-1,2-mannosyltransferase (ALG9) germline variants are linked to autosomal dominant polycystic kidney disease (ADPKD). Many individuals affected with ADPKD possess polycystic livers as a common extrarenal manifestation. We performed whole exome sequencing in a female with autosomal dominant polycystic liver disease (ADPLD) without kidney cysts and established the presence of a heterozygous missense variant (c.677G>C p.(Gly226Ala)) in ALG9. In silico pathogenicity prediction and 3D protein modeling determined this variant as pathogenic. Loss of heterozygosity is regularly seen in liver cyst walls. Immunohistochemistry indicated the absence of ALG9 in liver tissue from this patient. ALG9 expression was absent in cyst wall lining from ALG9- and PRKCSH-caused ADPLD patients but present in the liver cyst lining derived from an ADPKD patient with a PKD2 variant. Thus, heterozygous pathogenic variants in ALG9 are also associated with ADPLD. Somatic loss of heterozygosity of the ALG9 enzyme was seen in the ALG9 patient but also in ADPLD patients with a different genetic background. This expanded the phenotypic spectrum of ADPLD to ALG9.

Immune checkpoint activity regulates polycystic kidney disease progression.

Innate and adaptive immune cells modulate the severity of autosomal dominant polycystic kidney disease (ADPKD), a common kidney disease with inadequate treatment options. ADPKD has parallels with cancer, in which immune checkpoint inhibitors have been shown to reactivate CD8+ T cells and slow tumor growth. We have previously shown that in PKD, CD8+ T cell loss worsens disease. This study used orthologous early-onset and adult-onset ADPKD models (Pkd1 p.R3277C) to evaluate the role of immune checkpoints in PKD. Flow cytometry of kidney cells showed increased levels of programmed cell death protein 1 (PD-1)/cytotoxic T lymphocyte associated protein 4 (CTLA-4) on T cells and programmed cell death ligand 1 (PD-L1)/CD80 on macrophages and epithelial cells in Pkd1RC/RC mice versus WT, paralleling disease severity. PD-L1/CD80 was also upregulated in ADPKD human cells and patient kidney tissue versus controls. Genetic PD-L1 loss or treatment with an anti-PD-1 antibody did not impact PKD severity in early-onset or adult-onset ADPKD models. However, treatment with anti-PD-1 plus anti-CTLA-4, blocking 2 immune checkpoints, improved PKD outcomes in adult-onset ADPKD mice; neither monotherapy altered PKD severity. Combination therapy resulted in increased kidney CD8+ T cell numbers/activation and decreased kidney regulatory T cell numbers correlative with PKD severity. Together, our data suggest that immune checkpoint activation is an important feature of and potential novel therapeutic target in ADPKD.

Current Challenges and Perspectives on Developing a Clinical Trial Design for ADPKD.

Current Challenges and Perspectives on Developing a Clinical Trial Design for ADPKD.

A common intronic single nucleotide variant modifies PKD1 expression level.

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in PKD1 and PKD2 (PKD1/2), has unexplained phenotypic variability likely affected by environmental and other genetic factors. Approximately 10% of individuals with ADPKD phenotype have no causal mutation detected, possibly due to unrecognized risk variants of PKD1/2. This study was designed to identify risk variants of PKD genes through population genetic analyses. We used Wright's F-statistics (Fst) to evaluate common single nucleotide variants (SNVs) potentially favored by positive natural selection in PKD1 from 1000 Genomes Project (1KG) and genotyped 388 subjects from the Rogosin Institute ADPKD Data Repository. The variants with >90th percentile Fst scores underwent further investigation by in silico analysis and molecular genetics analyses. We identified a deep intronic SNV, rs3874648G> A, located in a conserved binding site of the splicing regulator Tra2-β in PKD1 intron 30. Reverse-transcription PCR (RT-PCR) of peripheral blood leukocytes (PBL) from an ADPKD patient homozygous for rs3874648-A identified an atypical PKD1 splice form. Functional analyses demonstrated that rs3874648-A allele increased Tra2-β binding affinity and activated a cryptic acceptor splice-site, causing a frameshift that introduced a premature stop codon in mRNA, thereby decreasing PKD1 full-length transcript level. PKD1 transcript levels were lower in PBL from rs3874648-G/A carriers than in rs3874648-G/G homozygotes in a small cohort of normal individuals and patients with PKD2 inactivating mutations. Our findings indicate that rs3874648G > A is a PKD1 expression modifier attenuating PKD1 expression through Tra2-β, while the derived G allele advantageously maintains PKD1 expression and is predominant in all subpopulations.

Polycystic kidneys: Genetic testing and correct classification clinically and therapeutically of increasing significance

Cystic kidney disease is a clinically and genetically diverse group of diseases, with more than 100 genes known to date. One in 500 is affected worldwide, mostly due to a malfunction of cilia. New genes have been identified recently for the most common form autosomal dominant polycystic kidney disease (ADPKD). Every fourth ADPKD patient is lacking a positive family history (mostly due to a de novo mutation); in these cases remaining family members can be relieved. Differentiation of entities just based on clinical and imaging data is often most challenging. However, an accurate classification is significant for the patient and family. Associated comorbidities and cross-organ complications can be detected early and targeted screening and monitoring can be facilitated. Relatives also benefit from an accurate and early diagnosis. Precise genetic counselling with indication of risks is only possible by knowing the concise disease genotype. Genetic diagnostics is becoming increasingly important in this context and in terms of risk stratification and drug-therapeutic options. The understanding of genotype-phenotype correlations has improved significantly in recent years. Wet and dry lab processes as well as the interpretation of genetic data for ADPKD require a high level of expertise. Differential diagnoses with mutations in other genes underlie patients with "ADPKD" or ADPKD-like phenotypes much more frequently than usually assumed. Due to the number and complexity of genes that need to be considered, a tailored NGS (Next Generation Sequencing) approach using a customized, well-balanced multi-gene panel is cost-effective and currently the method of choice. Differences in the quality of laboratories must be taken into account. With this, the genetic etiology and underlying mutation(s) can be found in most cases.

MO015: The Interaction of Gender and Genotype in the Development of Polycystic Liver Disease in ADPKD

Abstract BACKGROUND AND AIMS Liver cysts are the most common extra-renal manifestation in autosomal dominant polycystic kidney disease (ADPKD) and polycystic liver disease (PLD) may result in significant morbidity in a proportion of patients. The major objective of this study was to investigate the relationship between the incidence of liver cysts and PLD with age, gender and genotype in a longitudinal ADPKD patient cohort (n = 625) followed up between 2010 and 2021. METHOD A retrospective analysis of PLD was performed on all patients with available abdominal US (US, n = 565) or abdominal MRI/CT (n = 321) imaging. Liver cyst counts were obtained from routine clinical reports (US) or quantified by a single-blinded observer (MR/CT). Patients were divided into subgroups of different severity based on cyst numbers detected on US (QIAN 0–4) or MRI/CT (CHEN 0–3): QIAN 0 (0), 1 (<10), 2 (10–20), 3/4 (>20); CHEN 0 (0), 1 (<20), 2 (21–40), 3 (>40). Patients who were genotyped (n = 390) were classified into those with PKD1 (T, truncating or NT, non-truncating), PKD2, other genes (non-PKD1 or PKD2) or NMD (no mutation detected). The potential influence of genotype and gender on the incidence of liver cysts and the time to the development of PLD (defined as QIAN 3/4 or CHEN 3) was investigated by survival analysis (Kaplan–Meier plots). Hazard ratios (HR) were calculated and statistical significance was determined via Log-rank (Mantel-Cox) or Chi-square tests. RESULTS Liver cysts were detected in 61% of patients by US and 72% by MRI/CT, increasing with age. Kaplan–Meier plots showed a significant effect of gender for the presence of liver cysts (M: F HR of 0.74 US, 0.69 MR/CT). Genotype had a major effect on the prevalence of liver cysts (US, n = 344) with a median age of 46, 53, 59, 75 and 77 years for PKD1-T, PKD1-NT, PKD2, other genes or NMD, respectively. A similar trend was noted for patients with MR/CT imaging. The percentage of patients with PLD (QIAN 3/4 or CHEN 3) ranged between 26% (US) and 36% (MR/CT) with a median age for developing PLD of 51 (US; min-max range 23–80 years) and 50 years (MR/CT; min-max range 27–81 years), respectively. The incidence of PLD was more strongly influenced by gender (M: F HR 0.53 US, 0.56 MR/CT) and was highly enriched in patients with PKD1 or PKD2 mutations. CONCLUSION Female patients with a PKD1-T genotype appear to be at the highest risk of developing PLD. Genotypes other than PKD1 or PKD2 are unlikely to develop PLD. Further work is needed to improve risk stratification and treatments for PLD by identifying additional pathogenic factors.

Transcriptomic and metabolic profiling of Tolvaptan treated Autosomal dominant polycystic kidney disease (ADPKD) patient

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is the most common and life‐threatening genetic kidney disease that characterized by the aberrant renal tubule epithelial cells proliferation leads to the formation of multiple fluid‐filled cysts, and most of the ADPKD patient will leads to kidney failure by age of 50. Currently, dialysis or a transplant are the only treatments for end‐stage ADPKD patients. Tolvaptan is a is a selective vasopressin V2‐receptor antagonist which was used to treat hyponatremia in heart failure but was approved by FDA for ADPKD treatment in 2018. However, there are limitations for ADPKD patients to receive Tolvaptan treatment and significant side effects severely affect patient’s life quality. In our study, a 34‐year‐old man was diagnosed with familial ADPKD. He had cysts in kidney (Mayo class 1c) and liver and showed no symptoms other than hypertension. His baseline eGFR was 76.98 ml/min/1.732mg/dL but declined to 57.02 ml/min/1.732mg/dL two years after his first diagnosis, and there was an increase in number and size of the cysts due to the rapidly progressive ADPKD. Tolvaptan was started with the 45‐0‐15 dose and the patient was well‐tolerated. After 60 days of treatment, the renal function dramatic improved (73.02 ml/min/1.732mg/dL). With the titrate to 60‐0‐30 dose of tolvaptan, his eGFR maintains above than 60 ml/min/1.732mg/dL more than 3 months until present.MethodInformation of transcriptome and metabolome has significantly contributed to identifying potential therapeutic targets for the management of diseases. In our study, we collect his blood and urine before Tolvaptan treatment and 2 and 3 months after Tolvaptan treatment for transcriptomic and metabolic profiling. Total RNA was extracted using Trizol® Reagent (Invitrogen, USA) according to the manual. cDNA libraries were prepared by SureSelect XT HS2 mRNA Library Preparation kit (Agilent, USA) and sequenced on Nextseq. Differential expression analysis was performed using StringTie and DEseq2 with genome bias detection/correction using Welgene Biotech's in‐house pipeline. Genes with p value < 0.05 and > 2.0‐fold changes were considered significantly differentially expressed, and functional enrichment assay in differentially expressed genes of each experiment design was performed using clusterProfiler v3.6.ResultsOur data indicates that tight junction proteins (Log2 ratio: CRB3, 11.01; CLDN10, 10.09; MAPK10, 7.34), cytoskeleton regulating proteins (Log2 ratio: FGF17, 9.47; MYH14, 7.04) which also genes involved in the regulation of calcium and MAPK signaling and following focal adhesion proteins were significantly (p<0.05) preserved after 3 months Tolvaptan treatment. Furthermore, Hypoxanthine, Creatine, L‐a‐aminobutyric acid and Trimethylamine N‐oxide were significantly decreased in our metabolomics data analysis which is also indicates the inhibition of paracellular transportation in kidney epithelial/endothelial cells.ConclusionOur data indicates a potential molecular mechanism of Tolvaptan treatment in regulating the integrity of tight junction and kidney cells, and provides novel therapeutic targets in in ADPKD.

EP087: Identification of an apparently de novo PKD1 variant in a patient with polycystic kidneys, renal angiomyolipoma, and lymphangioleiomyomatosis

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic kidney diseases with a prevalence of approximately 1 in 1,000. Variants in multiple genes are known to cause this clinical phenotype including PKD1 (most common), PKD2, GANAB, and DNAJB11. While generally inherited, approximately 10% of ADPKD cases are caused by a de novo variant. Here we describe a case of an apparently de novo PKD1 variant identified in an ADPKD patient with unusual features through consultation with clinical genetics at an academic medical center.

Antioxidant enzyme peroxiredoxin 5 regulates cyst growth and ciliogenesis via modulating Plk1 stability.

Oxidative stress is emerging as a contributing factor to the homeostasis in cystic diseases. However, the role antioxidant enzymes play in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) remains elusive. Peroxiredoxin 5 (Prdx5) is an antioxidant enzyme that catalyzes the reduction of H2 O2 and alkyl hydroperoxide and plays an important role in different biological processes. In this study, we show that Prdx5 is downregulated in a PKD mutant mouse model and ADPKD patient kidneys. Knockdown of Prdx5 resulted in the formation of cysts in a three-dimensional mouse inner medullar collecting duct (IMCD) cell Matrigel culture system. The mechanisms of Prdx5 deficiency mediated cyst growth include: (1) induction of oxidative stress as indicated by increased mRNA expression of heme oxygenase-1, an oxidant stress marker; (2) activation of Erk, S6 and mTORC1, which contribute to cystic renal epithelial cell proliferation and cyst growth; (3) abnormal centrosome amplification and multipolar spindle formation which result in genome instability; (4) upregulation of Polo-like kinase 1 (Plk1) and Aurora kinase A, important mitotic kinases involved in cell proliferation and ciliogenesis; (5) impaired formation of primary cilia in mouse IMCD3 and retinal pigment epithelial cells, which could be rescued by inhibiting Plk1 activity; and (6) restraining the effect of Wnt3a and Wnt5a ligands on primary cilia in mouse IMCD3 cells, while regulating the activity of the canonical and non-canonical Wnt signaling in a separate cilia independent mechanism, respectively. Importantly, we found that targeting Plk1 with its inhibitor, volasertib, delayed cyst growth in Pkd1 conditional knockout mouse kidneys. Together, these findings indicate that Prdx5 is an important antioxidant that regulates cyst growth via diverse mechanisms, in particular, the Prdx5-Plk1 axis, and that induction and activation of Prdx5, alone or together with inhibition of Plk1, represent a promising strategy for combatting ADPKD.

Autosomal dominant polycystic kidney disease: possibly the least silent cause of chronic kidney disease.

Pain is the highest prioritized patient-reported outcome in people with autosomal dominant polycystic kidney disease (ADPKD) but it remains infrequently and inconsistently measured across countries, studies and trials. The study by El-Damanawi et al. integrated a network of ADPKD expert clinicians, pain specialists, researchers and patient representatives from the national UK PKD charity, with the aim of addressing the lack of validated ADPKD-specific pain assessment tools (APATs). The APAT designed by the authors included several pain measurement tools and was tested in ADPKD patients, although further validation through assessment in larger cohorts is needed. Establishing a standardized instrument for pain measurement will ensure that pain is measured and reported in a consistent way to inform decision-making and identify effective interventions aimed at managing pain and minimizing the impact pain has on patients with ADPKD. In this context, the APAT established by the authors is to be warmly welcomed.

Generation of human induced pluripotent stem cell line (MUi026-A) from a patient with autosomal dominant polycystic kidney disease carrying PKD1 point mutation

Autosomal dominant polycystic kidney disease (ADPKD) is one of the common genetic kidney disorders that are caused by mutations in PKD1 or PKD2 gene. In this report, the MUi026-A human induced pluripotent stem cell (hiPSC) line was established from the skin fibroblasts of a female ADPKD patient who had the PKD1 mutation with c.5878C > T. The iPSC line retained normal karyotype. The cells displayed embryonic stem cell-like characteristics with pluripotency marker expression and were able to differentiate into three germ layers.

P0043SYMPTOMS IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE: FINDINGS FROM QUALITATIVE PATIENT INTERVIEWS

Abstract Background and Aims Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) experience various symptoms due to increasing kidney volume and its associated complications. To understand symptom burden, qualitative interviews were conducted to characterize the ADPKD patient experience pertaining to the most common and disturbing symptoms. Method Combined concept elicitation and cognitive debriefing interviews were performed by trained interviewers following a preliminary conceptual model based on a targeted literature review. We currently report on the concept elicitation component, which explored relevant and bothersome symptoms in ADPKD patients, due to either the disease or associated treatments. Nineteen telephone interviews were conducted in four waves of 5, 4, 6, and 4 patients, respectively. Results The mean age of patients was 47 years (SD: 9 years); 68% (n=13) were female, and the mean estimated glomerular filtration rate (eGFR) was 41 ml/min/1.73m2 (SD: 25 ml/min/1.73m2), with the majority 47% (n=9) in stage 3 chronic kidney disease (CKD). The classes of treatments included antihypertensives (74%, n=14), vasopressin receptor antagonists (21%, n=4); diuretics (16%, n=3), analgesics (16%, n=3) and erythropoietin (5%, n=1). The most frequently mentioned symptoms were fatigue (89%, n=17), pain (84%, n=16), and nocturia (74%, n=14); all were considered at least moderately disturbing to patients’ lives. Most patients experienced constant fatigue (74%, n=14) that worsened over time. Patients’ descriptions of pain were variable, including back and side pain, severe cystic pain, and muscle pain; a few patients also mentioned shoulder pain, or pain due to kidney stones. Among patients reporting nocturia (n=14), about half (57%, n=8) rated nocturia on the upper end of the disturbance scale, regardless of number of voids per night, often accompanied by sleep disruption. While less frequently occurring, itchy skin, muscle cramping, abdominal swelling, and inability to eat were spontaneously mentioned among the most disturbing symptoms. Conclusion The novel component of this study is the significant disruption of nocturia in patients with ADPKD even in the absence of vasopressin receptor antagonist administration. In addition, it confirms the findings of the literature review and highlights the patient experience in ADPKD, most notably fatigue, nocturia, and pain as the most frequent and bothersome symptoms experienced by patients. Subjective evaluation of the ADPKD patient experience is critical to understand symptom severity and the burden of disease, to potentially quantify disease progression, and to assess the impact of emerging therapies.

Rene Policistico e trapianto di rene: accesso alla lista d’attesa e post trapianto: risultati della ricerca

Polycystic kidney disease and kidney transplantation: access to waiting list and post-transplant Autosomal-dominant polycystic kidney disease (ADPKD) is the leading genetic cause of end-stage renal disease (ESRD) worldwide. The number of ADPKD patients who are listed for transplantation or receive a kidney transplant is continuously increasing over time. AIRP conducted a survey to investigate the ADPKD patient journey, meaning the personal experience and expectations of people regarding kidney transplantation as therapeutic option of end-stage renal failure. The survey was conducted on 381 people with ADPKD, using computer-assisted web interviewing (CAWI). The results confirm that there are problems that need to be addressed before listing an ADPKD patient for a kidney transplantation, namely the patient’s comorbidities, the complexity of pre-transplant assessments and the shortage of organs. Pre-emptive transplantation from cadaver donor is a rare event in our country but it is a valid option, especially in case of living donation. Immunosuppression is well tolerated in a high percentage of subjects, but a follow-up is necessary to monitor negative side effects. Despite these problems, the outcome of kidney transplantation is optimal in these patients. Also, the relationship between patients and Nephrologists and/or Transplant Centers is important to ensure a positive outcome.

Il paziente con rene policistico negli ambulatori italiani

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease. PKD is a multisystem disorder associated with multiple bilateral renal cysts, slowly increasing kidney size and progressive chronic kidney disease. Approximately 50% of individuals with PKD will require renal replacement therapy by the sixth decade of life. More than 80% will also have multiple liver cysts, which can lead to local pressure effects. Cerebral haemorrhage, secondary to rupture of a berry aneurysm, occurs in up to 8% of individuals. Mitral valve prolapse occurs in up to 25% of patients. Patients with ADPKD have a worsening in the quality of life and a burden of disease similar to cancer patients. The quality of correct information given to patients and a warm reception have a positive impact on patients with ADPKD and contribute to an efficacious treatment program. AIRP conducted a survey to investigate the ADPKD patient journey, meaning the personal experience and expectations of people regarding factors such as disease management, relationships with the nephrologists and their team, and therapies. The survey was conducted on 370 people with ADPKD, using computer-assisted web interviewing (CAWI). The results show that patients with ADPKD with a good relationship with their care team, both nephrologist and nurse, respond better to therapies. Warm reception, dialogue, communication, support, clear explanation, reassurance and guidance altogether contribute to a successful treatment of every single person with ADPKD.

Primary cardiac manifestation of autosomal dominant polycystic kidney disease revealed by patient induced pluripotent stem cell-derived cardiomyocytes.

BackgroundMutations in PKD1 or PKD2 gene lead to autosomal dominant polycystic kidney disease (ADPKD). The mechanism of ADPKD progression and its link to increased cardiovascular mortality is still elusive.MethodsWe differentiated ADPKD patient induced pluripotent stem cells (iPSCs) to cardiomyocytes (CMs). The electrophysiological properties at the cellular level were analyzed by calcium imaging and whole cell patch clamping.FindingsThe ADPKD patient iPSC-CMs had decreased sarcoplasmic reticulum calcium content compared with Control-CMs. Spontaneous action potential of the PKD2 mutation line-derived CMs demonstrated slower beating rate and longer action potential duration. The PKD1 mutation line-derived CMs showed a comparable dose-dependent shortening of phase II repolarization with the Control-CMs, but a significant increase in beating frequency in response to L-type calcium channel blocker. The PKD1-mutant iPSC-CMs also showed a relatively unstable baseline as a greater percentage of cells exhibited delayed afterdepolarizations (DADs). Both the ADPKD patient iPSC-CMs showed more β-adrenergic agonist-elicited DADs compared with Control-CMs.InterpretationCharacterization of ADPKD patient iPSC-CMs provides new insights into the increased clinical risk of arrhythmias, and the results enable disease modeling and drug screening for cardiac manifestations of ADPKD.FundMinistry of Science and Technology, National Health Research Institutes, Academia Sinica Program for Technology Supporting Platform Axis Scheme, Thematic Research Program and Summit Research Program, and Kaohsiung Medical University Hospital, Taiwan.

PCP7 - The European ADPKD Forum (EAF): Translating Science into Policy to Improve ADPKD Patient Care in Europe

To demonstrate the long-term impact of implementing an international, multidisciplinary, expert working-group; dedicated to translating scientific and clinical advances into policy, to improve health and quality of life of people living with autosomal dominant polycystic kidney disease (ADPKD). Between 2013-2018 leading patient advocates, healthcare professionals and academics, representing nephrology, hepatology and genetics, have come together as the EAF, to develop policy-focused approaches to address unmet needs in ADPKD care in Europe. Focusing on low-level disease awareness amongst policymakers, practitioners and payers; variations in care; and absence of approved treatment options; the EAF has engaged with patient advocacy organisations and professional society representatives through publications, multi-stakeholder policy-events, conference activities, media releases (press, social, video), targeted communications and advocacy toolkits. The EAF Report and Brussels Declaration on ADPKD (co-published with PKD International and EGAN. 2015) provides strategic, policy-focused recommendations empowering stakeholders to become active partners in healthcare, policymaking, service design and research. Endorsed by 32 national and international societies they informed multiple national ADPKD collaborations. The Multidisciplinary Position Statement on ADPKD Care (Nephrol Dial Transplant. 2017) advocates for holistic patient-centered care services, referencing EU policy initiatives and achieving strong impact metrics. The ADPKD Patient Route Map (2018) enables patients to navigate their ADPKD services and provides checklists for self-management enhancing shared and informed decision-making. The EAF has provided a collaborative platform for clinical experts and patient advocates to raise awareness and develop impactful policy-focused recommendations, together with communications and tools designed to improve real-world patient care and empower patients. Multi-sector and multi-channel outreach has aided impact across clinical, academic, patient and policy-making communities. Advances in ADPKD services have included establishment of additional specialist centers and the European Reference Network for Rare Kidney Diseases, both advocated for by the EAF Report. However, variations in ADPKD services remain across Europe and warrant further work.

PSY24 - Impact of Autosomal Dominant Polycystic Kidney Disease (ADPKD) on Caregivers and Families

Autosomal dominant polycystic kidney disease (ADPKD) is a rare, dominantly inherited systemic disease resulting in gradual kidney enlargement and kidney failure over time. Commonly, multiple members of a family across several generations are affected by the disease and often patients with ADPKD also function as caregivers for other family members. This study explored the burden experienced by caregivers for patients with ADPKD. Focus groups with 139 caregivers for patients with ADPKD in 14 countries (Argentina, Australia, Brazil, Canada, China, Czech Republic, Hungary, Japan, Poland, Romania, South Korea, Spain, Taiwan, United States) using iterative, concept elicitation methodology to understand the impacts of caring for a patient with ADPKD. Caregivers for patients with ADPKD (66.9% female, 33.1% male) provide assistance with activities of daily living and emotional support. Furthermore, 25 caregivers (88% female, 12% male) were also diagnosed with ADPKD themselves, which elevated their burden. Almost all caregivers in the study provided care or support for immediate family members (94.8%) while a smaller percentage (2.9%) were assisting a distal relative or friend. Caregivers reported impacts on emotional (74.1%), social (38.5%), work/employment (26.6%), financial (23.7%), and physical (17.3%) aspects of their daily lives. There were slight differences in how caregivers in various regions emphasized impacts, and impacts varied depending on the disease stage of the ADPKD patient and the caregiver-patient relationship. Caregivers for patients reported substantial impacts on their daily lives which was globally consistent. Defining caregiver burden is essential to understanding ways of supporting the ADPKD population in the community.

A mutation affecting polycystin-1 mediated heterotrimeric G-protein signaling causes PKD.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the growth of renal cysts that ultimately destroy kidney function. Mutations in the PKD1 and PKD2 genes cause ADPKD. Their protein products, polycystin-1 (PC1) and polycystin-2 (PC2) have been proposed to form a calcium-permeable receptor-channel complex; however the mechanisms by which they function are almost completely unknown. Most mutations in PKD1 are truncating loss-of-function mutations or affect protein biogenesis, trafficking or stability and reveal very little about the intrinsic biochemical properties or cellular functions of PC1. An ADPKD patient mutation (L4132Δ or ΔL), resulting in a single amino acid deletion in a putative G-protein binding region of the PC1 C-terminal cytosolic tail, was found to significantly decrease PC1-stimulated, G-protein-dependent signaling in transient transfection assays. Pkd1ΔL/ΔL mice were embryo-lethal suggesting that ΔL is a functionally null mutation. Kidney-specific Pkd1ΔL/cond mice were born but developed severe, postnatal cystic disease. PC1ΔL protein expression levels and maturation were comparable to those of wild type PC1, and PC1ΔL protein showed cell surface localization. Expression of PC1ΔL and PC2 complexes in transfected CHO cells failed to support PC2 channel activity, suggesting that the role of PC1 is to activate G-protein signaling to regulate the PC1/PC2 calcium channel.

Identification of targets of IL-13 and STAT6 signaling in polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a life-threatening, highly prevalent monogenic disease caused by mutations in polycystin-1 (PC1) in 85% of patients. We have previously identified a COOH-terminal cleavage fragment of PC1, PC1-p30, which interacts with the transcription factor STAT6 to promote transcription. STAT6 is aberrantly active in PKD mouse models and human ADPKD, and genetic removal or pharmacological inhibition of STAT6 attenuates disease progression. High levels of IL-13, a STAT6-activating cytokine, are found in the cyst fluid of PKD mouse models and increased IL-13 receptors in ADPKD patient tissue, suggesting that a positive feedback loop exists between IL-13 and STAT6 is activated in cystic epithelial cells and contributes to disease progression. In this study, we aimed to identify genes aberrantly regulated by STAT6 to better understand how increased IL-13/STAT6 signaling may contribute to PKD progression. We demonstrate that the expression of periostin, galectin-3, and IL-24 is upregulated in various forms of PKD and that their aberrant regulation is mediated by IL-13 and STAT6 activity. Periostin and galectin-3 have previously been implicated in PKD progression. We support these findings by showing that periostin expression is increased after IL-13 treatment in kidney epithelial cells, that galectin-3 expression is increased after injecting IL-13 in vivo and that IL-24 expression is upregulated by both IL-13 treatment and PC1-p30 overexpression in mouse and human kidney cells. Overall, these findings provide insight into the possible mechanisms by which increased IL-13/STAT6 signaling contributes to PKD progression and suggest potential therapeutic targets.