Diagnosis Of Autosomal Dominant Polycystic Kidney Disease Research Articles

Abnormalities of IL-12 Family Cytokine Pathways in Autosomal Dominant Polycystic Kidney Disease Progression.

Background and Objectives: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most frequent genetic renal disease with a complex physiopathology. More and more studies sustain that inflammation plays a crucial role in ADPKD pathogenesis and progression. We evaluated IL-12 involvement in ADPKD pathophysiology by assessing the serum levels of its monomers and heterodimers. Materials and Methods: A prospective case-control study was developed and included 66 ADPKD subjects and a control group of 40 healthy subjects. The diagnosis of ADPKD was based on familial history clinical and imagistic exams. The study included subjects with eGFR > 60 mL/min/1.73 mp, with no history of hematuria or other renal disorders, with stable blood pressure in the last 6 months. We tested serum levels of monomers IL-12 p40 and IL-12 p35 and heterodimers IL-12 p70, IL-23, IL 35, assessed by ELISA method. Results: IL-12 family programming was abnormal in ADPKD patients. IL-12p70, IL-12p40, and IL-23 secretion increased, while IL-12p35 and IL-35 secretion decreased compared to control. IL-12p70, IL-12p40, and IL-23 had a progressive increase correlated with immune response amplification, a decrease of eGFR, an increase in TKV, and in albuminuria. On the other hand, IL-35 and IL-12p35 were correlated negatively with CRP and albuminuria and positively with eGFR in advanced ADPKD. Conclusions: The present study investigated IL-12 cytokine family members' involvement in ADPKD pathogenesis, enriching our understanding of inflammation in the most common renal genetic disorder.

Concomitant Wilms tumor and autosomal dominant polycystic kidney disease.

Concomitant Wilms tumor (WT) and autosomal dominant polycystic kidney disease (ADPKD) is exceedingly rare, presenting a diagnostic and technical challenge to pediatric surgical oncologists. The simultaneous workup and management of these disease processes are incompletely described. We performed a retrospective analysis of patients treated at our institution with concomitant diagnoses of WT and ADPKD. We also review the literature on the underlying biology and management principles of these conditions. We present three diverse cases of concomitant unilateral WT and ADPKD who underwent nephrectomy. One patient had preoperative imaging consistent with ADPKD with confirmatory testing postoperatively, one was found to have contralateral renal cysts intraoperatively with confirmatory imaging post nephrectomy, and one was diagnosed in childhood post nephrectomy. All patients are alive at last follow-up, and the patient with longest follow-up has progressed to end-stage kidney failure requiring transplantation and dialysis in adulthood. All patients underwent germline testing and were found to have no cancer predisposition syndrome or pathogenic or likely pathogenic variants for WT. Concomitant inheritance of ADPKD and development of WT are extremely rare, and manifestations of ADPKD may not present until late childhood or adulthood. ADPKD is not a known predisposing condition for WT. When ADPKD diagnosis is made by family history, imaging, and/or genetic testing before WT diagnosis and treatment, the need for extensive preoperative characterization of cystic kidney lesions in children and increased risk of post-nephrectomy kidney failure warrant further discussion of surgical approach and perioperative management strategies.

#2406 Echocardiographic characteristics of autosomal dominant polycystic kidney disease

Abstract Background and Aims Cardiovascular complications in patients with autosomal dominant polycystic kidney disease (ADPKD) are one of the most frequently investigated extrarenal manifestations. The results are many times contradictory. This is caused by a limited size of studied populations and high inter- and intrafamilial heterogeneity of ADPKD. Expanding knowledge of populations of patients from different regions and cohorts is crucial for improving the understanding and treatment of cardiovascular morbidity and mortality. This study aims to explore the prevalence of cardiovascular abnormalities in echocardiography and to analyze their relationships with clinical characteristics across different stages of CKD progression in patients with ADPKD. Method Sixty-eight patients were included in the study. All patients underwent transthoracic echocardiography with the use of GE Vingmed Ultrasound (GE Norway Health Tech, Oslo, Norway). Information about demography, prior medical history and taking antihypertension drugs was recorded. The results of creatinine, lipids and haemoglobin were collected. To diagnose the rapid progression of CKD, creatinine was sampled twice, in a one-year interval. Results Using different indicators of left ventricular hypertrophy (LVH), we found it in above 40% of ADPKD patients. A single associate of left ventricular mass was eGFR decline after one year of observation. Other highly prevalent findings were asymptomatic left ventricular diastolic dysfunction (ALVDD) (39%), left atrium (LA) enlargement (39%) and mild valvular regurgitations (80%). Ejection fraction, aortic root dimension, tricuspid annular plane systolic excursion (TAPSE) and prevalence of mitral valve prolapse were not importantly increased. Apart from age, the strong determinant of ALVDD diagnosis was the treatment with beta-blockers. Cardiac indices were not different across the eGFR stages. Conclusion LVH, LA enlargement, ALVDD and valvular regurgitations are characteristics of cardiac phenotype in ADPKD. Cardiac indices were not different across different stages of CKD pointing towards the diagnosis of ADPKD being main drive of their occurrence.

#1723 Genetic landscape of polycystic kidney disease in a Chinese cohort – experience using whole genome sequencing in a tertiary renal unit

Abstract Background and Aims Genetic testing has increasingly been employed to provide definitive diagnoses and prognostic information in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). We aim to explore the genetic landscape of ADPKD in a Chinese cohort utilizing whole genome sequencing and study its real-world clinical utility. Method From 1st January 2022 to 31st March 2023, we recruited 50 adult Chinese patients who had the clinical diagnosis of ADPKD followed up at Queen Mary Hospital and consented to the study protocol. The study was approved by the University Institution Review Board and local ethics committees. Genomic DNA was isolated from samples obtained from patients per standard protocol. Whole-genome sequencing was performed and analysed through the germline analysis pipeline. Diagnostic analysis was performed per American College of Medical Genetics (ACMG) guidelines and ClinGen variant curation expert panel specifications. Diagnostic variants were defined as those classified as ‘pathogenic’ or ‘likely pathogenic’. Potential clinical utility of genetic findings were studied case-by-case based on the Kidney Disease Improving Global Outcomes (KDIGO) 2023 Clinical Practice Guideline for the Evaluation, Management and Treatment of ADPKD. Results Among the 50 unrelated probands with ADPKD, half were males and the mean age at presentation was 38. 38% patients had incidental finding of kidney cysts on abdominal imaging performed for unrelated symptoms or health screening, 32% presented for screening due to positive family history and only 30% presented with typical symptoms of ADPKD. Cystic complications were present in 30%, with cyst haemorrhage being the most common, followed by kidney stones, cyst rupture and infection. 80% patients also had liver cysts and none had a history of cerebral aneurysms. The majority of our cohort (72%) had a family history of ADPKD. We identified diagnostic variants in 35 individuals, reaching a diagnostic yield of 70%. Diagnostic variants were identified in PKD1 (20/35), PKD2 (11/35), IFT140 (3/35) and ALG9 (1/35). The majority of diagnostic variants were protein-truncating (32/35), while non-truncating variants consisted of 1 in-frame deletion and 2 missense variants in PKD1. We identified 3 copy number variation:NC_000016.10:g.2110587_2111851del,NC_000016.10:g.2132339_2137621del,NC_000016.10:g.2036427_2101117del. The genetic findings allowed physicians to make definitive diagnosis in 9 patients with negative family history of ADPKD. The genetic findings provided important prognostic information as protein-truncating variants in PKD1 or PKD2 were associated with more severe disease compared to non-truncating variants. For the 3 patients harbouring heterozygous pathogenic variants in IFT140 (NM_014714.4:c.2659G>T, NM_014714.4:c.3780del, NM_014714.4:c.1035_1036del), they demonstrated a milder PKD phenotype with stable kidney function, normal kidneys size and absence of liver cysts 10 years after the diagnosis. The patient with heterozygous likely pathogenic ALG9 variant (NM_024740.2:c.1225del) also had milder PKD phenotype with normal kidney function and normal sized kidneys on USG 5 years after the diagnosis. In another male patient with young hypertension who was classified as Mayo Class 1C according to kidney imaging, identifying the pathogenic protein-truncating variant in PKD1 (NM_001009944.3:c.7288C>T) would render him eligible to tolvaptan treatment in view of the high PROPKD score (7). Furthermore, the genetic findings enabled an earlier diagnosis in a number of family members by cascade testing and genetic results were important to identify suitable living-related kidney donors. Conclusion Genetic testing utilizing whole genome sequencing has multiple clinical utility in ADPKD patients. It could provide a definitive diagnosis in those with atypical presentation or without family history, inform prognosis, guide treatment, determine living-related donor suitability and allow earlier diagnosis in other family members.

#339 Thyroid hormone levels critically contribute to ADPKD progression

Abstract Background and Aims Thyroid hormone (TH) signaling plays a crucial role in the regulation of the cell differentiation state, cell cycle and metabolism in various organs. Low TH levels are observed in most patients with chronic kidney disease, and correlate with cell de-differentiation and reactivation of the cell cycle. Despite this knowledge, possible alterations of TH signaling in Autosomal Dominant Polycystic Kidney Disease (ADPKD) and the capacity of TH to modulate anti-cystogenic and renoprotective pathways have not yet been studied. In this study we aimed to (i) investigate the role of TH signaling in the pathogenesis of ADPKD in patients and experimental models, and (ii) assess whether the pharmacological modulation of this pathway with TH (T3, T4) and TH analogs could arrest or reverse ADPKD progression. Method Ninety patients with a diagnosis of ADPKD based on renal ultrasonography findings or genetic testing were included in the study and divided into five subgroups of chronic kidney disease stages, according to the KDIGO classification. Serum TH was measured using ELISA and chemiluminescent immunoassays. The correlation between TH levels and renal function parameter (eGFR) in these patients was assessed using linear regression. 3D polycystic tubules were engineered from patient-derived cells as previously described (Benedetti et al. 2016). For the in vivo experiments, PCK rats—an animal model of ADPKD—were treated with T4 (10 μg/kg) or vehicle by gavage from 4 to 11 weeks of age. Age-matched SD rats were followed for the same length of time and used as controls. Results The analysis of patients’ data showed a strong linear correlation between the levels of FT3 and eGFR, and corresponding inverse correlation between rT3 (the inactivated form of T3) and eGFR. Treating patients-derived tubules with THs strongly inhibited cyst formation and growth. Interestingly, the results were validated in engineered polycystic tubules from three ADPKD patients with different mutations (missense, splice-site and stop-gain) in the PKD1 gene, further confirming that T4 plays an essential role in the cystogenesis and, presumably, progression of the disease in humans. Treating PCK rats—an animal model of ADPKD—with T4 resulted in a significant increase in T4 serum levels and a simultaneous reduction in the size of the macrocystic area compared to vehicle-treated PCK rats. Most importantly, T4 serum levels positively correlated with a reduction in both the size of the macrocystic area and loss of protein into the urine, indicating that TH signaling plays a role in the growth of cysts, and that exogenous T4 can slow down cystogenesis and improve renal function. Interestingly, our mechanistic studies revealed that T4 exerts its anti-cystogenic effects, at least partially, by binding to the membrane receptor αvβ3 and activating the MAPK cascade. Conclusion These results suggest that TH signaling plays a role in the progression of ADPKD and timely administration of T4, ideally at a relatively early stage of the disease, could delay progression or even reverse key clinical features of ADPKD.

Novel Potential Therapeutic Targets in Autosomal Dominant Polycystic Kidney Disease from the Perspective of Cell Polarity and Fibrosis.

Autosomal dominant polycystic kidney disease (ADPKD), a congenital genetic disorder, is a notable contributor to the prevalence of chronic kidney disease worldwide. Despite the absence of a complete cure, ongoing research aims for early diagnosis and treatment. Although agents such as tolvaptan and mTOR inhibitors have been utilized, their effectiveness in managing the disease during its initial phase has certain limitations. This review aimed to explore new targets for the early diagnosis and treatment of ADPKD, considering ongoing developments. We particularly focus on cell polarity, which is a key factor that influences the process and pace of cyst formation. In addition, we aimed to identify agents or treatments that can prevent or impede the progression of renal fibrosis, ultimately slowing its trajectory toward end-stage renal disease. Recent advances in slowing ADPKD progression have been examined, and potential therapeutic approaches targeting multiple pathways have been introduced. This comprehensive review discusses innovative strategies to address the challenges of ADPKD and provides valuable insights into potential avenues for its prevention and treatment.

Update on the Application of Ultrasonography in Understanding Autosomal Dominant Polycystic Kidney Disease.

With an estimated prevalence of 1 in 1000 individuals globally, autosomal dominant polycystic kidney disease (ADPKD) stands as the most prevalent inherited renal disorder. Ultrasonography (US) is the most widely used imaging modality in the diagnosis and monitoring of ADPKD. This review discusses the role of US in the evaluation of ADPKD, including its diagnostic accuracy, limitations, and recent advances. An overview of the pathophysiology and clinical manifestations of ADPKD has also been provided. Furthermore, the potential of US as a noninvasive tool for the assessment of disease progression and treatment response is examined. Overall, US remains an essential tool for the management of ADPKD, and ongoing research efforts are aimed at improving its diagnostic and prognostic capabilities.

Mutation Analysis of PKD1 and PKD2 Genes in a Large Italian Cohort Reveals Novel Pathogenic Variants Including a Novel Complex Rearrangement

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disease of the kidney. It occurs in adulthood but is also rarely diagnosed in early childhood. The majority of the disease-causing variants observed in ADPKD patients are in two genes: PKD1 and PKD2. Methods: 237 patients from 198 families with a clinical diagnosis of ADPKD were screened for PKD1 and PKD2 genetic variants using Sanger sequencing and multiple ligation-dependent probe amplification analysis. Results: Disease-causing (diagnostic) variants were identified in 173 families (211 patients), 156 on PKD1 and 17 on PKD2. Variants of unknown significance were detected in 6 additional families, while no mutations were found in the remaining 19 families. Among the diagnostic variants detected, 51 were novel. In ten families, seven large rearrangements were found and the molecular breakpoints of 3 rearrangements were identified. Renal survival was significantly worse for PKD1-mutated patients, particularly those carrying truncating mutations. In patients with PKD1 truncating (PKD1-T) mutations, disease onset was significantly earlier than in patients with PKD1 non-truncating variants or PKD2-mutated patients. Conclusions: Comprehensive genetic testing confirms its utility in diagnosing patients with ADPKD and contributes to explaining the clinical heterogeneity observed in this disease. Moreover, the genotype-phenotype correlation can allow for a more accurate disease prognosis.

Nutritional Status is Associated With Preserved Kidney Function in Patients With Autosomal Dominant Polycystic Kidney Disease

Malnutrition is a common complication in autosomal dominant polycystic kidney disease (ADPKD). We examined whether nutritional status is associated with the preservation of kidney function, using a cohort of typical ADPKD. We enrolled ambulatory ADPKD patients in 9 tertiary medical centers in Korea from May 2019 to December 2021. We excluded patients who were aged less than 18years, who had known end-stage kidney disease at the time of enrollment, who had a diagnosis of atypical ADPKD, and who were Tolvaptan users. The primary outcome was an estimated glomerular filtration rate (eGFR) decline >3mL/min/1.73m2, based on nutritional status assessed by subjective global assessment (SGA). We also evaluated an eGFR decline >1mL/min/1.73m2, an increase in urine protein-creatinine ratio (UPCR)>0, and an increase in UPCR >0.3 as secondary outcomes, based on SGA after the 1-year follow-up. A logistic regression (LR) model was used to calculate the odds ratio (OR) for the primary outcome. Because there were differences in several baseline variables, such as Mayo classification, serum hemoglobin, serum creatinine, and UPCR between SGA groups, we matched propensity scores. In total, 805 patients were prospectively enrolled. Among them, 236 patients who had 1-year follow-up data and typical imaging findings were analyzed to evaluate the effect of nutritional status on kidney function. SGA was used to assess the nutritional status. The mean age was 45.0±13.3years, and 49.6% of the patients were female. The mean eGFR was 81.9mL/min/1.73m2. Among the 236 patients, 91 (38.6%) experienced a 1-year eGFR decline >3mL/min/1.73m2. When a multivariable LR was applied, SGA 3-6 was identified as a significant factor related to a 1-year eGFR decline >3mL/min/1.73m2 (adjusted OR=1.22 [1.04-1.43]; P=.017). Despite matching propensity scores, the 1-year eGFR decline >3mL/min/1.73m2 was still higher in the SGA 3-6 group regardless of proteinuria. Good nutritional status is associated with better-preserved kidney function in non-obese typical ADPKD patients who do not take Tolvaptan.

Familial polycystic kidneys with no genetic confirmation: Are we sure it isADPKD?

Autosomal dominant polycystic kidney disease (ADPKD) is the most common heritable multifocal cystic disease encountered in clinical practice, and it is usually diagnosed in patients with family history by the evidence of markedly enlarged kidneys with multiple bilateral cysts at ultrasound (U.S.), computed tomography (CT) scan, or magnetic resonance imaging (MRI). In most cases, genetic testing is not required. Though ADPKD diagnosis is often straightforward, misdiagnosis is possible. Here we present a case of ADPKD misdiagnosis, followed by a review of the most important kidney heritable multifocal cystic diseases. Our case report demonstrates that ADPKD can be erroneously diagnosed when other kidney heritable multifocal cystic diseases occur without their distinguishing manifestations and when there is no genetic characterization among the relatives. A proper diagnosis of heritable diseases is crucial, as it allows an appropriate management of family members who carry disease allele, apart from patient management. Therefore, we suggest a careful differential diagnosis with possible molecular genetic analysis in presentations with familial cystic kidneys and suspicious clinical and radiological features.

Dual diagnosis of autosomal dominant polycystic kidney disease and sickle cell disease in a teenage male.

Sickle cell disease (SCD) and autosomal dominant polycystic kidney disease (ADPKD) are relatively common genetic conditions with considerable overlap in clinical presentation. In addition to similarities between the signs and symptoms in sickle cell nephropathy and ADPKD, more than half of SCD patients have kidney cysts. The co-occurrence of these two diseases has not been previously reported in the literature. A 16-year-old Black male with SCD had bilateral kidney enlargement and multiple simple cysts on ultrasound. Although kidney cysts are significantly more common in individuals affected with SCD, genetic testing with a broad kidney gene panel was performed to explore the possible presence of another underlying genetic cause of his cysts, in addition to SCD. A dual diagnosis of SCD and ADPKD was made following the identification of two copies of the common pathogenic sickle cell HBB variant (c.20A > T, p.Glu7Val) and a pathogenic missense variant in PKD1 (c.8311G > A, p.Glu2771Lys). SCD and ADPKD differ in pathophysiological mechanisms and treatment regimens. As such, it will be paramount for this teenager to be closely monitored for signs of diminished kidney function and to be co-managed as he transitions to adult care to ensure proper treatment and management. Early identification of individuals with both SCD and a co-occurring condition is crucial to ensuring proper clinical management. Furthermore, identifying and reporting additional patients with SCD and ADPKD dual diagnoses will help us to understand the co-occurring disease course and optimal treatments.

Novel method for the genomic analysis of PKD1 mutation in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease. Although next-generation sequencing (NGS) technology can be used to sequence tens of thousands of DNA molecules simultaneously. It has poor capture efficiency for the six PKD1 pseudogenes and GC-rich regions. Multiplex ligation-dependent probe amplification (MLPA) technology can detect consecutive deletions of exons, but it is less sensitive for single-base mutations. However, pathogenic genes might not be detected in some patients, even when using the above methods. Improving the detection rate of pathogenic genes is an important technical problem hindering clinical diagnosis of ADPKD. Four pedigrees of ADPKD patients with mutation sites not identified by NGS were examined by other methods. First, MLPA was performed. Then, pedigrees in which MLPA did not identify pathogenic genes were subjected to multiplex polymerase chain reaction (MPCR) and targeted region sequencing. Finally, the detected mutation sites were verified by Sanger sequencing. The results showed that MLPA detected the following PKD1 exonic deletion mutations in three pedigrees: PKD1-18nt-290nt, PKD1-up-257nt, PKD1-up-444nt and PKD1-3nt-141nt. A new mutation site was identified through targeted region sequencing in one pedigree: PKD1 NM_001009944: c.151T > C at the protein level, described as p. Cys51Arg. In summary, we established a system of genetic detection and analytical methods, from NGS to MLPA to targeted region sequencing and finally to Sanger sequencing. We combined MPCR and targeted region sequencing for the first time in ADPKD diagnosis, which further improved diagnosis accuracy. Moreover, we identified one new missense mutation and four new deletion mutations.

Exome Sequencing of a Clinical Population for Autosomal Dominant Polycystic Kidney Disease

Most studies of autosomal dominant polycystic kidney disease (ADPKD) genetics have used kidney specialty cohorts, focusing on PKD1 and PKD2. These can lead to biased estimates of population prevalence of ADPKD-associated gene variants and their phenotypic expression. To determine the prevalence of ADPKD and contributions of PKD1, PKD2, and other genes related to cystic kidney disease in a large, unselected cohort. This retrospective observational study used an unselected health system-based cohort in central and northeast Pennsylvania with exome sequencing (enrolled from 2004 to 2020) and electronic health record data (up to October 2021). The genotype-first approach included the entire cohort and the phenotype-first approach focused on patients with ADPKD diagnosis codes, confirmed by chart and imaging review. Loss-of-function (LOF) variants in PKD1, PKD2, and other genes associated with cystic kidney disease (ie, ALG8, ALG9, DNAJB11, GANAB, HNF1B, IFT140, SEC61B, PKHD1, PRKCSH, SEC63); likely pathogenic missense variants in PKD1 and PKD2. Genotype-first analysis: ADPKD diagnosis code (Q61.2, Q61.3, 753.13, 753.12); phenotype-first analysis: presence of a rare variant in PKD1, PKD2, or other genes associated with cystic kidney disease. Of 174 172 patients (median age, 60 years; 60.6% female; 93% of European ancestry), 303 patients had ADPKD diagnosis codes, including 235 with sufficient chart review data for confirmation. In addition to PKD1 and PKD2, LOF variants in IFT140, GANAB, and HNF1B were associated with ADPKD diagnosis after correction for multiple comparisons. Among patients with LOF variants in PKD1, 66 of 68 (97%) had ADPKD; 43 of 43 patients (100%) with LOF variants in PKD2 had ADPKD. In contrast, only 24 of 77 patients (31.2%) with a PKD1 missense variant previously classified as "likely pathogenic" had ADPKD, suggesting misclassification or variable penetrance. Among patients with ADPKD diagnosis confirmed by chart review, 180 of 235 (76.6%) had a potential genetic cause, with the majority being rare variants in PKD1 (127 patients) or PKD2 (34 patients); 19 of 235 (8.1%) had variants in other genes associated with cystic kidney disease. Of these 235 patients with confirmed ADPKD, 150 (63.8%) had a family history of ADPKD. The yield for a genetic determinant of ADPKD was higher for those with a family history of ADPKD compared with those without family history (91.3% [137/150] vs 50.6% [43/85]; difference, 40.7% [95% CI, 29.2%-52.3%]; P < .001). Previously unreported PKD1, PKD2, and GANAB variants were identified with pedigree data suggesting pathogenicity, and several PKD1 missense variants previously reported as likely pathogenic appeared to be benign. This study demonstrates substantial genetic and phenotypic variability in ADPKD among patients within a regional health system in the US.

Caregiver Burden of Autosomal Dominant Polycystic Kidney Disease: A Qualitative Study

There is limited published research on how autosomal dominant polycystic kidney disease (ADPKD) impacts caregivers. This study explored how caregivers of individuals with ADPKD perceive the burdens placed on them by the disease. Qualitative study consisting of focus groups and interviews. Discussions were conducted by trained interviewers using semi-structured interview guides. The research was conducted in 14 countries in North America, South America, Asia, Australia, and Europe. Eligible participants were greater than or equal to 18 years old and caring for a child or adult diagnosed with ADPKD. The concepts reported were coded using qualitative research software. Data saturation was reached when subsequent discussions introduced no new key concepts. Focus groups and interviews were held with 139 participants (mean age, 44.9 years; 66.9% female), including 25 participants who had a diagnosis of ADPKD themselves. Caregivers reported significant impact on their emotional (74.1%) and social life (38.1%), lost work productivity (26.6%), and reduced sleep (25.2%). Caregivers also reported worry about their financial situation (23.7%). In general, similar frequencies of impact were reported among caregivers with ADPKD versus caregivers without ADPKD, with the exception of sleep (8.0% vs 28.9%, respectively), leisure activities (28.0% vs 40.4% respectively), and work/employment (12.0% vs 29.8%, respectively). The study was observational and designed to elicit concepts, and only descriptive analyses were conducted. These findings highlight the unique burden on caregivers in ADPKD, which results in substantial emotional, social, and professional/financial impact.

Identification and Characterization of Novel Mutations in Chronic Kidney Disease (CKD) and Autosomal Dominant Polycystic Kidney Disease (ADPKD) in Saudi Subjects by Whole-Exome Sequencing.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a condition usually caused by a single gene mutation and manifested by both renal and extrarenal features, eventually leading to end-stage renal disease (ESRD) by the median age of 60 years worldwide. Approximately 89% of ADPKD patients had either PKD1 or PKD2 gene mutations. The majority (85%) of the mutations are in the PKD1 gene, especially in the context of family history. Objectives: This study investigated the genetic basis and the undiscovered genes that are involved in ADPKD development among the Saudi population. Materials and Methods: In this study, 11 patients with chronic kidney disease were enrolled. The diagnosis of ADPKD was based on history and diagnostic images: CT images include enlargement of renal outlines, renal echogenicity, and presence of multiple renal cysts with dilated collecting ducts, loss of corticomedullary differentiation, and changes in GFR and serum creatinine levels. Next-generation whole-exome sequencing was conducted using the Ion Torrent PGM platform. Results: Of the 11 Saudi patients diagnosed with chronic kidney disease (CKD) and ADPKD, the most common heterozygote nonsynonymous variant in the PKD1 gene was exon15: (c.4264G &gt; A). Two missense mutations were identified with a PKD1 (c.1758A &gt; C and c.9774T &gt; G), and one patient had a PKD2 mutation (c.1445T &gt; G). Three detected variants were novel, identified at PKD1 (c.1758A &gt; C), PKD2L2 (c.1364A &gt; T), and TSC2 (deletion of a'a at the 3'UTR, R1680C) genes. Other variants in PKD1L1 (c.3813_381 4delinsTG) and PKD1L2 (c.404C &gt; T) were also detected. The median age of end-stage renal disease for ADPK patients in Saudi Arabia was 30 years. Conclusion: This study reported a common variant in the PKD1 gene in Saudi patients with typical ADPKD. We also reported (to our knowledge) for the first time two novel missense variants in PKD1 and PKD2L2 genes and one indel mutation at the 3'UTR of the TSC2 gene. This study establishes that the reported mutations in the affected genes resulted in ADPKD development in the Saudi population by a median age of 30. Nevertheless, future protein-protein interaction studies to investigate the influence of these mutations on PKD1 and PKD2 functions are required. Furthermore, large-scale population-based studies to verify these findings are recommended.

Cystic Kidney Diseases That Require a Differential Diagnosis from Autosomal Dominant Polycystic Kidney Disease (ADPKD).

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cystic kidney disease, with patients often having a positive family history that is characterized by a similar phenotype. However, in atypical cases, particularly those in which family history is unclear, a differential diagnosis between ADPKD and other cystic kidney diseases is important. When diagnosing ADPKD, cystic kidney diseases that can easily be excluded using clinical information include: multiple simple renal cysts, acquired cystic kidney disease (ACKD), multilocular renal cyst/multilocular cystic nephroma/polycystic nephroma, multicystic kidney/multicystic dysplastic kidney (MCDK), and unilateral renal cystic disease (URCD). However, there are other cystic kidney diseases that usually require genetic testing, or another means of supplementing clinical information to enable a differential diagnosis of ADPKD. These include autosomal recessive polycystic kidney disease (ARPKD), autosomal dominant tubulointerstitial kidney disease (ADTKD), nephronophthisis (NPH), oral-facial-digital (OFD) syndrome type 1, and neoplastic cystic kidney disease, such as tuberous sclerosis (TSC) and Von Hippel-Lindau (VHL) syndrome. To help physicians evaluate cystic kidney diseases, this article provides a review of cystic kidney diseases for which a differential diagnosis is required for ADPKD.

Visual inspection reveals a novel pathogenic mutation in PKD1 missed by the variant caller in whole‑exome sequencing.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common type of inherited cystic kidney disease. The feasibility of whole‑exome sequencing (WES) to obtain molecular diagnosis of ADPKD is still in question as previous studies showed conflicting results. Utilizing WES on a patient with ADPKD, standard bioinformatics pipeline demonstrated no pathogenic variant in the genes of interest. By visualizing read alignments using the Integrative Genomics Viewer, a region with atypical alignment of numerous soft‑clipped reads at exon 45 of polycystin 1, transient receptor potential channel interacting (PKD1) gene was demonstrated. A total of four visual inspection steps were outlined to assess the origin of these soft‑clipped reads as strand bias during capture, poor mapping, sequencing error or DNA template contamination. Following assessment, the atypical alignment at PKD1 was hypothesized to be caused by an insertion/deletion mutation. Sanger sequencing confirmed the presence of a novel 20‑bp insertion in PKD1 (NM_001009944.3; c.12143_12144insTCC​CCG​CAG​TCT​TCC​CCG​CA; p.Val4048LeufsTer157), which introduced a premature stop codon and was predicted to be pathogenic. The present study demonstrated that WES could be utilized as a molecular diagnostic tool for ADPKD. Furthermore, visual inspection of read alignments was key in identifying the pathogenic variant. The proposed visual inspection steps may be incorporated into a typical WES data analysis workflow to improve the diagnostic yield.

Delay in funding of tolvaptan for polycystic kidney disease in Aotearoa New Zealand.

Autosomal dominant polycystic kidney disease (ADPKD) is the fifth most common cause of end stage kidney disease (ESKD) in Aotearoa New Zealand. Identification of two genes, PCKD1 and PCKD2, which cause the majority of this disease, has played a key role in the development of DNA-sequence molecular diagnostics. ADPKD is characterised by the formation and growth of multiple cysts within the kidney, with some but not all patients progressing to ESKD. The diagnosis of ADPKD is based on the presence of family history, and radiological imaging although increasingly genetic testing is being used for screening and diagnosis. Once diagnosed, standard management of ADPKD includes laboratory monitoring of chronic kidney disease (CKD) parameters, lowering of blood pressure, and a high fluid intake. Over the last decade much research has been undertaken for targeted therapies for ADPKD; however, despite funding of these medications overseas since May 2015, and applications to Te Pātaka Whaioranga, The Pharmaceutical Management Agency (PHARMAC), these therapies remain unavailable to New Zealanders resulting in an increased burden of disease to individuals and the whānau and financial cost to the health system.

MO008: Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) without a Clear Family History have Rapid Progression and Poor Prognosis

Abstract BACKGROUND AND AIMS A small percentage of patients with autosomal dominant polycystic kidney disease (ADPKD) have no clear family history. The clinical course and prognosis of the disease in this subgroup of patients may be different. The present study investigates the progression and prognostication of end-stage renal disease (ESRD) in a large cohort of patients with and without a family history of ADPKD. METHOD This study enrolled 291 patients who were being followed in a specialized outpatient ADPKD clinic. Patients having a total of more than 10 kidney cysts in a recent magnetic resonance imaging (MRI) scan were included in the study even if they had no clear family history or confirmatory genetic test. At enrollment, total kidney volume was calculated by MRI, and the Mayo Clinic Imagining Category (MCIC) was determined. The prediction of ESRD (future estimated-glomerular filtration rate [e-GFR &amp;lt; 10 mL/min] based on the Mayo Clinic formula (which takes into consideration age, TKV, e-GFR, gender, race and MCIC) was also calculated. Demographics, medical and laboratory data were recorded using a standardized form. T-test, x2 and Mann–Whitney test were used for statistical analysis. RESULTS Of the 291 patients included in the study, 34 (11.68%) had no clear family history of ADPKD, and 257 (88.32%) had a clear family history. Age, gender, presence or not, and age at diagnosis of hypertension as well as BMI were similar in the two groups (P = 0.369, 0.398, 0.170, 0.295, 0.597, respectively). The age at diagnosis of ADPKD was similar between patients with and without a clear family history (P = 0.125) as well as, the e-GFR, the stage of chronic kidney disease and albuminuria (P = NS). The TKV tended to be higher in patients without a clear family history (median, [range]), 2210.3 (440.7–9137.5) mL versus 1649.9 (215.7–10 425.9) mL in those with a family history of ADPKD (P = 0.09), and the same was valid for the height-adjusted TKV (P = 0.08). In MCIC 1C, 1D and 1E, more patients without a known family history of ADPKD were classified than patients with a family history of ADPKD (88.89% versus 70.14%), and vice versa in MCIC 1A and 1B (11.11% versus 29.86%; P = 0.04). Finally, the ESRD prediction was (median, [range]) 15.66 (1–42) years for the patients without a clear family history and 34.1 (1–346) years for those with a clear family history of ADPKD (P = 0.025). CONCLUSION Patients with ADPKD without a clear family history tend to have a more rapid progression and a worse renal prognosis than those with a clear family history of the same disease.

MO010: Parameters Associated with Progression, Prognosis and Tolvaptan Indication in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Abstract BACKGROUND AND AIMS The identification of possible risk factors for the progression of autosomal dominant polycystic kidney disease (ADPKD) is an emerging field, especially after the introduction of tolvaptan as the first disease-specific treatment. The present study aims to explore the associations between epidemiological, clinical and imaging data in a large cohort of ADPKD patients. METHOD This study was from a single outpatient clinic, following patients with ADPKD. Patients were included in the study if they had recently undergone a magnetic resonance imaging for the measurement of total kidney volume (TKV). For all patients, the Mayo Clinic Imagining Category (MCIC) and the prediction of end-stage renal disease (ESRD) (future estimated-glomerular filtration rate [e-GFR] &amp;lt;10 mL/min) based on the Mayo Clinic formula were calculated. Patients eligible for tolvaptan treatment (MCIC 1C, 1D, 1E, age &amp;lt;55 years old and e-GFR ≥25 mL/min) were identified. Characteristics including individual medical history, clinical and laboratory data were examined for possible associations with renal and imaging parameters using multinomial logistic regression and linear regression models. RESULTS A total of 250 patients were included. Based on measurements of height-adjusted TKV (ht-TKV) and age, 8.4% of the patients were classified as 1A, 19.6% as 1B, 34% as 1C, 24.8% as 1D and 13.2% as 1E, MCIC. In multivariable analysis, patient's age (P &amp;lt; 0.001), male sex (P &amp;lt; 0.001), parent's age at ESRD (adjusted for patient age) (P &amp;lt; 0.001) and hypertension (P = 0.009) were associated with log (ht-TKV). Parent's age at ESRD differed significantly between the MCICs of the offspring (mean±SD), 65.63 (12.13) in 1A, 61.9 (11.3) in 1B, 55.6 (9.6) in 1C, 51.64 (9.2) in 1D and 49.7 (8.3) in 1E, (P &amp;lt; 0.001). Similarly, there were significant differences in the presence and age of hypertension onset (P =0.0005 and P = 0.0004, respectively). In 157 patients (74 females and 83 males) who were eligible for tolvaptan treatment, the age at ADPKD diagnosis, the age at hypertension onset and the parent's age at ESRD were significantly lower (P &amp;lt; 0.001 for all) when compared to noneligible patients. Finally, factors associated with the prediction score of ESRD were hypertension, uric acid and the age at ESRD of the affected parent (P = 0.038, 0.014 and 0.010, respectively). CONCLUSION As a heritability estimator, the age at which an affected parent had reached ESRD was significantly associated with a worse phenotype, prognosis and tolvaptan indication. Hypertension was associated with poor prognosis and an aggravated phenotype, whereas age at diagnosis of the disease and hypertension onset were associated with tolvaptan indication in ADPKD.