Autosomal Dominant Polycystic Kidney Disease Patients Research Articles

Otomozal dominant polikistik böbrek hastalığında tolvaptan kullanımı: Tek merkez deneyimi

Aim: Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease that progresses to end-stage renal disease (ESRD). Tolvaptan is a disease-modifying agent that slows cyst growth and kidney disease progression in ADPKD. In this study, we examined the effects and side effects of tolvaptan in high-risk ADPKD patients using tolvaptan. We share our experience of this study.
 
 Methods: Twenty-seven ADPKD patients who were at high risk according to the Mayo Clinical Classification and accepted treatment were included in the study. Tolvaptan 60 mg/day orally was started in patients to slow the ADPKD. The daily dose was increased to 120 mg depending on the patients’ response to tolvaptan treatment and their tolerance to side effects. The patients were followed up during tolvaptan treatment to observe the effects and side effects of the medication.
 
 Results: The mean age of the patients was 40.3±8.2. Hypertension was present in 81.5% of the patients, and they mostly used renin angiotensin aldosterone system inhibitors. As aquaretic side effects of tolvaptan treatment, there was thirst in 14 patients (51.9%), polydipsia in 10 patients (37%), dry mouth in 5 patients (18.5%), and nocturia in 4 patients (14.8%). In addition, although liver enzyme elevation, hypernatremia, and acute kidney injury were observed in one patient each, these side effects did not lead to permanent discontinuation of the drug. Polyuria was observed in all patients, but the patients tolerated the polyuria well and continued to use tolvaptan treatment. 
 
 Conclusion: Although the patients experienced side effects related to tolvaptan treatment, none of the patients discontinued the drug permanently. We observed that patients generally tolerated tolvaptan treatment well.

Total and Extracellular Vesicle cAMP Contents in Urine Are Associated with Autosomal Dominant Polycystic Kidney Disease (ADPKD) Progression.

ADPKD is the most common genetic renal disease, characterized by the presence of multiple cysts which, through slow and gradual growth, lead to glomerular filtration rate (GFR) decline and end-stage renal disease. Cystic growth is associated with increased intracellular levels of 3',5'-cyclic adenosine monophosphate (cAMP). Extracellular vesicles (EVs) are proposed to participate in "remote sensing" by transporting different cargoes, but their relevance to ADPKD progression is poorly understood. This study aimed to determine whether cAMP is contained in urinary EVs and, if so, how total and/or EV cAMP contents participate in disease progression. Fourteen ADPKD patients, naïve for V2 receptor antagonism treatment, and seven controls were studied. Progression was evaluated by estimating GFR (eGFR) and height-adjusted total kidney volume (htTKV). Fresh morning urine was collected to determine cAMP by the competitive radioligand assay. Urine EVs were isolated using an adapted centrifugation method and characterized by electron microscopy, dynamic light scanning, flow cytometry with FITC CD63 labeling, protein and RNA content, and AQP2 and GAPDH mRNA detection. Total and EV cAMP was measurable in both control and patient urine samples. Total cAMP was significantly correlated with eGFR and its annual change but inversely correlated with htTKV. The cAMP-EVs showed a bimodal pattern with htTKV, increasing to ~1 L/m and falling at larger sizes. Our results demonstrate that urine cAMP correlates with ADPKD progression markers, and that its extracellular delivery by EVs could reflect the architectural disturbances of the organ.

The Efficacy, the Treatment Response and the Aquaretic Effects of a Three-Year Tolvaptan Regimen in Polycystic Kidney Disease Patients.

Tolvaptan, a selective vasopressin V2 receptor antagonist, is the first and only approved specific treatment for Autosomal-Dominant Polycystic Kidney Disease (ADPKD), and is used in current clinical practice. Real clinical data are missing. In this retrospective study, 41 ADPKD patients received tolvaptan for 3 years, from 2018 to 2021. Total kidney volume (TKV) was measured using Magnetic Resonance Imaging, at initiation and at the end of the treatment period. A complete biochemistry/hematology profile and a 24 h urine volume collection were performed monthly for the first 18 months and every 3 months thereafter. At the end of the treatment period, the median (IQR) estimated Glomerular Filtration Rate (e-GFR) was 5.3 (-1.3, 8.7) mL/min higher than the expected e-GFR decline without treatment, while the prediction for End Stage Chronic Kidney Disease (ESKD) had been prolonged by 1 (0, 2) year. Total Kidney Volume did not change significantly (2250 (1357) mL at 3 years of treatment vs. 2180 (1091) mL expected without treatment, p = 0.48). Younger patients with a relatively preserved e-GFR, lower hypertension burden, better familiar renal prognosis and more severe imaging data showed better outcomes. The aquaretic adverse effects of tolvaptan did not affect renal function and electrolyte balance in 51 patients, in a follow-up period of 18 months. Consequently, tolvaptan seems to be effective in preventing progression of ADPKD when administered in a timely manner in patients with better familiar renal history, shorter hypertension duration and worse imaging profile. Increased diuresis does not affect treatment efficacy.

Automated prognosis of renal function decline in ADPKD patients using deep learning

An accurate prognosis of renal function decline in Autosomal Dominant Polycystic Kidney Disease (ADPKD) is crucial for early intervention. Current biomarkers used are height-adjusted total kidney volume (HtTKV), estimated glomerular filtration rate (eGFR), and patient age. However, manually measuring kidney volume is time-consuming and subject to observer variability. Additionally, incorporating automatically generated features from kidney MRI images, along with conventional biomarkers, can enhance prognostic improvement. To address these issues, we developed two deep-learning algorithms. Firstly, an automated kidney volume segmentation model accurately calculates HtTKV. Secondly, we utilize segmented kidney volumes, predicted HtTKV, age, and baseline eGFR to predict chronic kidney disease (CKD) stages >=3A, >=3B, and a 30% decline in eGFR after 8 years from the baseline visit. Our approach combines a convolutional neural network (CNN) and a multi-layer perceptron (MLP). Our study included 135 subjects and the AUC scores obtained were 0.96, 0.96, and 0.95 for CKD stages >=3A, >=3B, and a 30% decline in eGFR, respectively. Furthermore, our algorithm achieved a Pearson correlation coefficient of 0.81 between predicted and measured eGFR decline. We extended our approach to predict distinct CKD stages after eight years with an AUC of 0.97. The proposed approach has the potential to enhance monitoring and facilitate prognosis in ADPKD patients, even in the early disease stages.

Abdominal Imaging in ADPKD: Beyond Total Kidney Volume.

In the context of autosomal dominant polycystic kidney disease (ADPKD), measurement of the total kidney volume (TKV) is crucial. It acts as a marker for tracking disease progression, and evaluating the effectiveness of treatment strategies. The TKV has also been recognized as an enrichment biomarker and a possible surrogate endpoint in clinical trials. Several imaging modalities and methods are available to calculate the TKV, and the choice depends on the purpose of use. Technological advancements have made it possible to accurately assess the cyst burden, which can be crucial to assessing the disease state and helping to identify rapid progressors. Moreover, the development of automated algorithms has increased the efficiency of total kidney and cyst volume measurements. Beyond these measurements, the quantification and characterization of non-cystic kidney tissue shows potential for stratifying ADPKD patients early on, monitoring disease progression, and possibly predicting renal function loss. A broad spectrum of radiological imaging techniques are available to characterize the kidney tissue, showing promise when it comes to non-invasively picking up the early signs of ADPKD progression. Radiomics have been used to extract textural features from ADPKD images, providing valuable information about the heterogeneity of the cystic and non-cystic components. This review provides an overview of ADPKD imaging biomarkers, focusing on the quantification methods, potential, and necessary steps toward a successful translation to clinical practice.

Current and Advance Treatment Approaches of Autosomal Dominant Polycystic Kidney Disease

Polycystic kidney disease is a genetic or acquired disorder in which balloon-like structures called cysts which are filled with fluid are formed inside the kidneys. The most common type of PKD is autosomal dominant polycystic kidney disease (ADPKD). The major cause of ADPKD are found to be abnormalities in the genes, and these abnormalities are inherited within generations. Genetic mutations such as spontaneous mutations are observed in some cases of ADPKD. Other causes of ADPKD can be hypertension and proteinuria. ADPKD develops due to mutations in the genes PKD1 or PKD2. It is found that 85% of the ADPKD patients have mutated PKD1 and 15% of the ADPKD patients have mutated PKD2. It is the 4th common cause which results in End-Stage Renal Disease (ESRD). Different researches and studies are undergoing to find novel treatments for the diseases. There is a need to have a clear understanding of molecular and genetic pathogenesis of ADPKD to help build novel therapies. After the approval of Tolvaptan, an V2R antagonist, slow growth of cyst and less chances of kidney failure were observed in ADPKD patients. Some other therapies like mTOR pathways inhibitors, somatostatin therapies also help in halting the progression of disease. Complementary therapies such as ayurveda and homeopathy, yoga, acupuncture which can help prevent the progression and symptoms of ADPKD. More and more advancement of technologies, stem cell and nanoscience have emerged in finding solutions for renal replacement therapies and restoration of renal function. Keywords: Autosomal dominant polycystic kidney disease (ADPKD), complementary therapies, stem cell and nanoscience.

Leukopenia in autosomal dominant polycystic kidney disease: a single-center cohort of kidney transplant candidates with post-transplantation follow-up.

Autosomal dominant polycystic kidney disease (ADPKD) has occasionally been associated with lower peripheral white blood cell (WBC) counts. This study aimed to investigate the peripheral blood cell counts in a large cohort of kidney transplant recipients before and after kidney transplantation and its potential impact on post-transplant outcomes. This was a retrospective study with long-term follow-up data of 2090 patients who underwent a first kidney transplantation in the Leuven University Hospitals, of whom 392 had ADPKD. In total, 2090 patients who underwent a first kidney transplantation in the Leuven University Hospitals were included, of whom 392 had ADPKD. Both pre- and post-transplantation, ADPKD patients had significantly lower total WBC counts, and more specifically lower neutrophil, lymphocyte and eosinophil counts compared with the non-ADPKD patients. This observation was independent of potential confounders such as level of inflammation, smoking habit, vitamins and pre-transplant medication. Overall survival and kidney transplant survival were significantly better in ADPKD vs non-ADPKD transplant recipients and a longer time to first infection was observed. However, no association between blood cell counts and outcome differences was found. In conclusion, this large single-center study reports a strong and independent association between ADPKD and lower peripheral WBC counts both before and after kidney transplantation. Considering the role of inflammation in disease progression, further investigation into the role of WBC in ADPKD is needed.

Standardized 4-point scoring scale of [18F]-FDG PET/CT imaging helps in the diagnosis of renal and hepatic cyst infections in patients with autosomal dominant polycystic kidney disease: a validation cohort.

Autosomal dominant polycystic kidney disease (ADPKD) is prone to multiple complications, including cyst infection (CyI). 2-Deoxy-2-[18F]fluoro-d-glucose positron emission tomography/computed tomography ([18F]-FDG PET/CT) imaging has proved useful in the diagnosis of renal and hepatic CyI. A 4-point scale comparing the uptake of [18F]-FDG in the suspected infected cyst versus the hepatic physiological background has been recently proposed. We performed an independent validation of this semi-quantitative scoring system. All ADPKD patients hospitalized between January 2009 and November 2019 who underwent an [18F]-FDG PET/CT for suspected CyI were retrospectively identified using computer-based databases. Medical files were reviewed. CyI was conventionally defined by the combination of fever (≥38°C), abdominal pain, increased plasma C-reactive protein levels (≥70mg/L), absence of any other cause of inflammation and favourable outcome after ≥21days of antibiotics. [18F]-FDG uptake of the suspected CyI was evaluated using a 4-point scale comparing the uptake of [18F]-FDG around the infected cysts with the uptake in the hepatic parenchyma. Statistics were performed using SAS version 9.4. Fifty-one [18F]-FDG PET/CT scans in 51 patients were included, of which 11 were cases of CyI. The agreement between the 4-point scale and the gold-standard criteria of CyI was significant [odds ratio of 6.03 for CyI in case of a score ≥3 (P = .014)]. The corresponding sensitivity, specificity, and positive and negative predictive values of [18F]-FDG PET/CT using the 4-point scale were 64% [Clopper-Pearson 95% confidence interval (CI) 30%-89%], 78% (95% CI 62%-89%), 44% (95% CI 20%-70%) and 89% (95% CI 73%-97%), respectively. Our independent validation cohort confirms the use of a semi-quantitative 4-point scoring system of [18F]-FDG PET/CT imaging in the diagnosis of CyI in patients with ADPKD. Considering its performance metrics with high specificity and negative predictive value, the scoring system is particularly useful to distinguish other causes of clinical inflammation than CyI and as such avoid unnecessarily long antibiotic treatment.

La risonanza magnetica pesata in diffusione (DWI) per la quantificazione del volume delle cisti e la caratterizzazione del tessuto non cistico nella malattia policistica renale: lo studio dell’Istituto Mario Negri

Beyond total kidney and cyst volume, non-cystic tissue plays an important role in autosomal dominant polycystic kidney disease (ADPKD) progression. Recent advancements in magnetic resonance imaging (MRI) offer the possibility to study kidney microstructure and function, besides anatomy. In particular, Diffusion Weighted Imaging (DWI), an MRI technique sensitive to water molecule motion (diffusion) in biological tissues, allows to investigate microstructure. This study, recently published in the European Radiology scientific journal, proposes and preliminary validates a novel method to segment cystic and non-cystic volume on DWI scans from ADPKD patients. The study also provides evidence of DWI potential in characterising non-cystic kidney tissue, denoted by higher diffusion and lower perfusion than healthy tissue, in line with its fibrotic nature and the likely presence of microcysts. Overall, this study provides evidence in support of DWI potential in ADPKD. DWI could complement existing biomarkers for noninvasively staging, monitoring, and predicting ADPKD progression and evaluating the impact of novel therapies, possibly targeting damaged non-cystic tissue besides cyst expansion.

The Role of Angiotensin II Type 1 Receptor A1166C Polymorphism in Autosomal Dominant Polycystic Kidney Disease.

Introduction Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic disorder that affects the kidney, which affects all ethnical groups worldwide, with varied clinical presentations and severity. The studies done in various parts of the world on the association between angiotensin II type 1 receptor (AT1R) A1166C gene polymorphism and ADPKD patientshave revealed inconsistent results. This study was done to assess the role of AT1R A1166C gene polymorphism in ADPKDin the South Indian population, which is the first of its kind. Methodology This is a case-control study, conducted at a tertiary care centerin South India. This study was concerned with the frequency of exposure (genotype) in ADPKD patients. Peripheral blood samples from 85 unrelated ADPKD patients and 94 controls without diabetes, hypertension, or any kidney-related disease were collected. The AT1R A1166C polymorphism was compared between (i) the cases and controls, (ii) early and late stages of chronic kidney disease(CKD) (ADPKD) subjects, and (iii) ADPKD subjects with and without hypertension. Results Among the ADPKD patients, 45 (52.9%) subjects showed early stage (CKD stages 1-3), and 40 (47%) subjects showed late stage CKD (CKD stages 4 and 5). The genotype distribution of the studied 85 ADPKD patients was almost similar. No significant association was found between the genotype distribution of AT1R A1166C polymorphism in AA vs. AC (OR = 1.11; 95% CI = 0.37-3.32; p < 0.844) and A vs. C (OR = 1.11; 95% CI = 0.38-3.32; p < 0.847) between cases and controls. The genotype distributions in genetic model AA vs. AC (OR = 3.07; 95% CI = 0.56-16.8; p < 0.177) and allelic model A vs. C (OR = 2.13; 95% CI = 0.40-11.3; p < 0.364) between the early and late CKD stages of ADPKD were also not significant. No significant association of gene polymorphism was found between the non-hypertensive and hypertensive groups of ADPKD. Conclusion The results of our study suggest there is no significant association between AT1R A1166C polymorphisms and ADPKD in the South Indian population. Further, the gene polymorphism is not related to the progression of ADPKD or the presence of hypertension in ADPKD cases in South India.

Assessment of Cardiovascular Disease in Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited kidney disease which leads to progressive kidney failure. About 5–10% of patients requiring renal replacement therapy are affected by ADPKD. Cardiovascular diseases are the main causes of morbidity and mortality in these patients with ADPKD; arterial hypertension (AH) is the first symptom with a very early onset. Anyway, some other cardiovascular abnormalities have been reported in ADPKD regardless of the presence of AH. With this background, we conducted a systematic review, collecting all randomized controlled trials (RCTs) and quasi-RCTs found on the main databases; we evaluated the evidence about different imaging techniques to grade the cardiovascular risk in a very early stage of disease. This review aims to describe all cardiovascular assessments in ADPKD patients to improve clinicians’ ability to discover cardiovascular involvement early, allowing appropriate therapies promptly.

#3065 INVESTIGATION OF NOTCH PATHWAY ACTIVATION AND ITS RELATION TO GREMLIN IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Abstract Background and Aims Activation of the NOTCH signalling pathway has been described in several progressive kidney diseases. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disease caused by PKD1 or PKD2 mutations, which codify for the Polycystin-1 and Polycystin-2 proteins, respectively. ADPKD prevalence is among 1:800 and 1:1000 of live births and is characterized by fluid-filled renal cysts. During this process the production of chemokines, cytokines and growth factors by epithelial cells, interstitial fibroblasts and inflammatory cells, such as macrophages, increases, leading to end-stage renal disease (ESRD). GREMLIN has been proposed GREMLIN as an important mediator of chronic kidney disease in preclinical studies. In addition, urinary levels of GREMLIN may be a biomarker in any renal disease. However, there are no studies on GREMLIN in polycystic kidney disease. Method We have done the studies in an orthologous murine model of polycystic kidney disease (Pkd1cond/cond;Tam-Cre−/+) where we investigated the role of GREMLIN and its related mechanisms (its receptor VEGFR2 and the Notch signalling pathway) in different stages of renal cystic progression. The polycystic phenotype was induced in lactating mice by administering tamoxifen to the mother on postnatal days 10 and 11, causing a deletion in Pkd1 gene. Studies were performed considering different sacrifice points: at 18, 30 and 45 days. Furthermore, in urine and renal tissue from ADPKD patients, we studied the expression of GREMLIM. Results We have been able to see how in Pkd1−/+ mutant mice, grem-1 renal expression (that encoding GREMLIN protein), was increased from 18 days, with a significant increase at 30 days. This increase was associated with progressive cysts expansion and detriment in renal function measured by BUN. These results were confirmed at the protein level by western blot. Immunohistochemistry revealed positive GREMLIM staining since pre-cystic tubuloepithelial cells, which remained elevated in the tubules at later times. Positive GREMLIN expression was observed in biopsy samples of cysts from ADPKD patients as well as GREMLIN protein presence in urine samples. In the polycystic model, GREMLIN induction was correlated with VEGFR2 activation in the same tubular segments. Cyst formation was associated with activation of the NOTCH pathway, characterized by NOTCH1 and NOTCH3 activation. Conclusion Thus, we can suggest that GREMLIN expression may be an important mediator of renal damage progression in ADPKD and this protein would act through the Notch pathway.

#5172 ASSESSMENT OF THE RELATIONSHIP BETWEEN RENAL VOLUME, PAIN, DEPRESSION, AND ANXIETY IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Abstract Background and Aims The most prevalent hereditary kidney disease is autosomal dominant polycystic kidney disease (ADPKD). Multiple cysts developing in the kidneys are a defining feature of this systemic, progressive disease. The quality of life, psychosocial load, and discomfort associated with renal volume in people with ADPKD have not been well studied. This study aimed to examine the relationship between renal volume, psychological issues brought on by pain and the burden of the disease, and deteriorating sleep quality in ADPKD patients. Method The study included sixty patients who were being treated in the nephrology clinic at the Bursa Uludag University Faculty of Medicine Hospital. The ADPKD Pain and Discomfort Scale (ADPKD-PDS), Beck Depression Inventory Questionnaire, Beck Anxiety Scale, Pittsburgh Sleep Quality Scale (PSQI), and Insomnia Severity Index (ISI) were assessed. The computed tomography ellipsoid formula was used to determine the total kidney volume, and kidney volume adjusted for body size was obtained for each patient. The eGFR values computed using the CKD-EPI algorithm and the patients' baseline biochemical parameters were recorded. Results The mean age at diagnosis was 31±13, and the mean total kidney volume (TKV) was 1526.35±1595.90. Eight (13.3%) individuals were determined to have mild mood disorders, whereas seven (11.7%) patients had borderline clinical depression. Four individuals (6.7%) were found to have severe anxiety. It was shown that 25% of the patients had poor sleep quality. There was no statistically significant difference in kidney volume between the depression groups or between the pain and discomfort scale sub-dimensions. (Table-1) Conclusion It was shown that, in accordance with the literature, the severity of depression increased as the patients' sleep quality declined in ADPKD patients. However, there was no significant relationship between kidney volume and the degree of anxiety, depression, pain or discomfort.

#3521 ASSOCIATION BETWEEN NEPROLITHIASIS AND KIDNEY DISEASE PROGRESSION IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE PATIENTS: A PROSPECTIVE COHORT STUDY

Abstract Background and Aims Nephrolithiasis is a common complication in Autosomal dominant polycystic kidney disease (ADPKD) patients and is known to occur in up to 8% to 36% of the patients. A few in vitro and in vivo studies showed that kidney and ureter stone formation could accelerate renal disease progression in ADPKD. However, its association between nephrolithiasis and renal function deterioration remains unknown in ADPKD patients. Methods This is a study from single center prospective cohort called HOPE-PKD. A total of 410 study subjects with abdominal computed tomography (CT) scan within 1 year before the enrollment were analyzed. Study subjects were divided into two groups according to the CT results as follows: Patients with papillary calcification, calyceal stone, ureter stone, or renal stone were classified as a stone group (n = 80, 19.5%), and patients only with renal cyst calcification or without any stones in the kidney and ureter were classified as a no-stone group (n = 330, 80.5%). The primary outcome was defined as the initiation of renal replacement therapy due to end-stage renal disease. The secondary outcome was a composite outcome of a 50% decline in estimated glomerular filtration rate (eGFR), doubling serum creatinine from baseline, or the initiation of renal replacement therapy. The hazard ratios (HRs) and 95% confidence interval (95% CI) for the outcome were analyzed using multivariate Cox regression analysis. Results There was no difference in the baseline characteristics between the stone group and the no-stone group. During a median 5.18 [interquartile range 3.41 - 8.03] year of follow-up, the primary and secondary outcomes occurred in 51 (12.4%) and 96 (23.4%) patients, respectively. In the unadjusted Cox regression analysis, there was no significant difference in the survival analysis between the two groups. However, after adjusting possible confounding factors (age, sex, body mass index, eGFR, comorbidity of hypertension and diabetes, serum uric acid, phosphorous and calcium level, results of PKD1 and PKD2 gene analysis, and Mayo classification), the stone group showed an increased risk of the primary and secondary outcome of HR 2.84 (95% CI 1.26 - 6.38; p-value 0.012) and HR 1.83 (95% CI 1.03 - 3.27; p-value 0.041), respectively compared to the no-stone group (Figure 1). Conclusion This is the first prospective cohort study showing that nephrolithiasis is associated with poor renal outcomes in patients with APDKD. Further clinical studies of nephrolithiasis in ADPKD patients are warranted to improve renal outcomes.

#6060 A NOVEL CT-BASED RADIOMICS APPROACH FOR KIDNEY FUNCTION EVALUATION IN ADPKD

Abstract Background and Aims Clinical management of autosomal dominant polycystic kidney disease (ADPKD) might take advantage of the use of new tools to predict risk of progression towards end stage kidney disease (ESKD). The aim of this study is to develop and validate a model based on radiomic features to predict kidney function among patients with ADPKD obtained from CT scans performed for the determination of total kidney volume (TKV). Method We retrospectively selected a cohort of 58 patients with ADPKD who underwent CT scan from February 2020 to March 2021, including 30 patients with eGFR ≥ 60 mL/min/1.73 m2 and 28 with eGFR &amp;lt; 60 mL/min/1.73 m2 at baseline. An expert radiologist generated a region of interest (ROI) segmentation for cystic kidney compounds, obtaining 58 ROIs from which we extracted 217 radiomic features using a dedicated software. We built three different logistic regression models to predict kidney function based on different predictors: height-adjusted TKV (ht-TKV), a selected radiomic feature (F_cm_merged.clust.tend), and both. Area under the curve (AUC) of the receiver operating characteristic (ROC) and accuracy were employed to evaluate models’ performance in discriminating between the two eGFR groups. Internal 3-fold cross-validation (CV) was performed. Results The ht-TKV, radiomic and combined models presented respectively an AUC (95% confidence interval) of 0.79 (0.67, 0.91), 0.83 (0.72, 0.93), 0.84 (0.74, 0.94), confirmed by the CV. Mean (standard deviation) values of the accuracy over CV iterations were 0.67 (0.10), 0.77 (0.09), 0.77 (0.09) for the three models. A model combining ht-TKV with a radiomic feature based on CT images from polycystic kidneys resulted effective in the prediction of baseline kidney function in our cohort. Furthermore, a logistic regression model based on a different radiomic feature (F_cm.2.5Dmerged.info.corr.2) selected among a subcohort of 29 ADPKD patients with a clinical follow-up, predicted rapid progression with a AUC of 0.81, a sensitivity of 100% and a specificity of 53%. Conclusion This is among the first studies which aimed to investigate, in a clinical setting, radiomics potential ability in discriminating eGFR at baseline and to explore as well whether a reliable radiomic feature could be taken into account in predicting faster rapid kidney function impairment over time. Further studies should implement a model extension to predict kidney function slope in order to confirm the role of radiomics in ADPKD management.

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.

Evaluation of advanced imaging biomarkers at kidney failure in patients with ADPKD: a pilot study.

Autosomal dominant polycystic kidney disease (ADPKD) presents with variable disease severity and progression. Advanced imaging biomarkers may provide insights into cystic and non-cystic processes leading to kidney failure in different age groups. This pilot study included 39 ADPKD patients with kidney failure, stratified into three age groups (<46, 46-56, >56 years old). Advanced imaging biomarkers were assessed using an automated instance cyst segmentation tool. The biomarkers were compared with an age- and sex-matched ADPKD cohort in early chronic kidney disease (CKD). Ht-total parenchymal volume correlated negatively with age at kidney failure. The median Ht-total parenchymal volume was significantly lower in patients older than 56 years. Cystic burden was significantly higher at time of kidney failure, especially in patients who reached it before age 46 years. The cyst index at kidney failure was comparable across age groups and Mayo Imaging Classes. Advanced imaging biomarkers showed higher correlation with Ht-total kidney volume in early CKD than at kidney failure. Cyst index and parenchymal index were relatively stable over 5 years prior to kidney failure, whereas Ht-total cyst volume and cyst parenchymal surface area increased significantly. Age-related differences in advanced imaging biomarkers suggest variable pathophysiological mechanisms in ADPKD patients with kidney failure. Further studies are needed to validate the utility of these biomarkers in predicting disease progression and guiding treatment strategies.

Cerebrovascular Pulsatility Index Is Reduced in Autosomal Dominant Polycystic Kidney Disease

Introduction: Cerebrovascular dysfunction, characterized by increased brain pulsatile flow, reduced cerebrovascular reactivity, and cerebral hypoperfusion precedes the onset of dementia and is linked to cognitive dysfunction. Autosomal dominant polycystic kidney disease (ADPKD) may increase the risk of dementia, and intracranial aneurysms are more prevalent in ADPKD patients. However, cerebrovascular function has not been previously characterized in patients with ADPKD. Methods: Using transcranial Doppler, we compared middle cerebral artery (MCA) pulsatility index (PI, cerebrovascular stiffness) and MCA blood velocity response to hypercapnia (normalized for blood pressure and end-tidal CO₂, cerebrovascular reactivity) in patients with early-stage ADPKD versus age-matched healthy controls. We also administered the NIH cognitive toolbox (cognitive function) and measured carotid-femoral pulse-wave velocity (PWV, aortic stiffness). Results: Fifteen participants with ADPKD (9F, 27 ± 4 yrs, eGFR: 106 ± 22 mL/min/1.73 m²) were compared to 15 healthy controls (8F, 29 ± 4 yrs, eGFR: 109 ± 14 mL/min/1.73 m²). MCA PI was unexpectedly lower in ADPKD (0.71 ± 0.07) versus controls (0.82 ± 0.09 AU; p < 0.001); however, normalized MCA blood velocity in response to hypercapnia did not differ between groups (2.0 ± 1.2 vs. 2.1 ± 0.8 %Δ/mm Hg; p = 0.85). Lower MCA PI was associated with a lower crystalized composite score (cognition), which persisted after adjustment for age, sex, eGFR, and education (β = 0.58, p = 0.007). There was no association of MCA PI with carotid-femoral PWV (r = 0.01, p = 0.96), despite greater carotid-femoral PWV in ADPKD, suggesting MCA PI reflects vascular properties other than arterial stiffness (such as low wall shear stress) in ADPKD. Discussion/Conclusion: MCA PI is lower in patients with ADPKD. Follow-up research on this observation is merited as low PI has been associated with intracranial aneurysm in other populations.

The safety and efficacy of tolvaptan in the treatment of patients with autosomal dominant polycystic kidney disease: A systematic review and meta-analysis

BackgroundThe irreversible progression of autosomal dominant polycystic kidney disease (ADPKD) to end-stage renal disease (ESRD) is delayed by tolvaptan. Therefore, we aim to systematically estimate and evaluate the efficacy and safety of tolvaptan in the treatment of ADPKD. MethodsTwo reviewers independently searched all published randomized controlled trials studies in PubMed, EMBASE, Web of Science and Cochrane databases, extracted data, assessed bias risk and rated the quality of evidence. Data were analyzed by the RevMan software. ResultsWe identified 8 trials including 2135 patients. Both of the decline of estimated glomerular filtration rate (eGFR) [MD=1.89, 95% CI (0.74, 3.04), P=0.001] and total kidney volume (TKV) [MD=−3.32, 95% CI (−4.57, −2.07), P<0.001] were delayed in tolvaptan group compared with placebo group in ADPKD patients. The use of tolvaptan delayed TKV progression in the different-month subgroups [MD=−69.99, 95% CI (−91.05, −48.94), P<0.001]. Tolvaptan reduced renal pain [RR=0.66, 95% CI (0.54, 0.81), P<0.001] and hematuria events [RR=0.55, 95% CI (0.41, 0.74), P<0.001] in ADPKD patients. However, the prevalence of thirst [RR=2.75, 95% CI (2.34, 3.24), P<0.001] and nocturia events [RR=3.01, 95% CI (1.27, 7.11), P=0.01] were increased in tolvaptan group. There is no significant difference of hypertension events [RR=0.92, 95% CI (0.82, 1.03), P=0.13] in tolvaptan group compared placebo group. ConclusionsThis meta-analysis suggests that tolvaptan may improve clinical progression in patients with ADPKD without significantly increasing the risk of adverse reactions.

Clinical features and prognosis of autosomal dominant polycystic kidney disease with cerebrovascular complications.

This retrospective study was used to evaluate the clinical and imaging characteristics and the prognosis of autosomal dominant polycystic kidney disease (ADPKD) with cerebrovascular complications. We retrospectively analyzed 30 patients with ADPKD complicated with intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), unruptured intracranial aneurysms (UIAs), or Moyamoya disease (MMD) who were admitted to Jinling Hospital from January 2001 to January 2022. We analyzed the clinical manifestations and imaging characteristics of ADPKD patients with cerebrovascular complications and followed up on their long-term outcomes. 30 patients, 17 men and 13 women, with an average age of 47.5 (40.0, 54.0) years were included in this study, including 12 cases of ICH, 12 cases of SAH, 5 cases of UIA, and 1 case of MMD. The 8 patients who died during follow-up had a lower Glasgow Coma Scale (GCS) on admission (p=0.024) and a significantly higher serum creatinine (p=0.004) and blood urea nitrogen (p=0.006) than the 22 patients with long-term survival. Intracranial aneurysms, SAH, and ICH are the most common cerebrovascular diseases in ADPKD. Patients with low GCS score or worse renal function have a poor prognosis, which can lead to disability and even death.