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Autosomal dominant polycystic kidney disease (ADPKD) is a genetic kidney disorder with multiple cyst formation that progresses to chronic kidney disease (CKD) and end-stage kidney disease. Plant-based diets have attracted considerable attention because they may prevent CKD development. This study investigated whether adherence to a plant-based diet is associated with kidney function in patients with ADPKD. The overall plant-based diet index (PDI), healthful PDI (hPDI), and unhealthful PDI (uPDI) were calculated using dietary intake data. Among 106 ADPKD patients, 37 (34.91%) were classified as having advanced CKD (eGFR < 60 mL/min/1.73 m 2 ). The overall PDI and hPDI were lower, but the uPDI was higher in patients with advanced CKD than in those with early CKD. The hPDI was negatively correlated with the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio. Moreover, the hPDI was inversely associated with advanced CKD [odds ratio (OR): 0.117 (95% confidence interval (CI): 0.039-0.351), p < 0.001], and the uPDI was positively associated with advanced CKD [OR: 8.450 (95% CI: 2.810-25.409), p < 0.001]. The findings of the current study demonstrate that greater adherence to a healthful plant-based diet is associated with improved kidney function in ADPKD patients.

Introduction: We focused on neutrophil gelatinase-associated lipocalin (NGAL) and autosomal dominant polycystic kidney disease (ADPKD) progression., Methods: ADPKD patients with an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m 2 were included. Serum NGAL level and NGAL to eGFR ratio (NGR), height-adjusted total kidney volume (hTKV) were assessed initially. Patients were followed-up for 5 years., Results: Sixty one patients were enrolled and initial eGFR was 73.6 (48.9-101.5) ml/min/1.73m 2 . EGFR declined by 3.7 mL/min/1.73m 2 per year. Thirty four patients (55.7%) exhibited rapid progression. Rapid progression group had lower serum NGAL levels (p < 0.001) and higher hTKV (p < 0.001). Lower serum NGAL level was a risk factor for rapid progression (p < 0.001). NGR was not associated with rapid progression. Serum NGAL level was predictive in for rapid progression ROC analysis (cut-off <10.62 ng/mL)., Conclusion: Relatively lower serum NGAL levels can predict worse outcomes in ADPKD and can provide risk stratification in patients with ADPKD., (© 2024 International Society for Apheresis and Japanese Society for Apheresis.)

Mayo Imaging Classification (MIC) for predicting future kidney growth in autosomal dominant polycystic kidney disease (ADPKD) patients is calculated from a single MRI/CT scan assuming exponential kidney volume growth and height-adjusted total kidney volume at birth to be 150 mL/m. However, when multiple scans are available, how this information should be combined to improve prediction accuracy is unclear. Herein, we studied ADPKD subjects ( n = 36 ) with 8+ years imaging follow-up (mean = 11 years) to establish ground truth kidney growth trajectory. MIC annual kidney growth rate predictions were compared to ground truth as well as 1- and 2-parameter least squares fitting. The annualized mean absolute error in MIC for predicting total kidney volume growth rate was 2.1 % ± 2 % compared to 1.1 % ± 1 % ( p = 0.002 ) for a 2-parameter fit to the same exponential growth curve used for MIC when 4 measurements were available or 1.4 % ± 1 % ( p = 0.01 ) with 3 measurements averaging together with MIC. On univariate analysis, male sex ( p = 0.05 ) and PKD2 mutation ( p = 0.04 ) were associated with poorer MIC performance. In ADPKD patients with 3 or more CT/MRI scans, 2-parameter least squares fitting predicted kidney volume growth rate better than MIC, especially in males and with PKD2 mutations where MIC was less accurate., (© 2024. The Author(s).)

Background: Tolvaptan, a vasopressin V2 receptor antagonist, is used for treating autosomal dominant polycystic kidney disease (ADPKD). We focused on changes in urinary osmolality (U-Osm) after tolvaptan initiation to determine whether they were associated with the therapeutic response to tolvaptan., Methods: This was a single-centre, prospective, observational cohort study. Seventy-two patients with ADPKD who received tolvaptan were recruited. We analysed the relationship between changes in U-Osm and annual estimated glomerular filtration rate (eGFR) in terms of renal prognostic value using univariable and multivariable linear regression analyses., Results: The mean value of U-Osm immediately before tolvaptan initiation was 351.8 ± 142.2 mOsm/kg H2O, which decreased to 97.6 ± 23.8 mOsm/kg H2O in the evening. The decrease in U-Osm was maintained in the outpatient clinic 1 month later. However, the 1-month values of U-Osm showed higher variability (160.2 ± 83.8 mOsm/kg H2O) than did those in the first evening of tolvaptan administration. Multivariate analysis revealed that the baseline eGFR, baseline urinary protein and U-Osm change in the evening of the day of admission (initial U-Osm drop) were significantly correlated with the subsequent annual change in eGFR., Conclusions: U-Osm can be measured easily and rapidly, and U-Osm change within a short time after tolvaptan initiation may be a useful index for the renal prognosis in actual clinical practice., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Autosomal polycystic kidney disease (ADPKD) is the most common genetic form of kidney failure, reflecting unmet needs in management. Prescription of the only approved treatment (tolvaptan) is limited to persons with rapidly progressing ADPKD. Rapid progression may be diagnosed by assessing glomerular filtration rate (GFR) decline, usually estimated (eGFR) from equations based on serum creatinine (eGFRcr) or cystatin-C (eGFRcys). We have assessed the concordance between eGFR decline and identification of rapid progression (rapid eGFR loss), and measured GFR (mGFR) declines (rapid mGFR loss) using iohexol clearance in 140 adults with ADPKD with ≥3 mGFR and eGFRcr assessments, of which 97 also had eGFRcys assessments. The agreement between mGFR and eGFR decline was poor: mean concordance correlation coefficients (CCCs) between the method declines were low (0.661, range 0.628 to 0.713), and Bland and Altman limits of agreement between eGFR and mGFR declines were wide. CCC was lower for eGFRcys. From a practical point of view, creatinine-based formulas failed to detect rapid mGFR loss (-3 mL/min/y or faster) in around 37% of the cases. Moreover, formulas falsely indicated around 40% of the cases with moderate or stable decline as rapid progressors. The reliability of formulas in detecting real mGFR decline was lower in the non-rapid-progressors group with respect to that in rapid-progressor patients. The performance of eGFRcys and eGFRcr-cys equations was even worse. In conclusion, eGFR decline may misrepresent mGFR decline in ADPKD in a significant percentage of patients, potentially misclassifying them as progressors or non-progressors and impacting decisions of initiation of tolvaptan therapy.

Introduction: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney condition caused by a single-gene mutation. It leads patients to kidney failure in more than 50% of cases by the age of 60, and, given the dominant inheritance, this disease is present in the family history in more than 90% of cases., Areas Covered: This review aims to analyze the set of preclinical and early-phase studies to provide a general view of the current progress on ADPKD therapeutic options. Articles from PubMed and the current status of the trials listed in clinicaltrials.gov were examined for the review., Expert Opinion: Many potential therapeutic targets are currently under study for the treatment of ADPKD. A few drugs have reached the clinical phase, while many are currently still in the preclinical phase. Organoids could be a novel approach to the study of drugs in this phase. Other than pharmacological options, very important developing approaches are represented by gene therapy and the use of MiRNA inhibitors.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background: The Mayo Imaging Classification was developed to predict the rate of disease progression in patients with autosomal dominant polycystic kidney disease. This study aimed to validate its ability to predict kidney outcomes in a large multicenter autosomal dominant polycystic kidney disease cohort., Methods: Included were patients with ≥1 height-adjusted total kidney volume (HtTKV) measurement and ≥3 eGFR values during ≥1-year follow-up. Mayo HtTKV class stability, kidney growth rates, and eGFR decline rates were calculated. The observed eGFR decline was compared with predictions from the Mayo Clinic future eGFR equation. The future eGFR prediction equation was also tested for nonlinear eGFR decline. Kaplan-Meier survival analysis and Cox regression models were used to assess time to kidney failure using Mayo HtTKV class as a predictor variable., Results: We analyzed 618 patients with a mean age of 47±11 years and mean eGFR of 64±25 ml/min per 1.73 m 2 at baseline. Most patients (82%) remained in their baseline Mayo HtTKV class. During a mean follow-up of 5.1±2.2 years, the mean total kidney volume growth rates and eGFR decline were 5.33%±3.90%/yr and -3.31±2.53 ml/min per 1.73 m 2 per year, respectively. Kidney growth and eGFR decline showed considerable overlap between the classes. The observed annual eGFR decline was not significantly different from the predicted values for classes 1A, 1B, 1C, and 1D but significantly slower for class 1E. This was also observed in patients aged younger than 40 years and older than 60 years and those with PKD2 mutations. A polynomial model allowing nonlinear eGFR decline provided more accurate slope predictions. Ninety-seven patients (16%) developed kidney failure during follow-up. The classification predicted the development of kidney failure, although the sensitivity and positive predictive values were limited., Conclusions: The Mayo Imaging Classification demonstrated acceptable stability and generally predicted kidney failure and eGFR decline rate. However, there was marked interindividual variability in the rate of disease progression within each class., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by kidney cyst formation and progressive kidney function loss. Dietary interventions such as caloric restriction, intermittent fasting, and ketogenic diet have recently emerged as potential strategies to induce metabolic reprogramming and slow ADPKD progression. We review the available evidence supporting the efficacy and safety of these interventions in ADPKD. Dietary interventions show promise in managing ADPKD by improving metabolic health and reducing oxidative stress. However, while preclinical studies have shown favorable outcomes, limited clinical evidence supports their effectiveness. In addition, the long-term consequences of these dietary interventions, including their effect on adverse events in patients with ADPKD, remain uncertain. To optimize ADPKD management, patients are advised to follow a dietary regimen that aims to achieve or maintain an ideal body weight and includes high fluid intake, low sodium, and limited concentrated sweets. Caloric restriction seems particularly beneficial for patients with overweight or obesity because it promotes weight loss and improves metabolic parameters. Supplementation with curcumin, ginkgolide B, saponins, vitamin E, niacinamide, or triptolide has demonstrated uncertain clinical benefit in patients with ADPKD. Notably, β -hydroxybutyrate supplements have shown promise in animal models; however, their safety and efficacy in ADPKD require further evaluation through well-designed clinical trials. Therefore, the use of these supplements is not currently recommended for patients with ADPKD. In summary, dietary interventions such as caloric restriction, intermittent fasting, and ketogenic diet hold promise in ADPKD management by enhancing metabolic health. However, extensive clinical research is necessary to establish their effectiveness and long-term effects. Adhering to personalized dietary guidelines, including weight management and specific nutritional restrictions, can contribute to optimal ADPKD management. Future research should prioritize well-designed clinical trials to determine the benefits and safety of dietary interventions and supplementation in ADPKD., (Copyright © 2023 by the American Society of Nephrology.)

Introduction: Juxtaglomerular apparatus (JGA)-mediated homeostatic mechanism links to how sodium-glucose cotransporter 2 inhibitors (SGLT2is) slow progression of chronic kidney disease (CKD) and may link to how tolvaptan slows renal function decline in autosomal dominant polycystic kidney disease (ADPKD)., Area Covered: JGA-mediated homeostatic mechanism has been hypothesized based on investigations of tubuloglomerular feedback and renin-angiotensin system. We reviewed clinical trials of SGLT2is and tolvaptan to assess the relationship between this mechanism and these drugs., Expert Opinion: When sodium load to macula densa (MD) increases, MD increases adenosine production, constricting afferent arteriole (Af-art) and protecting glomeruli. Concurrently, MD signaling suppresses renin secretion, increases urinary sodium excretion, and counterbalances reduced sodium filtration. However, when there is marked increase in sodium load per-nephron, as in advanced CKD, MD adenosine production increases, relaxing Af-art and maintaining sodium homeostasis at the expense of glomeruli. The beneficial effects of tolvaptan on renal function in ADPKD may also depend on the JGA-mediated homeostatic mechanisms since tolvaptan inhibits sodium reabsorption in the thick ascending limb.The JGA-mediated homeostatic mechanism regulates Af-arts, constricting to relaxing according to homeostatic needs. Understanding this mechanism may contribute to the development of pharmacotherapeutic compounds and better care for patients with CKD.

PKD1 (polycystin 1) and PKD2 (polycystin 2) are expressed in a variety of different cell types, including arterial smooth muscle and endothelial cells. PKD1 is a transmembrane domain protein with a large extracellular N-terminus that is proposed to act as a mechanosensor and receptor. PKD2 is a member of the transient receptor potential (TRP) channel superfamily which is also termed TRPP1. Mutations in the genes which encode PKD1 and PKD2 lead to autosomal dominant polycystic kidney disease (ADPKD). ADPKD is one of the most prevalent monogenic disorders in humans and is associated with extrarenal and vascular complications, including hypertension. Recent studies have uncovered mechanisms of activation and physiological functions of PKD1 and PKD2 in arterial smooth muscle and endothelial cells. It has also been found that PKD function is altered in the vasculature during ADPKD and hypertension. We will summarize this work and discuss future possibilities for this area of research., (© 2023 John Wiley & Sons Ltd.)

Background: Dysregulated energy metabolism is a recently discovered key feature of autosomal dominant polycystic kidney disease (ADPKD). Cystic cells depend on glucose and are poorly able to use other energy sources such as ketone bodies. Raising ketone body concentration reduced disease progression in animal models of polycystic kidney diseases. Therefore, we hypothesized that higher endogenous plasma beta-hydroxybutyrate (BHB) concentrations are associated with reduced disease progression in patients with ADPKD., Methods: We analyzed data from 670 patients with ADPKD participating in the Developing Intervention Strategies to Halt Progression of ADPKD (DIPAK) cohort, a multi-center prospective observational cohort study. BHB was measured at baseline using nuclear magnetic resonance spectroscopy. Participants were excluded if they had type 2 diabetes, were using disease-modifying drugs (e.g. tolvaptan, somatostatin analogs), were not fasting or had missing BHB levels, leaving 521 participants for the analyses. Linear regression analyses were used to study cross-sectional associations and linear mixed-effect modeling for longitudinal associations., Results: Of the participants, 61% were female, with an age of 47.3 ± 11.8 years, a height-adjusted total kidney volume (htTKV) of 834 [interquartile range (IQR) 495-1327] mL/m and an estimated glomerular filtration rate (eGFR) of 63.3 ± 28.9 mL/min/1.73 m2. The median concentration of BHB was 94 (IQR 68-147) µmol/L. Cross-sectionally, BHB was associated neither with eGFR nor with htTKV. Longitudinally, BHB was positively associated with eGFR slope {B = 0.35 mL/min/1.73 m2 [95% confidence interval (CI) 0.09 to 0.61], P = .007}, but not with kidney growth. After adjustment for potential confounders, every doubling in BHB concentration was associated with an improvement in the annual rate of eGFR by 0.33 mL/min/1.73 m2 (95% CI 0.09 to 0.57, P = .008)., Conclusion: These observational analyses support the hypothesis that interventions that raise BHB concentration could reduce the rate of kidney function decline in patients with ADPKD., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by epithelial proliferation and progressive cyst enlargement. Using a non-targeted high-resolution metabolomics approach, we analyzed biofluids from 36 ADPKD and 18 healthy controls with estimated glomerular filtration rate (eGFR) > 60 ml/min to identify features specific to ADPKD or that associate with disease severity [eGFR or height-corrected total kidney volume (htTKV)]. Multiple pathways differed between ADPKD subjects and controls, with the histidine pathway being the most highly represented. Plasma histidine, urinary N-methylhistamine, methylimidazole-acetaldehyde, and imidazole-acetaldehyde, as well as 3-methylhistidine and anserine were increased, while plasma N-acetylhistamine and urinary imidazole-acetic acid were decreased in ADPKD compared to controls. In ADPKD, urinary histidine and a histidine derivative, urocanate (a precursor of glutamate), were significantly associated. HtTKV and eGFR were inversely associated with urinary glutamine and plasma 4-imidazolone-5-propionic acid, respectively. Supernatant from cultured human ADPKD renal cystic epithelia demonstrated increased aspartate and glutamate levels at 8 and 24 hours compared to primary tubular epithelia (p < 0.001). Following exposure over 48 hours to α-fluromethylhistidine, an inhibitor of histamine production, primary human PKD1 cyst epithelia proliferation increased significantly from baseline (p < 0.01) and greater than non-cystic epithelia (p < 0.05). The histidine ammonia lyase inhibitor nitromethane reversed α-fluromethylhistidine-induced cyst epithelia proliferation indicating a role for glutamate in cyst growth. In conclusion, histidine metabolism is altered preferentially leading to glutamate production and epithelial proliferation in ADPKD and associates with disease severity., (© 2024 The American Clinical and Climatological Association.)

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disease characterized by the accumulation of fluid-filled cysts in the kidneys, leading to renal volume enlargement and progressive kidney function impairment. Disease severity, though, may vary due to allelic and genetic heterogeneity. This study aimed to determine genotype-phenotype correlations between PKD1 truncating and non-truncating mutations and kidney function decline in ADPKD patients., Methods: We established a single-center retrospective cohort study in Kuwait where we followed every patient with a confirmed PKD1-ADPKD diagnosis clinically and genetically. Renal function tests were performed annually. We fitted generalized additive mixed effects models with random intercepts for each individual to analyze repeated measures of kidney function across mutation type. We then calculated survival time to kidney failure in a cox proportional hazards model. Models were adjusted for sex, age at visit, and birth year., Results: The study included 22 truncating and 20 non-truncating (42 total) patients followed for an average of 6.6 years (range: 1-12 years). Those with PKD1 truncating mutations had a more rapid rate of eGFR decline (-4.7 mL/min/1.73 m2 per year; 95% CI: -5.0, -4.4) compared to patients with PKD1 non-truncating mutations (-3.5 mL/min/1.73 m2 per year; 95% CI: -4.0, -3.1) (p for interaction &lt;0.001). Kaplan-Meier survival analysis of time to kidney failure showed that patients with PKD1 truncating mutations had a shorter renal survival time (median 51 years) compared to those with non-truncating mutations (median 56 years) (P for log-rank = 0.008)., Conclusion: In longitudinal and survival analyses, patients with PKD1 truncating mutations showed a faster decline in kidney function compared to patients PKD1 non-truncating mutations. Early identification of patients with PKD1 truncating mutations can, at best, inform early clinical interventions or, at least, help suggest aggressive monitoring., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Purpose: Autosomal dominant polycystic kidney disease (ADPKD) is a renal disease with genetic transmisson. Mutations in the PKD1 and PKD2 genes, which encode integral membrane proteins of the cilia of primary renal tubule epithelial cells, are seen in ADPKD. The aim of this study was to evaluate the sinonasal epithelium, which is epithelium with cilia, by measuring the nasal mucociliary clearance time, and to investigate the effect of ADPKD on nasal mucociliary clearance., Methods: The study included 34 patients, selected from patients followed up in the Nephrology Clinic, and 34 age and gender-matched control group subjects. The nasal mucociliary clearance time (NMCT) was measured with the saccharin test., Results: The mean age of the study subjects was 47.15 ± 14.16 years in the patient group and 47.65 ± 13.85 years in the control group. The eGFR rate was determined as mean 72.06 ± 34.26 mL/min in the patient group and 99.79 ± 17.22 mL/min in the control group (p < 0.001). The NMCT was determined to be statistically significantly longer in the patient group (903.6 ± 487.8 s) than in the control group (580 ± 259 s) (p = 0.006)., Conclusions: The study results showed that the NMCT was statistically significantly longer in patients with ADPKD compared to the control group, but in the linear regression analysis results, no correlation was determined between eGFR and NMCT., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and affects 1 in 1,000 individuals. There is accumulating evidence suggesting that there are shared cellular mechanisms responsible for cystogenesis in human and murine PKD and that reprogramming of metabolism is a key disease feature. In this study, we used a targeted metabolomics approach in an orthologous mouse model of PKD ( Pkd1 RC/RC ) to investigate the metabolic modifications a cystic kidney undergoes during disease progression. Using the Kyoto Encyclopedia of Genes and Genomes pathway database, we identified several biologically relevant metabolic pathways that were altered early in this disease (in 3-mo-old Pkd1 RC/RC mice), the most highly represented being arginine biosynthesis and metabolism and tryptophan and phenylalanine metabolism. During the next 6 mo of disease progression, multiple uremic solutes accumulated in the kidney of cystic mice, including several established markers of oxidative stress and endothelial dysfunction (allantoin, asymmetric dimethylarginine, homocysteine, malondialdehyde, methionine sulfoxide, and S -adenosylhomocysteine). Levels of kynurenines and polyamines were also augmented in kidneys of Pkd1 RC/RC versus wild-type mice, as were the levels of bacteria-produced indoles, whose increase within PKD kidneys suggests microbial dysbiosis. In summary, we confirmed previously published and identified novel metabolic markers and pathways of PKD progression that may prove helpful for diagnosis and monitoring of cystic kidney disease in patients. Furthermore, they provide targets for novel therapeutic approaches that deserve further study and hint toward currently understudied pathomechanisms. NEW & NOTEWORTHY This report delineates the evolution of metabolic changes occurring during autosomal dominant polycystic kidney disease (ADPKD) progression. Using an orthologous model, we performed kidney metabolomics and confirmed dysregulation of metabolic pathways previously found altered in nonorthologous or rapidly-progressive PKD models. Importantly, we identified novel alterations, including augmentation of kynurenines, polyamines, and indoles, suggesting increased inflammation and microbial dysbiosis that provide insights into PKD pathomechanisms and may prove helpful for diagnosing, monitoring, and treating ADPKD.

Background and Objectives: Clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD), including evidence of vascular dysfunction, can begin in childhood. Curcumin is a polyphenol found in turmeric that reduces vascular dysfunction in rodent models and humans without ADPKD. It also slows kidney cystic progression in a murine model of ADPKD. We hypothesized that oral curcumin therapy would reduce vascular endothelial dysfunction and arterial stiffness in children/young adults with ADPKD., Design, Setting, Participants, & Measurements: In a randomized, placebo-controlled, double-blind trial, 68 children/young adults 6-25 years of age with ADPKD and eGFR>80 ml/min per 1.73 m 2 were randomized to either curcumin supplementation (25 mg/kg body weight per day) or placebo administered in powder form for 12 months. The coprimary outcomes were brachial artery flow-mediated dilation and aortic pulse-wave velocity. We also assessed change in circulating/urine biomarkers of oxidative stress/inflammation and kidney growth (height-adjusted total kidney volume) by magnetic resonance imaging. In a subgroup of participants ≥18 years, vascular oxidative stress was measured as the change in brachial artery flow-mediated dilation following an acute infusion of ascorbic acid., Results: Enrolled participants were 18±5 (mean ± SD) years, 54% were girls, baseline brachial artery flow-mediated dilation was 9.3±4.1% change, and baseline aortic pulse-wave velocity was 512±94 cm/s. Fifty-seven participants completed the trial. Neither coprimary end point changed with curcumin (estimated change [95% confidence interval] for brachial artery flow-mediated dilation [percentage change]: curcumin: 1.14; 95% confidence interval, -0.84 to 3.13; placebo: 0.33; 95% confidence interval, -1.34 to 2.00; estimated difference for change: 0.81; 95% confidence interval, -1.21 to 2.84; P =0.48; aortic pulse-wave velocity [centimeters per second]: curcumin: 0.6; 95% confidence interval, -25.7 to 26.9; placebo: 6.5; 95% confidence interval, -20.4 to 33.5; estimated difference for change: -5.9; 95% confidence interval, -35.8 to 24.0; P =0.67; intent to treat). There was no curcumin-specific reduction in vascular oxidative stress or changes in mechanistic biomarkers. Height-adjusted total kidney volume also did not change as compared with placebo., Conclusions: Curcumin supplementation does not improve vascular function or slow kidney growth in children/young adults with ADPKD., Clinical Trial Registry Name and Registration Number: Curcumin Therapy to Treat Vascular Dysfunction in Children and Young Adults with ADPKD, NCT02494141., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022&#95;02&#95;07&#95;CJN08950621.mp3., (Copyright © 2022 by the American Society of Nephrology.)

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in the polycystin 1 ( PKD1 ) or polycystin 2 genes, presents with progressive development of kidney cysts and eventual end-stage kidney disease with limited treatment options. Previous work has shown that metformin reduces cyst growth in rapid ADPKD mouse models via inhibition of cystic fibrosis transmembrane conductance regulator-mediated fluid secretion, mammalian target of rapamycin, and cAMP pathways. The present study importantly tested the effectiveness of metformin as a therapy for ADPKD in a more clinically relevant Pkd1 RC/RC mouse model, homozygous for the R3277C knockin point mutation in the Pkd1 gene. This mutation causes ADPKD in humans. Pkd1 RC/RC male and female mice, which have a slow progression to end-stage kidney disease, received metformin (300 mg/kg/day in drinking water vs. water alone) from 3 to 9 or 12 mo of age. As previously reported, Pkd1 RC/RC females had a more severe disease phenotype as compared with males. Metformin treatment reduced the ratio of total kidney weight-to-body weight relative to age-matched and sex-matched untreated controls at both 9 and 12 mo and reduced the cystic index in females at 9 mo. Metformin also increased glomerular filtration rate, lowered systolic blood pressure, improved anemia, and lowered blood urea nitrogen levels relative to controls in both sexes. Moreover, metformin reduced gene expression of key inflammatory markers and both gene and protein expression of kidney injury marker-1 and cyclin-dependent kinase-1 versus untreated controls. Altogether, these findings suggest several beneficial effects of metformin in this highly relevant slowly progressive ADPKD mouse model, which may help inform new ADPKD therapies in patients. NEW & NOTEWORTHY Metformin treatment improved ADPKD disease severity in a relevant, slowly progressive ADPKD mouse model that recapitulates a PKD-associated PKD1 mutation. Relative to controls, metformin reduced kidney weight/body weight, cystic index and BUN levels, while improving GFR, blood pressure and anemia. Metformin also reduced key inflammatory and injury markers, along with cell proliferation markers. These findings suggest several beneficial effects of metformin in this ADPKD mouse model, which may help inform new ADPKD therapies in patients.

Introduction: The activation of the sympathetic nervous system, which usually leads to a swift surge in blood pressure in the morning hours (MBPS) may be the cause of left ventricular hypertrophy (LVH) and endothelial dysfunction (ED) in early autosomal dominant polycystic kidney disease (ADPKD) patients. We studied the association between MBPS and LVH in ADPKD patients with preserved renal functions., Methods: Patients with ADPKD with preserved renal functions were enrolled. Prewaking MBPS was calculated using ambulatory blood pressure monitoring. The patients were categorized as MBPS (≥median) and non-MBPS (2 , p  < 0.001) and mean awake SBP surge was higher (42 vs 20 mmHg, p  < 0.001) and FMD (%) was lower (14.4 ± 6.6 vs 18.9 ± 5.7, p  = 0.009) in MBPS group. In the binary logistic regression analysis, the presence of MBPS in model 1 (OR: 6.625, 95% CI [1.048-41.882] p  = 0.044), and age in model 2 (OR: 1.160, 95% CI [1.065-1.263] p  = 0.001) were the only independent determinant of LVH., Conclusions: MBPS seems to be an important and independent determinant of LVH in ADPKD patients with preserved renal functions. It may be worth assessing the effect of reduction in MBPS as a new therapeutic target to prevent LVH in-patients-with-ADPKD.

Cilia dysfunction in autosomal-dominant polycystic kidney disease (ADPKD) may impair the integrity of glymphatic system and be implicated in the progression of cerebral small vessel disease (SVD), although the link between the two diseases has not been investigated. We evaluated the association of ADPKD pathology with SVD pattern and severity. Overall, 304 individuals in an ADPKD (chronic kidney disease stage ≤4 and age ≥50 years) cohort and their age, sex, and estimated glomerular filtration rate (eGFR)-matched controls were retrospectively included. ADPKD severity was classified into 1 A-B, 1 C, and 1 D-E, according to age and height-adjusted total kidney volume. SVD parameters included white-matter hyperintensity (WMH) severity scale, enlarged perivascular space (ePVS) score, and degree of lacunes or cerebral microbleeds (CMBs). After adjustments for age, sex, eGFR, and cerebrovascular risk factor parameters, ADPKD was associated with higher ePVS scores ( P  < 0.001), but not with the WMH severity or degree of lacunes or CMBs. In the ADPKD subgroup, higher ADPKD severity class was associated with higher ePVS scores ( P  < 0.001), WMH severity ( P  = 0.003), and degree of lacunes ( P  = 0.002). ADPKD associated cilia dysfunction may induce chronic cerebral glymphatic system dysfunction, which may contribute to the specific progression of ePVS compared with other SVD markers.

Background: In autosomal dominant polycystic kidney disease (ADPKD), endothelial dysfunction (ED) is common and occurs much earlier than kidney function impairment. The impact of smoking on ED in ADPKD patients has not been previously studied. The aim of this study was to investigate the potential contribution of smoking habits to ED and subclinical atherosclerosis in these patients., Methods: This case-control study included 54 ADPKD patients with preserved renal function and 45 healthy control subjects. ED was assessed using ischemia-induced forearm flow-mediated dilatation (FMD). Carotid intima-media thickness (CIMT) was measured from 10 mm proximal to the right common carotid artery. Clinical demographic characteristics and laboratory data were recorded for the patients and control group. Regression analysis was used to determine independent associations of ED and CIMT., Results: FMD was significantly lower in the ADPKD patients (19.5 ± 5.63 vs. 16.56 ± 6.41, p  = .018). Compared with nonsmoker ADPKD patients, smoker patients had significantly lower FMD values (18.19 ± 6.52 vs. 13.79 ± 5.27, p  = .013). In multiple regression analysis, age ( β  = -0.294, 95% CI: -0.392: -1.96, p  = .001) for FMD and smoking ( β   =  1.328, 95% CI: 0.251, 2.404, p  = .017) for CIMT were independent predictors., Conclusions: Patients with ADPKD had more impaired endothelial function and subclinical atherosclerosis compared with control subjects. Smoking may increase the risk of subclinical atherosclerosis in ADPKD patients.

This review focuses on the most recent advances in the understanding of the electrolyte transport-related mechanisms important for the development of severe inherited renal disorders, autosomal dominant (AD) and recessive (AR) forms of polycystic kidney disease (PKD). We provide here a basic overview of the origins and clinical aspects of ARPKD and ADPKD and discuss the implications of electrolyte transport in cystogenesis. Special attention is devoted to intracellular calcium handling by the cystic cells, with a focus on polycystins and fibrocystin, as well as other calcium level regulators, such as transient receptor potential vanilloid type 4 (TRPV4) channels, ciliary machinery, and purinergic receptor remodeling. Sodium transport is reviewed with a focus on the epithelial sodium channel (ENaC), and the role of chloride-dependent fluid secretion in cystic fluid accumulation is discussed. In addition, we highlight the emerging promising concepts in the field, such as potassium transport, and suggest some new avenues for research related to electrolyte handling., (© 2021 The Author(s).)

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressively enlarging cysts. Here we elucidate the interplay between oxidative stress, mitochondrial dysfunction, and metabolic derangement using two mouse models of PKD1 mutation, PKD1 RC/null and PKD1 RC/RC . Mouse kidneys with PKD1 mutation have decreased mitochondrial complexes activity. Targeted proteomics analysis shows a significant decrease in proteins involved in the TCA cycle, fatty acid oxidation (FAO), respiratory complexes, and endogenous antioxidants. Overexpressing mitochondrial-targeted catalase (mCAT) using adeno-associated virus reduces mitochondrial ROS, oxidative damage, ameliorates the progression of PKD and partially restores expression of proteins involved in FAO and the TCA cycle. In human ADPKD cells, inducing mitochondrial ROS increased ERK1/2 phosphorylation and decreased AMPK phosphorylation, whereas the converse was observed with increased scavenging of ROS in the mitochondria. Treatment with the mitochondrial protective peptide, SS31, recapitulates the beneficial effects of mCAT, supporting its potential application as a novel therapeutic for ADPKD., (© 2021. The Author(s).)

Objective: Arterial hypertension (AH) represents a major risk factor for cardiovascular disease and is associated to several complications, such as prolonged corrected QT (QTc) interval and impaired heart rate variability (HRV). Secondary causes of AH include autosomal dominant polycystic kidney disease (ADPKD) and atherosclerotic renal artery stenosis (ARAS), both known to be related to arrhythmic risk and autonomic imbalance. The aim of the study is to evaluate whether global autonomic activity and QTc interval differently affect ADPKD and ARAS hypertensive patients., Patients and Methods: An observational study was performed on 59 patients: 16 ADPKD patients and 19 diagnosed with ARAS, compared to 24 healthy controls (HC). All patients underwent clinical evaluation, biochemical lab tests, 24-hour electrocardiogram (ECG) and renal Doppler ultrasound. HRV was assessed through the analysis of 24-hour ECG to detect standard deviation of normal-to-normal RR intervals (SDNN). QTc interval was defined as prolonged when > 440 msec., Results: SDNN was significantly lower in ADPKD and ARAS patients than HC (p < 0.0001) and no significant differences were found between ADPKD and ARAS patients (p > 0.05). QTc was found significantly higher in ARAS patients than HC (p = 0.001) and in ARAS patients than ADPKD patients (p = 0.004)., Conclusions: The pathogenesis of hypertension in ADPKD and ARAS patients is related to the activation of the renin angiotensin aldosterone system (RAAS). In ADPKD, cyst enlargement leads to kidney ischemia and renin release, associated to endothelial dysfunction, low nitric oxide and sympathetic tone activation. Differently, reduction in renal perfusion pressure activates RAAS and renal adrenergic nerves in ARAS patients. We can speculate that prolonged QTc interval is more present in ARAS vs. ADPKD hypertensive patients due to a greater activation of RAAS. We suggest adding 24-hour HRV evaluation in association with traditional risk factors in course of ADPKD and ARAS hypertension to better stratify cardiovascular risk in these groups of patients.

The vasopressin V2 receptor antagonist tolvaptan delays the progression of autosomal dominant polycystic kidney disease (ADPKD). However, some patients discontinue tolvaptan because of severe adverse aquaretic events. This open-label, randomized, controlled, counterbalanced, crossover trial investigated the effects of trichlormethiazide, a thiazide diuretic, in patients with ADPKD receiving tolvaptan (n = 10) who randomly received antihypertensive therapy with or without trichlormethiazide for 12 weeks. The primary and secondary outcomes included amount and osmolarity of 24-h urine and health-related quality-of-life (HRQOL) parameters assessed by the Kidney Disease Quality of Life-Short Form questionnaire, renal function slope, and plasma/urinary biomarkers associated with disease progression. There was a significant reduction in urine volume (3348 ± 584 vs. 4255 ± 739 mL; P < 0.001) and a significant increase in urinary osmolarity (182.5 ± 38.1 vs. 141.5 ± 38.1 mOsm; P = 0.001) in patients treated with trichlormethiazide. Moreover, trichlormethiazide improved the following HRQOL subscales: effects of kidney disease, sleep, emotional role functioning, social functioning, and role/social component summary. No significant differences were noted in renal function slope or plasma/urinary biomarkers between patients treated with and without trichlormethiazide. In patients with ADPKD treated with tolvaptan, trichlormethiazide may improve tolvaptan tolerability and HRQOL parameters., (© 2021. The Author(s).)

Background: Factors affecting decline in renal function and cyst growth in patients with autosomal polycystic kidney disease (ADPKD) are not fully described, particularly in Japan., Methods: This was the first multi-facility, prospective, observational cohort study conducted in ADPKD patients at 14 centers in Japan. Patients in the J-PKD registry were assessed from December 2009 to June 2012 (follow-up until June 2017). Patients' data including estimated glomerular filtration rate (eGFR) and total kidney volume (TKV) were assessed initially and a maximum of five times annually. Contributing factors to eGFR decline and TKV growth were identified using multiple linear regression analysis., Results: Of the 340 patients in the J-PKD registry, data analysis was performed for 192 patients in whom serial changes for both eGFR and TKV were obtained. eGFR slope, eGFR change, and TKV change values were as follows: - 2.7 (- 4.2 to - 1.5) (ml/min/1.73 m 2 /year), - 5.0 (- 9.6 to - 2.3) (%/year), and 4.78 (0.86-8.22) (%/year), respectively. Lower high-density lipoprotein (HDL) cholesterol was an independent predictor of eGFR decline, using both eGFR slope and change (P = 0.04, P = 0.02, respectively), whereas lower hemoglobin and higher uric acid were significantly associated with greater eGFR change only (P = 0.02, P = 0.002, respectively). Younger age and higher fasting blood sugar were independent predictors of greater TKV change (P = 0.01, P = 0.02, respectively)., Conclusions: This real-world study in Japan identified risk factors for renal function decline in ADPKD patients. These included lower HDL cholesterol, lower hemoglobin and higher uric acid for eGFR decline, and youth and higher blood sugar levels for TKV growth., (© 2021. Japanese Society of Nephrology.)

Objective: We aimed to construct/validate a radiomics method based on MR FS-T2WI sequence for the evaluation of kidney function in patients with autosomal dominant polycystic kidney disease (ADPKD)., Patients and Methods: The clinical data and MRI images of 114 patients with ADPKD were retrospectively analyzed. With a glomerular filtration rate of 60 mL/min per 1.73 m2 as the cutoff value, patients were divided into two groups, where there were 59 patients with GFR ≥60 mL/min per 1.73 m2 (including CKD1 and CKD2 phase) and 55 patients with GFR <60 mL/min per 1.73 m2 (including CKD3 phase and higher). All patients underwent the 3.0T MR scan of the kidney. Then, the kidney were delineated layer by layer based on the FS-T2WI sequence to obtain the volume of interest (VOI) for radiomics features extraction. The optimal radiomics features were selected by least absolute shrinkage and selection operator (LASSO). Three kinds of data modality including the pure clinical data, the pure image data and the clinical-image fused data were utilized to establish three types of models (clinical, image and with their combination) separately by five machine learning classifiers: k-nearest-neighbors (KNN), support vector machine (SVM), logistic regression (LR), random forests (RF) and multi-layer perception (MLP). Receiver operating characteristic (ROC) curve, areas under the curve (AUC), sensitivity, specificity and precision were employed to evaluate the model's effectiveness to diagnosis the glomerular filtration rate of patients with ADPKD based on different models. Besides, Delong test was applied to compare ROCs between models., Results: 960 radiomics features were extracted from each VOIs, and clinical information included the gender and age of each patient. After feature selection, 23 and 21 features based on pure image data and clinical-image fused data were independently used to construct models for the kidney function evaluation. The clinical-image fused model (AUC=0.89) has better performance than the pure image model (p=0.046) and pure clinical model (p<0.001). Clinical-image fused model based on LR classifier showed the best diagnostic efficiency, with AUC=0.89, sensitivity=0.8867 and specificity=0.7959., Conclusions: The MR FS-T2WI radiomics analysis based on clinical-image fused model is instrumental in evaluating and predicting the kidney function of patients with polycystic kidney disease.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a progressive condition that eventually leads to end-stage renal disease. A phase 3 trial of tolvaptan (TEMPO 3:4; NCT00428948) and its open-label extension (TEMPO Extension Japan: TEMPO-EXTJ; NCT01280721) were conducted in patients with ADPKD. In this post hoc analysis, effects on renal function and the safety profile of tolvaptan were assessed over a long-term period that included the 3-year TEMPO 3:4 and the approximately 3-year TEMPO-EXTJ trials., Methods: Patients from Japanese trial sites who completed TEMPO 3:4 were offered participation in TEMPO-EXTJ. Patients whose efficacy parameters were measured at year 2 in TEMPO-EXTJ for efficacy evaluation were included. The annual slope of the estimated glomerular filtration rate (eGFR) and growth in total kidney volume (TKV) were analyzed., Results: In patients who received tolvaptan in TEMPO 3:4 and TEMPO-EXTJ, the annual slope of eGFR (mL/min/1.73 m 2 ) was - 3.480 in TEMPO 3:4 and - 3.417 in TEMPO-EXTJ, with no apparent effect of an approximately 3.6-month off-treatment interval between the two trials. In patients who received a placebo in TEMPO 3:4 before initiating tolvaptan in TEMPO-EXTJ, the slope of eGFR was significantly less steep from TEMPO 3:4 (- 4.287) to TEMPO-EXTJ (- 3.364), a difference of 0.923 (P = 0.0441)., Conclusion: The TEMPO-EXTJ trial supports a sustained beneficial effect of tolvaptan on eGFR. In patients who received a placebo in TEMPO 3:4, initiation of tolvaptan in TEMPO-EXTJ was associated with a significant slowing of eGFR decline., (© 2021. The Author(s).)

PKD2 gene variants account for 4.5% to 20% of patients with autosomal dominant polycystic kidney disease (ADPKD). Little is known about the clinical characteristics of PKD2 variants in Chinese patients with ADPKD. Herein, we performed a comprehensive search for variants of PKD2 gene in 44 Chinese ADPKD pedigrees and a total of 37 variants were identified. Of these 37 variants, 18 were nonsense variants, 10 frameshift variants, 4 missense variants, and 5 splice site variants. 11/37 variants were detected for the first time. The median age at diagnosis was 30.5 years, and positive family history was detected in 77.27% patients, liver cysts in 68.18%, hypertension in 45.45%, nephrolithiasis in 31.82%, macro-hematuria in 22.73%, and proteinuria in 13.63%. The level of estimated glomerular filtration rate in 8/39 patients were blow 60 ml/min/1.73m 2 . 11/17 patients were classified as rapid progression by Mayo Clinic classification. The end stage renal disease (ESRD) events were reported in 9/22 pedigrees, and the presence of nephrolithiasis and macro-hematuria were significantly associated with ESRD in the pedigrees with PKD2 variants. The identified variants and clinical features will facilitate the early diagnosis and prognosis prediction in Chinese ADPKD patients with PKD2 variants., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of kidney failure, accounting for 5%-10% of cases. Predicting which patients with ADPKD will progress rapidly to kidney failure is critical to assess the risk-benefit ratio of any intervention and to consider early initiation of long-term kidney protective measures that will maximize the cumulative benefit of slowing disease progression. Surrogate prognostic biomarkers are required to predict future decline in kidney function. Clinical, genetic, environmental, epigenetic, and radiologic factors have been studied as predictors of progression to kidney failure in ADPKD. A complex interaction of these prognostic factors determines the number of kidney cysts and their growth rates, which affect total kidney volume (TKV). Age-adjusted TKV, represented by the Mayo imaging classification, estimates each patient's unique rate of kidney growth and provides the most individualized approach available clinically so far. Tolvaptan has been approved to slow disease progression in patients at risk of rapidly progressive disease. Several other disease-modifying treatments are being studied in clinical trials. Selection criteria for patients at risk of rapid progression vary widely among countries and are based on a combination of age, baseline glomerular filtration rate (GFR), GFR slope, baseline TKV, and TKV rate of growth. This review details the approach in assessing the risk of disease progression in ADPKD and identifying patients who would benefit from long-term therapy with disease-modifying agents., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: In autosomal dominant polycystic kidney disease (ADPKD), cyst development and enlargement lead to ESKD. Macrophage recruitment and interstitial inflammation promote cyst growth. TWEAK is a TNF superfamily (TNFSF) cytokine that regulates inflammatory responses, cell proliferation, and cell death, and its receptor Fn14 (TNFRSF12a) is expressed in macrophage and nephron epithelia., Methods: To evaluate the role of the TWEAK signaling pathway in cystic disease, we evaluated Fn14 expression in human and in an orthologous murine model of ADPKD. We also explored the cystic response to TWEAK signaling pathway activation and inhibition by peritoneal injection., Results: Meta-analysis of published animal-model data of cystic disease reveals mRNA upregulation of several components of the TWEAK signaling pathway. We also observed that TWEAK and Fn14 were overexpressed in mouse ADPKD kidney cysts, and TWEAK was significantly high in urine and cystic fluid from patients with ADPKD. TWEAK administration induced cystogenesis and increased cystic growth, worsening the phenotype in a murine ADPKD model. Anti-TWEAK antibodies significantly slowed the progression of ADPKD, preserved renal function, and improved survival. Furthermore, the anti-TWEAK cystogenesis reduction is related to decreased cell proliferation-related MAPK signaling, decreased NF- κ B pathway activation, a slight reduction of fibrosis and apoptosis, and an indirect decrease in macrophage recruitment., Conclusions: This study identifies the TWEAK signaling pathway as a new disease mechanism involved in cystogenesis and cystic growth and may lead to a new therapeutic approach in ADPKD., (Copyright © 2021 by the American Society of Nephrology.)

Purpose: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease that may progress to end-stage renal disease, characterized by increased kidney volume due to cystic formations. In this study, we aimed to investigate the relationship between serum uromodulin levels, total kidney volume and estimated glomerular filtration rate (eGFR) in patients with ADPKD., Methods: This study included a total of 54 ADPKD patients and 18 healthy volunteers (control group). Total kidney volumes were calculated through magnetic resonance images using ellipsoid method. Serum uromodulin measurements were measured using an ELISA method., Results: Serum uromodulin levels were lower in patients compared with the control group (2.47 ± 0.16 vs 2.6 ± 0.28, p = 0.021). There was no significant difference in uromodulin values among the patients in chronic kidney disease (CKD) stages 1-2, 3 and 4-5. TKV measurements of CKD stage 4-5 patients were significantly higher than the stage 1-2 patients (p = 0.015). A negative correlation was observed between TKV and eGFR (r = - 0.433, p = 0.001). A positive correlation was observed between uromodulin and eGFR (r = 0.274, p = 0.02). When the serum levels of uromodulin and the level of eGFR were evaluated using simple linear regression analysis, R 2 value was found to be 0.075, suggesting that 7.5% change in serum uromodulin values corresponds with the change in eGFR value., Conclusion: These findings are consistent with previous studies that reported that serum uromodulin may be a good biomarker for demonstrating renal function in the early stages of CKD, before eGFR levels deteriorate. Serum uromodulin level may be useful in demonstrating renal functions in the follow-up of individuals with ADPKD.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder that leads to end stage renal disease (ESRD). Cyst expansion in ADPKD is strongly associated with the decline in renal function. However, the correlation between total kidney volume (TKV) and glomerular filtration rate (GFR) at an early stage has not been well demonstrated. There is growing evidence that utilization of estimated GFR (eGFR) may induce misleading information in a population with near normal renal function. Therefore, a more accurate method is essential., Methods: A prospective cohort of ADPKD patients was conducted with clinical data and laboratory collection. Measured GFR (mGFR) was assessed by iohexol plasma clearance method using ultra performance liquid chromatography. eGFR was calculated using the CKD-EPI equation. Kidney volumes were evaluated using MRI imaging protocol., Results: Thirty two patients completed the study. The mean age was 56 years old. The mean initial mGFR was 83.8 mL/min/1.73m 2 . The mean change in mGFR per year was -2.99 mL/min/1.73m 2 /year. The mean initial height-adjusted TKV (htTKV) was 681.0 mL/m. The mean percentage change in htTKV per year (%ΔhtTKV/y) was 4.77 %/year. mGFR had a better association with clinical parameters than eGFR. Initial mGFR was significantly and inversely correlated with initial htTKV and age. The percentage change in mGFR per year was significantly and inversely correlated with the %ΔhtTKV/y and 24-hr urine albumin. The %ΔhtTKV/y was significantly correlated with initial htTKV., Conclusions: Our studies demonstrated that mGFR using iohexol is a more reliable and accurate method than eGFR for evaluating GFR changes in the early stages of ADPKD patients. There is a strong inverse correlation between kidney volume and mGFR in an Asian ADPKD population. The initial htTKV is a good predictor of kidney volume progression. The %ΔhtTKV/y is a good early surrogate marker for the decline in renal function. 24-hr urine albumin is also a good indicator for renal progression.

Background: Tolvaptan slowed the rates of total kidney volume (TKV) growth and renal function decline over a 3-year period in patients with autosomal dominant polycystic kidney disease (ADPKD) enrolled in the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 trial (NCT00428948). In this post hoc analysis of Japanese patients from TEMPO 3:4, we evaluated whether the effects of tolvaptan on TKV and on renal function are interrelated., Methods: One hundred and forty-seven Japanese patients from TEMPO 3:4 were included in this analysis (placebo, n = 55; tolvaptan, n = 92). Tolvaptan-treated patients were stratified into the responder group (n = 37), defined as tolvaptan-treated patients with a net decrease in TKV from baseline to year 3, and the non-responder group (n = 55), defined as tolvaptan-treated patients with a net increase in TKV., Results: Mean changes during follow-up in the placebo, responder, and non-responder groups were 16.99%, - 8.33%, and 13.95%, respectively, for TKV and - 12.61, - 8.47, and - 8.58 mL/min/1.73 m 2 , respectively, for estimated glomerular filtration rate (eGFR). Compared with the placebo group, eGFR decline was significantly slowed in both the responder and non-responder groups (P < 0.05)., Conclusion: Tolvaptan was effective in slowing eGFR decline, regardless of TKV response, over 3 years in patients with ADPKD in Japan. Treatment with tolvaptan may have beneficial effects on slowing of renal function decline even in patients who have not experienced a reduction in the rate of TKV growth by treatment with tolvaptan.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder caused by mutations in the polycystic kidney disease (PKD) gene. Although tolvaptan has benefits for renal involvement, the different effects depending on the gene mutation type are unknown. Thus, we explore the different effects of tolvaptan on the annual changes in total kidney volume (%TKV) and estimated glomerular filtration rate (eGFR) according to the gene mutation type in ADPKD patients., Methods: In total, 135 ADPKD patients were screened, and 22 patients taking tolvaptan for at least a year were retrospectively studied at the Kurume University Hospital. We examined the decline in renal function and %TKV by computed tomography and analyzed the gene mutation. Patients were classified into the following four groups according to gene mutation type: PKD1-truncated, PKD1-non-truncated, PKD2, and mutation not found. Patients were treated with tolvaptan, and the effects of tolvaptan were analyzed according to the gene mutation type., Results: Patients (age: 52.3 ± 11.2 years) were administered tolvaptan at a dose of 45 or 60 mg. No variation was observed in the annual changes in eGFR (%eGFR) (before: - 10.5% ± 13.9%, after: - 14.4% ± 8.1%, P = 0.139), whereas %TKV was significantly improved after the tolvaptan treatment (before: 14.9% ± 8.0%, after: - 5.4% ± 7.6%, P < 0.001). Unlike %eGFR, tolvaptan treatment significantly improved %TKV, regardless of the type of gene mutation., Conclusions: A year treatment with tolvaptan significantly improved %TKV in patients with ADPKD, regardless of the gene mutation type.

Background: The phase 3 Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO 3:4) clinical trial demonstrated the beneficial effect of tolvaptan on kidney growth and function in subjects aged 18-50 years over a 3-year period. However, it did not specifically assess the use of tolvaptan in adolescents and young adults (AYAs) with ADPKD., Methods: A post hoc analysis of the TEMPO 3:4 trials was performed for patients aged 18-24 years. The primary outcome was the annual rate of change in total kidney volume (TKV). The secondary outcome was to evaluate long-term safety of tolvaptan using Hy's law of hepatotoxicity., Results: A total of 51 patients in the 18-24 age group were analyzed (tolvaptan: 29, placebo: 22). The tolvaptan group had a lower mean percentage of TKV growth per year compared to the placebo group (3.9% vs. 6.5%, P = 0.0491). For secondary outcomes, 63 patients in the AYA subgroup were evaluated. In both the AYA and adult groups, none of the patients met the criteria for Hy's law of hepatotoxicity., Conclusions: This post hoc analysis suggests that tolvaptan, with appropriate patient selection and management, can provide effective and acceptably safe treatment in AYAs with ADPKD., Impact: Tolvaptan slows the increase in total kidney volume in patients aged 18-24 years with ADPKD. Tolvaptan posed no risk of potential liver injury measured via Hy's law of hepatotoxicity in the AYA stratum. This study suggests that tolvaptan has beneficial outcomes in AYAs. This post hoc analysis suggests the need for additional studies with a larger pediatric patient population. The impact is significant as tolvaptan had not been specifically examined in the AYA patient population previously.

Background and Objectives: Predicting disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) poses a challenge, especially in early-stage disease when kidney function is not yet affected. Ongoing growth of cysts causes maximal urine-concentrating capacity to decrease from early on. We therefore hypothesized that the urine-to-plasma urea ratio, as a reflection of the urine-concentrating capacity, can be used as a marker to predict ADPKD progression., Design: The urine-to-plasma urea ratio was calculated by dividing concentrations of early morning fasting spot urine urea by plasma urea. First, this ratio was validated as surrogate marker in 30 patients with ADPKD who underwent a prolonged water deprivation test. Thereafter, association with kidney outcome was evaluated in 583 patients with ADPKD with a broad range of kidney function. Multivariable mixed-model regression was used to assess association with eGFR slope, and logarithmic regression to identify patients with rapidly progressive disease, using a cutoff of -3.0 ml/min per 1.73 m 2 per year. The urine-to-plasma urea ratio was compared with established predictors, namely, sex, age, baseline eGFR, Mayo Clinic height-adjusted total kidney volume class, and PKD gene mutation., Results: The maximal urine-concentrating capacity and urine-to-plasma urea ratio correlated strongly ( R =0.90; P <0.001). Next, the urine-to-plasma urea ratio was significantly associated with rate of eGFR decline during a median follow-up of 4.0 (interquartile range, 2.6-5.0) years, both crude and after correction for established predictors ( β =0.58; P =0.02). The odds ratio of rapidly progressive disease was 1.35 (95% confidence interval, 1.19 to 1.52; P <0.001) for every 10 units decrease in urine-to-plasma urea ratio, with adjustment for predictors. A combined risk score of the urine-to-plasma urea ratio, Mayo Clinic height-adjusted total kidney volume class, and PKD mutation predicted rapidly progressive disease better than each of the predictors separately., Conclusions: The urine-to-plasma urea ratio, which is calculated from routine laboratory measurements, predicts disease progression in ADPKD in addition to other risk markers., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021&#95;01&#95;27&#95;CJN10470620&#95;final.mp3., (Copyright © 2021 by the American Society of Nephrology.)

The omission of outcomes that are of relevance to patients, clinicians, and regulators across trials in autosomal dominant polycystic kidney disease (ADPKD) limits shared decision making. The Standardized Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD) Initiative convened an international consensus workshop on October 25, 2018, to discuss the identification and implementation of a potential core outcome set for all ADPKD trials. This article summarizes the discussion from the workshops and the SONG-PKD core outcome set. Key stakeholders including 11 patients/caregivers and 47 health professionals (nephrologists, policy makers, industry, and researchers) attended the workshop. Four themes emerged: "Relevance of trajectory and impact of kidney function" included concerns about a patient's prognosis and uncertainty of when they may need to commence kidney replacement therapy and the lack of an early prognostic marker to inform long-term decisions; "Discerning and defining pain specific to ADPKD" highlighted the challenges in determining the origin of pain, adapting to the chronicity and repeated episodes of pain, the need to place emphasis on pain management, and to have a validated measure for pain; "Highlighting ADPKD consequences" encompassed cyst-related complications and reflected patient's knowledge because of family history and the hereditary nature of ADPKD; and "Risk for life-threatening but rare consequences" such as cerebral aneurysm meant considering both frequency and severity of the outcome. Kidney function, mortality, cardiovascular disease, and pain were established as the core outcomes for ADPKD., (Copyright © 2020 National Kidney Foundation, Inc. All rights reserved.)

Objective: To detect the mutation site in a pedigree affected with autosomal dominant polycystic kidney disease (ADPKD) and verify its impact on the protein function., Methods: Peripheral blood samples were collected from the proband and his pedigree members for the extraction of genomic DNA. Mutational analysis was performed on the proband through whole-exome sequencing. Suspected variant was verified by Sanger sequencing. A series of molecular methods including PCR amplification, restriction enzyme digestion, ligation and transformation were also used to construct wild-type and mutant eukaryotic expression vectors of the PKD2 gene, which were transfected into HEK293T and HeLa cells for the observation of protein expression and cell localization., Results: The proband was found to harbor a c.2051dupA (p. Tyr684Ter) frame shift mutation of the PKD2 gene, which caused repeat of the 2051st nucleotide of its cDNA sequence and a truncated protein. Immunofluorescence experiment showed that the localization of the mutant protein within the cell was altered compared with the wild-type, which may be due to deletion of the C-terminus of the PKD2 gene., Conclusion: The c.2051dupA (p. Tyr684Ter) mutation of the PKD2 gene probably underlay the pathogenesis of ADPKD in this pedigree.

Introduction: Mayo clinic classification (MCC) has been proposed in patients with autosomal dominant polycystic kidney disease (ADPKD) to identify who may experience a rapid decline of renal function. Our aim was to validate this predictive model in a population from southern Spain., Methods: ADPKD patients with measurements of height-adjusted total kidney volume (HtTKV) and baseline estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 were selected. Last eGFR was estimated with Mayo Clinic (MC) equation and bias and accuracy were studied. We also analyzed predictive capacity of MCC classes using survival analysis and Cox regression models., Results: We included 134 patients with a mean follow-up of 82 months. While baseline eGFR was not different between classes, last eGFR decreased significantly with them. eGFR variation rate was different according to the MCC class with a more rapid decline in 1C, 1D, and 1E classes. Final eGFR predicted was not significantly different from the real one, with an absolute bias of 0.6 ± 17.0 mL/min/1.73 m2. P10 accuracy was low ranging from 37.5 to 59.5% in classes 1C, 1D, and 1E. Using MC equation, the rate of eGFR decline was underestimated in 1C, 1D, and 1E classes. Cox regression analysis showed that MCC class is a predictor of renal survival after adjusting with baseline eGFR, age, sex, and HtTKV, with 1D and 1E classes having the worst prognosis., Conclusion: MCC classification is able to identify patients who will undergo a more rapid decline of renal function in a Spanish population. Prediction of future eGFR with MC equation is acceptable as a group, although it shows a loss of accuracy considering individual values. The rate of eGFR decline calculated using MC equation can underestimate the real rate presented by patients of 1C, 1D, and 1E classes., (© 2021 S. Karger AG, Basel.)

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the presence of numerous fluid-filled cysts, extensive fibrosis, and the progressive decline in kidney function. Transforming growth factor-β1 (TGF-β1), an important mediator for renal fibrosis and chronic kidney disease, is overexpressed by cystic cells compared with normal kidney cells; however, its role in PKD pathogenesis remains undefined. To investigate the effect of TGF-β1 on cyst growth, fibrosis, and disease progression, we overexpressed active TGF-β1 specifically in collecting ducts (CDs) of phenotypic normal ( Pkd1 RC/+ ) and Pkd1 RC/RC mice. In normal mice, CD-specific TGF-β1 overexpression caused tubule dilations by 5 wk of age that were accompanied by increased levels of phosphorylated SMAD3, α-smooth muscle actin, vimentin, and periostin; however, it did not induce overt cyst formation by 20 wk. In Pkd1 RC/RC mice, CD overexpression of TGF-β1 increased cyst epithelial cell proliferation. However, extensive fibrosis limited cyst enlargement and caused contraction of the kidneys, leading to a loss of renal function and a shortened lifespan of the mice. These data demonstrate that TGF-β1-induced fibrosis constrains cyst growth and kidney enlargement and accelerates the decline of renal function, supporting the hypothesis that a combined therapy that inhibits renal cyst growth and fibrosis will be required to effectively treat ADPKD.

Autosomal Dominant Polycystic Kidney Disease is an inherited multisystemic disorder of the renal tubules with subsequent formation of multiple cysts and enlargement of the kidney, affecting various organs. Diagnosis is initially suspected in those with family history and/or individuals who develop hypertension early on (secondary hypertension) or certain symptoms. Renal function is initially preserved for years secondary to compensatory mechanisms. Associated conditions include: liver cysts, berry aneurysms, kidney stones, etc. The disease course is variable, but patients often progress to end-stage renal failure by age 60. There is no known cure, however, risk factor modification at early stages is critical. Renal transplant is the optimal treatment in ESRD., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Autosomal dominant polycystic kidney disease causes chronic kidney disease and end-stage renal disease. Mechanisms include cyst production, multiplication, and enlargement leading to increased kidney size, and ultimately kidney failure. Although there is no known cure, NPs are uniquely positioned to help patients manage their symptoms and delay onset of kidney failure and need for dialysis.

Background and Objectives: We assessed safety and efficacy of another somatostatin receptor analog, pasireotide long-acting release, in severe polycystic liver disease and autosomal dominant polycystic kidney disease. Pasireotide long-acting release, with its broader binding profile and higher affinity to known somatostatin receptors, has potential for greater efficacy., Design, Setting, Participants, & Measurements: Individuals with severe polycystic liver disease were assigned in a 2:1 ratio in a 1-year, double-blind, randomized trial to receive pasireotide long-acting release or placebo. Primary outcome was change in total liver volume; secondary outcomes were change in total kidney volume, eGFR, and quality of life., Results: Of 48 subjects randomized, 41 completed total liver volume measurements ( n =29 pasireotide long-acting release and n =12 placebo). From baseline, there were -99±189 ml/m absolute and -3%±7% change in annualized change in height-adjusted total liver volume (from 2582±1381 to 2479±1317 ml/m) in the pasireotide long-acting release group compared with 136±117 ml/m absolute and 6%±7% increase (from 2387±759 to 2533±770 ml/m) in placebo ( P <0.001 for both). Total kidney volumes decreased by -12±34 ml/m and -1%±4% in pasireotide long-acting release compared with 21±21 ml/m and 4%±5% increase in the placebo group ( P =0.05 for both). Changes in eGFR were similar between groups. Among the n =48 randomized, adverse events included hyperglycemia (26 of 33 [79%] in pasireotide long-acting release versus four of 15 [27%] in the placebo group; P <0.001), and among the 47 without diabetes at baseline, 19 of 32 (59%) in the pasireotide long-acting release group versus one of 15 (7%) in the placebo group developed diabetes ( P =0.001)., Conclusions: Another somatostatin analog, pasireotide long-acting release, slowed progressive increase in both total liver volume/total kidney volume growth rates without affecting GFR decline. Participants experienced higher frequency of adverse events (hyperglycemia and diabetes)., Clinical Trial Registry Name and Registration Number: Pasireotide LAR in Severe Polycystic Liver Disease, NCT01670110 PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020&#95;08&#95;28&#95;CJN13661119.mp3., (Copyright © 2020 by the American Society of Nephrology.)

After reading this review article on ADPKD, participants should be able to: Identify people at high risk for ADPKD. Conduct a diagnostic evaluation. Initiate evidence-based therapy to slow kidney progression and treat extra-renal manifestations.

Background: Concentration of the urine is primarily regulated via vasopressin dependent aquaporin-2 water channels in the apical membrane of kidney principal cells. It is unclear whether urine concentration ability in ADPKD differs from other patients with similar degree of impaired renal function (non-ADPKD patients). The purpose of this case control study was to measure urine concentration ability in ADPKD patients compared to non-ADPKD patients and healthy controls., Methods: A seventeen hour long water deprivation test was carried out in 17 ADPKD patients (CKD I-IV), 16 non-ADPKD patients (CKD I-IV), and 18 healthy controls. Urine was collected in 4 consecutive periods during water deprivation (12 h, 1 h, 2 h and 2 h, respectively) and analyzed for osmolality (u-Osm), output (UO), fractional excretion of sodium (FE Na ), aquaporin2 (u-AQP2) and ENaC (u-ENaC). Blood samples were drawn trice (after 13-, 15-, and 17 h after water deprivation) for analyses of osmolality (p-Osm), vasopressin (p-AVP), and aldosterone (p-Aldo)., Results: U-Osm was significantly lower and FE Na significantly higher in both ADPKD patients and non-ADPKD patients compared to healthy controls during the last three periods of water deprivation. During the same periods, UO was higher and secretion rates of u-AQP2 and u-ENaC were lower and at the same level in the two groups of patients compared to controls. P-AVP and p-Osm did not differ significantly between the three groups. P-Aldo was higher in both groups of patients than in controls., Conclusions: Urine concentration ability was reduced to the same extent in patients with ADPKD and other chronic kidney diseases with the same level of renal function compared to healthy controls. The lower urine excretion of AQP2 and ENaC suggests that the underlying mechanism may be a reduced tubular response to vasopressin and aldosterone., Trial Registration: Current Controlled Trial NCT04363554 , date of registration: 20.08.2017.

BACKGROUNDA treatment option for autosomal dominant polycystic kidney disease (ADPKD) has highlighted the need to identify rapidly progressive patients. Kidney size/age and genotype have predictive power for renal outcomes, but their relative and additive value, plus associated trajectories of disease progression, are not well defined.METHODSThe value of genotypic and/or kidney imaging data (Mayo Imaging Class; MIC) to predict the time to functional (end-stage kidney disease [ESKD] or decline in estimated glomerular filtration rate [eGFR]) or structural (increase in height-adjusted total kidney volume [htTKV]) outcomes were evaluated in a Mayo Clinic PKD1/PKD2 population, and eGFR and htTKV trajectories from 20-65 years of age were modeled and independently validated in similarly defined CRISP and HALT PKD patients.RESULTSBoth genotypic and imaging groups strongly predicted ESKD and eGFR endpoints, with genotype improving the imaging predictions and vice versa; a multivariate model had strong discriminatory power (C-index = 0.845). However, imaging but not genotypic groups predicted htTKV growth, although more severe genotypic and imaging groups had larger kidneys at a young age. The trajectory of eGFR decline was linear from baseline in the most severe genotypic and imaging groups, but it was curvilinear in milder groups. Imaging class trajectories differentiated htTKV growth rates; severe classes had rapid early growth and large kidneys, but growth later slowed.CONCLUSIONThe value of imaging, genotypic, and combined data to identify rapidly progressive patients was demonstrated, and reference values for clinical trials were provided. Our data indicate that differences in kidney growth rates before adulthood significantly define patients with severe disease.FUNDINGNIDDK grants: Mayo DK058816 and DK090728; CRISP DK056943, DK056956, DK056957, and DK056961; and HALT PKD DK062410, DK062408, DK062402, DK082230, DK062411, and DK062401.

Rationale & Objective: Trials in autosomal dominant polycystic kidney disease (ADPKD) have increased, but their impact on decision making has been limited. Because heterogeneity in reported outcomes may be responsible, we assessed their range and variability in ADPKD trials., Study Design: Systematic review., Setting & Study Population: Adult participants in clinical trials in ADPKD., Selection Criteria for Studies: We included trials that studied adults and were published in English. For trials that enrolled patients without ADPKD, only those enrolling ≥50% of participants with ADPKD were included., Data Extraction: We extracted information on all discrete outcome measures, grouped them into 97 domains, and classified them into clinical, surrogate, and patient-reported categories. For each category, we choose the 3 most frequently reported domains and performed a detailed analysis of outcome measures., Analytical Approach: Frequencies and characteristics of outcome measures were described., Results: Among 68 trials, 1,413 different outcome measures were reported. 97 domains were identified; 41 (42%) were surrogate, 30 (31%) were clinical, and 26 (27%) were patient reported. The 3 most frequently reported domains were in the surrogate category: kidney function (54; 79% of trials; using 46 measures), kidney and cyst volumes (43; 63% of trials; 52 measures), and blood pressure (27; 40% of trials, 30 measures); in the clinical category: infection (10; 15%; 21 measures), cardiovascular events (9; 13%; 6 measures), and kidney failure requiring kidney replacement therapy (8; 12%; 5 measures); and in the patient-reported category: pain related to ADPKD (16; 24%; 26 measures), pain for other reasons (11; 16%; 11 measures), and diarrhea/constipation/gas (10; 15%; 9 measures)., Limitations: Outcome measures were assessed for only the top 3 domains in each category., Conclusions: The outcomes in ADPKD trials are broad in scope and highly variable. Surrogate outcomes were most frequently reported. Patient-reported outcomes were uncommon. A consensus-based set of core outcomes meaningful to patients and clinicians is needed for future ADPKD trials., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Autosomal dominant polycystic kidney disease (ADPKD) is considered the most common inherited renal disease. Patient-Reported Outcomes (PROs) and patient experience in ADPKD are difficult to quantify and have not been well studied, particularly in the early stages of the disease. There is evidence to suggest that early-stage ADPKD patients have a lower Health-Related Quality of Life (HRQoL) than the general population due to the signs and symptoms of early-stage ADPKD. However, no research has been carried out on the HRQoL of early-stage ADPKD patients using validated ADPKD-specific PRO measures. Additionally, a new disease progression delaying treatment option has recently emerged for ADPKD. Patient preference for this treatment and unmet treatment needs have not yet been investigated., Methods: The ACQUIRE study is a prospective, observational study investigating the influence of early-stage ADPKD-related symptoms and treatments on PROs. It aims to collect real-world data on patient demographics, treatment patterns, clinical outcomes, and PROs such as HRQoL, treatment satisfaction and treatment preference in early-stage ADPKD. Adult ADPKD patients in stages 1-3 of chronic kidney disease (CKD) with evidence of rapidly progressing disease are being recruited from seven European countries. At baseline and every 3 months, for a follow-up period of 18 months, general and disease-specific questionnaires are completed remotely to capture patients' own assessment of their overall and ADPKD-related HRQoL. A Discrete Choice Experiment (DCE) is also used to investigate the value patients place on different attributes of hypothetical treatment options (e.g. treatment outcomes, side effects) and the role each attribute plays in determining overall patient treatment preference., Discussion: The results of this study will highlight the real-world effects of ADPKD-related challenges on PROs including HRQoL, treatment experience and satisfaction; and help physicians gain greater insight into likely disease outcomes based on early-stage patient symptoms and patients' experience with treatment. Data captured by the DCE may inform ADPKD treatment decision-making from a patient perspective. The DCE will also provide insights into which patients are more likely to perceive benefit from treatments based on the value and trade-offs they place on specific treatment attributes., Trial Registration: NCT02848521 . Protocol Number/Version: 156-303-00096/Final.