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There is a broad phenotypic spectrum of monogenic polycystic kidney diseases (PKDs). These disorders often involve cilia-related genes and lead to the development of fluid-filled cysts and eventual kidney function decline and failure. Preimplantation genetic testing for monogenic (PGT-M) disorders has moved into the clinical realm. It allows prospective parents to avoid passing on heritable diseases to their children, including monogenic PKD. The PGT-M process involves embryo generation through in vitrofertilization, with subsequent testing of embryos and selective transfer of those that do not harbor the specific disease-causing variant(s). There is a growing body of literature supporting the success of PGT-M for autosomal-dominant and autosomal-recessive PKD, although with important technical limitations in some cases. This technology can be applied to many other types of monogenic PKD and ciliopathies despite the lack of existing reports in the literature. PGT-M for monogenic PKD, like other forms of assisted reproductive technology, raises important ethical questions. When considering PGT-M for kidney diseases, as well as the potential to avoid disease in future generations, there are regulatory and ethical considerations. These include limited government regulation and unstandardized consent processes, potential technical errors, high cost and equity concerns, risks associated with pregnancy for mothers with kidney disease, and the impact on all involved in the process, including the children who were made possible with this technology.

AbstractThe use of iterative algebraic methods applied to the reconstruction of computed tomography (CT) medical images is proliferating to reconstruct high-quality CT images using far fewer views than through analytical methods. This would imply reducing the dose of X-rays applied to patients who require this medical test. Least-squares methods are a promising approach to reconstruct the images with few projections obtaining high quality. In addition, since these techniques involve a high computational load, it is necessary to develop efficient methods that make use of high-performance-computing tools to accelerate reconstructions. In this paper, three least-squares methods are analyzed—Least-Squares Model Based (LSMB), Least-Squares QR (LSQR), and Least-Squares Minimal Residual (LSMR)—to determine whether the LSMB method provides faster convergence and thus lower computational times. Moreover, a block version of both the LSQR method and the LSMR method was implemented. With them, multiple right-hand sides (multiple slices) can be solved at the same time, taking advantage of the parallelism obtained with the implementation of the methods using the Intel Math Kernel Library. The two implementations are compared in terms of convergence, time, and quality of the images obtained, reducing the number of projections and combining them with a regularization and acceleration technique. The experiments show how the implementations are scalable and obtain images of good quality from a reduced number of views, with the LSQR method being better suited for this application.

In this contribution, the Ewald method has efficiently been applied to accelerate the computation of the rectangular waveguide Green’s functions (GFs) derivatives. Based on previous works, we have outlined new approximation formulae that avoid the evaluation of computationally expensive complementary error functions of complex argument, needed by the Ewald method. This is possible when the internal medium of the rectangular waveguide is homogeneous and lossless. On the other hand, different convergence numerical studies have been carried out, showing a similar convergence rate for computing the original GFs and their derivatives. Moreover, we have checked that the computational time is only slightly increased for obtaining the derivatives as compared to the original GFs, after the application of these new techniques. The newly derived expressions are useful for the evaluation of electromagnetic fields, the characterization of dielectric materials and step discontinuities between rectangular waveguides, and the analysis of rectangular cavities using integral equation formulations. For validation, the electric field produced by a surface electric current density with a rectangular pulse distribution has been evaluated, using the new proposed expressions. These results have been compared to simulations provided by full-wave finite elements commercial software to verify their correctness, exhibiting a good agreement.

This article presents a new approach to manufacturing and assembling inexpensive, lightweight devices using 3-D-printed waveguides, and surface-mount technology (SMT). Specifically, we have employed stereolithography (SLA) and a combination of electroless and electroplating processes to develop cavity filters in the $X$ - and $C$ -bands. The filters can be efficiently integrated into planar circuits via a reliable and simple transition that enables surface-mount assembly. Two resonator topologies, circular and rectangular, were examined and compared to develop $X$ -band filters, and a triplet topology has been developed for the $C$ -band. The measured frequency responses were consistent with simulations, with insertion losses below 2 and 1.43 dB for $X$ - and $C$ -bands, respectively. We have conducted several Monte Carlo analyses and a dimensional study to assess the impact of manufacturing tolerances on filter performance. Furthermore, a rectangular cavity resonator has been used to approximate the effective conductivity of the deposited copper coating, considering the detrimental effects of oxidation and surface roughness. The resulting effective conductivity of 17.7 MS/m was found to be higher than the current state-of-the-art values. Finally, SMT assembly offers several advantages over traditional methods, including reduced size, simplified assembly, and integration with planar systems. The results presented in this work indicate that combining 3-D printing and SMT provides a simple and efficient solution for developing lightweight and highly integrated components with superior performance.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of numerous kidney cysts which leads to kidney failure. ADPKD is responsible for approximately 10% of patients with kidney failure. Overwhelming evidence supports that vasopressin and its downstream cyclic adenosine monophosphate signaling promote cystogenesis, and targeting vasopressin 2 receptor with tolvaptan and other antagonists ameliorates cyst growth in preclinical studies. Tolvaptan is the only drug approved by Food and Drug Administration to treat ADPKD patients at the risk of rapid disease progression. A major limitation of the widespread use of tolvaptan is aquaretic events. This review discusses the potential strategies to improve the tolerability of tolvaptan, the progress on the use of an alternative vasopressin 2 receptor antagonist lixivaptan, and somatostatin analogs. Recent advances in understanding the pathophysiology of PKD have led to new approaches of treatment via targeting different signaling pathways. We review the new pharmacotherapies and dietary interventions of ADPKD that are promising in the preclinical studies and investigated in clinical trials.

To evaluate the performance of an internally developed and previously validated artificial intelligence (AI) algorithm for magnetic resonance (MR)–derived total kidney volume (TKV) in autosomal dominant polycystic kidney disease (ADPKD) when implemented in clinical practice.

ABSTRACTThe increasing replacement of traditional lamps by LED technology opens the door to research into visual performance under their multiple possible spectral power distributions. The correlated color temperature and S/P-ratio are considered parameters characterizing the spectrum of a light source. The lack of firm conclusions motivates the analysis in this work of the influence of LED spectrum, which is defined by the correlated color temperature and S/P-ratio, on a representative night-driving task, visual reaction time. A two-channel and four primaries photostimulator was used as set-up for measuring reaction time in off-axis vision, at mesopic illumination conditions and for a range of stimulus contrasts. The experimental conditions included a wide range of correlated color temperatures, ranging from 1870 to 6350 K, and different S/P-ratios for the same temperature. A total of 16 young subjects participated in the experiments. The results show significant shorter reaction times for those conditions in which the spectrum has greater short-wavelength content. This is corroborated by the greater stimulation of rods and S-cones obtained in the calculation of their excitation level. However, the definition of the spectrum using the correlated color temperature and S/P-ratio does not equally define the results obtained. For the same temperature, a higher S/P-ratio provides lower reaction time values, but for the same S/P ratio reaction time is independent of the temperature. LED light sources with high short-wavelength content provide faster response on the basis of a greater excitation of rods and S-cones. The S/P-ratio is the best parameter to justify the effect of spectrum on reaction time, as considers the spectral sensitivity of the visual system in its calculation.

The only treatment approved for PKD inhibits production of cAMP, the main PKA activator. It is only partially effective, likely because side effects restrict dosing and because other sources of cAMP and mechanisms of cAMP-independent PKA activation exist. Which PKA isozyme(s) promotes PKD is uncertain and selective PKA inhibitors usable in vivohave not been available. Experiments in a mouse model show PKA-I is the main PKA isozyme promoting cystogenesis and that constitutive PKA-I downregulation and a novel, highly selective PKA inhibitor ameliorate PKD. The dose of PKA inhibitor used had no detectable adverse effects. This information provides a strong rationale for a strategy that may be more effective, or substantially increase the efficacy of the currently approved treatment.

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.

Autosomal dominant polycystic kidney disease (ADPKD), primarily due to PKD1or PKD2mutations, causes progressive kidney cyst development and kidney failure. There is significant intrafamilial variability likely due to the genetic background and environmental/lifestyle factors; variability that can be modeled in PKD mice. Here, we characterized mice homozygous for the PKD1hypomorphic allele, p.Arg3277Cys (Pkd1RC/RC), inbred into the BALB/cJ (BC) or the 129S6/SvEvTac (129) strains, plus F1 progeny bred with the previously characterized C57BL/6J (B6) model; F1(BC/B6) or F1(129/B6). By one-month cystic disease in both the BC and 129 Pkd1RC/RCmice was more severe than in B6 and continued with more rapid progression to six to nine months. Thereafter, the expansive disease stage plateaued/declined, coinciding with increased fibrosis and a clear decline in kidney function. Greater severity correlated with more inter-animal and inter-kidney disease variability, especially in the 129-line. Both F1 combinations had intermediate disease severity, more similar to B6 but progressive from one-month of age. Mild biliary dysgenesis, and an early switch from proximal tubule to collecting duct cysts, was seen in all backgrounds. Preclinical testing with a positive control, tolvaptan, employed the F1(129/B6)-Pkd1RC/RCline, which has moderately progressive disease and limited isogenic variability. Magnetic resonance imaging was utilized to randomize animals and provide total kidney volume endpoints; complementing more traditional data. Thus, we show how genetic background can tailor the Pkd1RC/RCmodel to address different aspects of pathogenesis and disease modification, and describe a possible standardized protocol for preclinical testing.

Patients with autosomal dominant polycystic disease (ADPKD) may require bilateral nephrectomy (BN) in addition to kidney transplantation (KT) for symptom control. This study aims to compare simultaneous BNKT to contemporaneous controls by reviewing our cohort of ADPKD patients who underwent KT from a living donor from January 2014 to October 2019. Symptomatic patients who underwent laparoscopic BNKT were compared to KT alone. Clinical differences related to undertaking bilateral nephrectomies showed increased total kidney volumes (P< .001). We assessed operative parameters, complications, and clinical outcomes. The complications were classified according to the Clavien‐Dindo system. In 148 transplant recipients, 51 underwent BNKT, and 97 KT alone. There was no difference in baseline demographics. BNKT recipients had longer cold ischemia time, required more ICU care, increased blood transfusions and longer hospital stays. The kidney function was similar in the first year in both groups, with no difference in delayed graft function, readmissions or severe grade III and IV complications within 3 months after surgery. Laparoscopic BNKT is safe and feasible at the time of living donor KT. Although higher acuity care is needed with a longer initial hospital stay, there are comparable posttransplant patient and allograft outcomes. For patients with symptomatic polycystic kidneys, laparoscopic bilateral native nephrectomies at the time of kidney transplantation is safe and effective, with comparable patient survival, allograft survival, and kidney function as kidney transplantation alone.

ALPPS procedure is gaining interest. Indications and technical aspects of this technique are still under debate [1].

Excessive salt intake and vasopressin may promote cyst growth in autosomal dominant polycystic kidney disease and glomerular filtration rate (GFR) decline in chronic kidney disease. Kramers et al.confirmed the effects of salt in a large autosomal dominant polycystic kidney disease cohort. Copeptin mediated 72% and 25% of the salt effects on GFR decline and kidney growth. Kidney growth did not significantly contribute to the copeptin-mediated salt effect on GFR. Differences in kidney growth and GFR decline trajectories and factors other than cyst growth contributing to GFR decline may explain the divergent effects.

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.

Objective: Limited data is available assessing the efficacy and safety of different anticoagulation (AC) strategies for prevention of thromboembolic events, major bleeding, and all-cause mortality in patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF). In this systematic review, we conducted a literature search to examine the possible association between different AC strategies and prevention of these adverse outcomes. Methods: Scientific databases (PubMed, EMBASE, and Scopus) were searched using relevant medical subject headings and keywords to retrieve studies published through September of 2019. Studies assessing the outcomes of interest in patients with HCM and AF receiving AC versus no AC as well as direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) were selected. Results: This review identified 14 observational studies evaluating thromboembolic events by AC strategies in 8,479 participants with concomitant HCM and AF. The use of AC was associated with a lower pooled incidence rate of total thromboembolic events at 9.5% (112 events in 1,175 patients) compared to 22.1% with no AC (108 events in 489 patients). In addition, the use of DOACs was associated with a lower pooled incidence rate of thromboembolic events at 4.7% (169 events in 3,576 patients) compared to 8.7% with VKAs (281 events in 3,239 patients). Furthermore, the use of DOACs compared to VKAs was associated with a lower pooled incidence rate of major bleeding and all-cause mortality at 3.8% (136 events in 3,576 patients) versus 6.8% (220 events in 3,239 patients) and 4.1% (124 events in 3,008 patients) versus 16.1% (384 events in 2,380 patients), respectively. Conclusions: AC of patients with concomitant HCM and AF was associated with a lower incidence of thromboembolic events when compared to antiplatelet therapy or no treatment. Treatment with DOACs was also associated with a lower incidence of thromboembolic events, major bleeding, and all-cause mortality when compared to VKAs. [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited, progressive nephropathy accounting for 4-10% of end stage renal disease worldwide. PKD1and PKD2are the most common disease loci, but even accounting for other genetic causes, about 7% of families remain unresolved. Typically, these unsolved cases have relatively mild kidney disease and often have a negative family history. Mosaicism, due to de novomutation in the early embryo, has rarely been identified by conventional genetic analysis of ADPKD families. Here we screened for mosaicism by employing two next generation sequencing screens, specific analysis of PKD1and PKD2employing long-range polymerase chain reaction, or targeted capture of cystogenes. We characterized mosaicism in 20 ADPKD families; the pathogenic variant was transmitted to the next generation in five families and sporadic in 15. The mosaic pathogenic variant was newly discovered by next generation sequencing in 13 families, and these methods precisely quantified the level of mosaicism in all. All of the mosaic cases had PKD1mutations, 14 were deletions or insertions, and 16 occurred in females. Analysis of kidney size and function showed the mosaic cases had milder disease than a control PKD1population, but only a few had clearly asymmetric disease. Thus, in a typical ADPKD population, readily detectable mosaicism by next generation sequencing accounts for about 1% of cases, and about 10% of genetically unresolved cases with an uncertain family history. Hence, identification of mosaicism is important to fully characterize ADPKD populations and provides informed prognostic information.

Research has been conducted on sugarcane genomes. The authors have investigated the genome complexity of sugarcane via the use of large-scale expressed sequence tag program, and they report that a vast number of unique genes has been identified, and that 90% of sugarcane expressed genes have been tagged.

In the TEMPO 3:4 Trial, treatment with tolvaptan, a vasopressin V2 receptor antagonist, slowed the increase in total kidney volume and decline in estimated glomerular filtration rate (eGFR) in autosomal dominant polycystic kidney disease (ADPKD). We investigated whether plasma copeptin levels, a marker of plasma vasopressin, are associated with disease progression, and whether pre-treatment copeptin and treatment-induced change in copeptin are associated with tolvaptan treatment efficacy. This post hoc analysis included 1,280 TEMPO 3:4 participants (aged 18-50 years, estimated creatinine clearance ≥60 ml/min and total kidney volume ≥750 mL) who had plasma samples available at baseline for measurement of copeptin using an automated immunofluorescence assay. In placebo-treated subjects, baseline copeptin predicted kidney growth and eGFR decline over 3 years. These associations were independent of sex, age, and baseline eGFR, but were no longer statistically significant after additional adjustment for baseline total kidney volume. In tolvaptan-treated subjects, copeptin increased from baseline to week 3 (6.3 pmol/L versus 21.9 pmol/L, respectively). In tolvaptan-treated subjects with higher baseline copeptin levels, a larger treatment effect was noted with respect to kidney growth rate and eGFR decline. Tolvaptan-treated subjects with a larger percentage increase in copeptin from baseline to week 3 had a better disease outcome, with less kidney growth and eGFR decline after three years. Copeptin holds promise as a biomarker to predict outcome and tolvaptan treatment efficacy in ADPKD.

Supplemental digital content is available in the text.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by cyst and kidney growth, which is hypothesized to cause loss of functioning renal mass and eventually end-stage kidney disease. However, the time course of decline in glomerular filtration rate (GFR) is poorly defined. The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease study is a 14-year observational cohort study of 241 adults with ADPKD. As an estimate of the rate of kidney growth, participants were stratified into 5 subclasses based on baseline age and magnetic resonance imaging measurements of total kidney volume (TKV) according to the method of Irazabal. GFR trajectories spanning over four decades of life were reconstructed and fitted using mixed polynomial models, which were validated using data from the HALT-PKD study. GFR trajectories were nonlinear, with a period of relative stability in most participants, followed by accelerating decline. The shape and slope of these trajectories were strongly associated with baseline Irazabal class. Patients with PKD1 mutations had a steeper GFR decline than patients with PKD2 mutations or with no detected mutation, largely mediated by the effect of genotype on Irazabal class. Thus, GFR decline in ADPKD is nonlinear, and its trajectory throughout adulthood can be predicted from a single measurement of kidney volume. These models can be used for clinical prognostication, clinical trial design, and patient selection for clinical interventions. Our findings support a causal link between growth in kidney volume and GFR decline, adding support for the use of TKV as a surrogate endpoint in clinical trials.

Food allergy is a very frequent and increasingly common disease in children and adolescents. It affects quality of life and can even be life-threatening. Given that 10–18% of allergic/anaphylactic food reactions take place in schools, it is essential to provide school personnel with training on the management of reactions.

In autosomal dominant polycystic kidney disease (ADPKD), obtaining measured total kidney volume (mTKV) by magnetic resonance (MR) imaging and manual tracing is time consuming. Two alternative MR imaging methods have recently been proposed to estimate TKV (eTKVellipsoidand eTKVPANK), which require less time.

The diagnosis of autosomal dominant polycystic kidney disease (ADPKD) relies on imaging criteria in the setting of a positive familial history. Molecular analysis, seldom used in clinical practice, identifies a causative mutation in >90% of cases in the genes PKD1, PKD2,or rarely GANAB. We report the clinical and genetic dissection of a 7-generation pedigree, resulting in the diagnosis of 2 different cystic disorders. Using targeted next-generation sequencing of 65 candidate genes in a patient with an ADPKD-like phenotype who lacked the familial PKD2mutation, we identified a COL4A1mutation (p.Gln247*) and made the diagnosis of HANAC (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome. While 4 individuals had ADPKD-PKD2, various COL4A1-related phenotypes were identified in 5 patients, and 3 individuals with likely digenic PKD2/COL4A1disease reached end-stage renal disease at around 50 years of age, significantly earlier than observed for either monogenic disorder. Thus, using targeted next-generation sequencing as part of the diagnostic approach in patients with cystic diseases provides differential diagnoses and identifies factors underlying disease variability. As specific therapies are rapidly developing for ADPKD, a precise etiologic diagnosis should be paramount for inclusion in therapeutic trials and optimal patient management.

El síndrome metabólico (SM) es un conjunto de condiciones metabólicas que incluyen obesidad abdominal, reducción de las concentraciones de colesterol unido a las high density lipoproteins(c-HDL, «lipoproteínas de alta densidad»), triglicéridos elevados, aumento de la presión arterial e hiperglucemia. Dado que se trata de una enfermedad multicausal, el objetivo de este estudio es identificar las variables psicológicas, emocionales y de estilo de vida que pueden ejercer una influencia sobre los diferentes componentes del SM.

Previous clinical studies of autosomal dominant polycystic kidney disease (ADPKD) reported that loss of kidney function usually follows a steep and relentless course. A detailed examination of individual patterns of decline in estimated glomerular filtration rate (eGFR) has not been performed.

Background: The HALT PKD trial in early autosomal dominant polycystic kidney disease (ADPKD) showed that intensive control of systolic blood pressure to 95-110 mmHg was associated with a 14% slower rate of kidney volume growth compared to standard control. It is unclear whether this result was due to greater blockade of the renin-angiotensin-aldosterone system (RAAS) by allowing the use of higher drug doses in the low blood pressure arm, or due to the lower blood pressure per se. Methods: In this secondary analysis of HALT PKD Study A, we categorized participants into high and low dose groups based on the median daily equivalent dose of RAAS blocking drugs used after the initial dose titration period. Using linear mixed models, we compared the percent change in total kidney volume and the slope of estimated glomerular filtration rate (eGFR) between the 2 groups. We also assessed the effects of time-varying dose and time-varying blood pressure parameters on these outcomes. Results: Subjects in the high dose group (n=252) did not experience a slower increase in total kidney volume than those in the low-dose (n=225) group, after adjustment for age, sex, genotype, and BP arm. The chronic slope of eGFR decline was similar in the 2 groups. Higher time-varying systolic blood pressure was associated with a steeper decline in eGFR. Conclusion: ADPKD progression (as detected by eGFR decline and TKV increase) was ameliorated by intense blood pressure control as opposed to pharmacologic intensity of RAAS blockade.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive enlargement of kidney cysts leading to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Identification of an early biomarker that can predict progression of CKD is urgently needed. In an earlier Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study (a prospective, multicenter, observational analysis of 241 patients with ADPKD initiated in 2000), baseline height-adjusted total kidney volume (htTKV) was shown to be associated with development of CKD stage 3 after eight years of follow-up. Here we conducted an extended study and found that in a multivariable logistic regression model, baseline htTKV was shown to be a strong, independent predictor for the development of CKD after a median follow-up of 13 years. The odds ratio of reaching each CKD stage per 100 mL/m increment in htTKV was 1.38 (95% confidence interval 1.19-1.60) for stage 3, 1.42 (1.23-1.64) for stage 4, and 1.35 (1.18-1.55) for stage 5 or ESRD. Baseline htTKV was also associated with relative decreases in the glomerular filtration rate of 30%, and 57% or more. Moreover, the rate of change in htTKV was negatively correlated with the slope of the glomerular filtration rate. While ADPKD genotype was also associated with CKD outcomes, it was not an independent prognostic factor after adjusting for htTKV. Thus, baseline total kidney volume and the rate of kidney growth are strongly associated with the development of advanced stages of CKD. These findings support the use of total kidney volume as a prognostic and potentially monitoring biomarker in ADPKD.

Magnetic resonance imaging (MRI) examinations provide high-resolution information about the anatomic structure of the kidneys and are used to measure total kidney volume (TKV) in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Height-adjusted TKV (HtTKV) has become the gold-standard imaging biomarker for ADPKD progression at early stages of the disease when estimated glomerular filtration rate (eGFR) is still normal. However, HtTKV does not take advantage of the wealth of information provided by MRI. Here we tested whether image texture features provide additional insights into the ADPKD kidney that may be used as complementary information to existing biomarkers. A retrospective cohort of 122 patients from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study was identified who had T2-weighted MRIs and eGFR values over 70 mL/min/1.73m2at the time of their baseline scan. We computed nine distinct image texture features for each patient. The ability of each feature to predict subsequent progression to CKD stage 3A, 3B, and 30% reduction in eGFR at eight-year follow-up was assessed. A multiple linear regression model was developed incorporating age, baseline eGFR, HtTKV, and three image texture features identified by stability feature selection (Entropy, Correlation, and Energy). Including texture in a multiple linear regression model (predicting percent change in eGFR) improved Pearson correlation coefficient from -0.51 (using age, eGFR, and HtTKV) to -0.70 (adding texture). Thus, texture analysis offers an approach to refine ADPKD prognosis and should be further explored for its utility in individualized clinical decision making and outcome prediction.

Rare kidney diseases encompass at least 150 different conditions, most of which are inherited. Although individual rare kidney diseases raise specific issues, as a group these rare diseases can have overlapping challenges in diagnosis and treatment. These challenges include small numbers of affected patients, unidentified causes of disease, lack of biomarkers for monitoring disease progression, and need for complex care. To address common clinical and patient issues among rare kidney diseases, the KDIGO Controversies Conference entitled, Common Elements in Rare Kidney Diseases, brought together a panel of multidisciplinary clinical providers and patient advocates to address five central issues for rare kidney diseases. These issues encompassed diagnostic challenges, management of kidney functional decline and progression of chronic kidney disease, challenges in clinical study design, translation of advances in research to clinical care, and provision of practical and integrated patient support. Thus, by a process of consensus, guidance for addressing these challenges was developed and is presented here.

ADPKD is caused by pathogenic variants in PKD1or PKD2, encoding polycystin-1 and -2 proteins. Polycystins are expressed in osteoblasts and chondrocytes in animal models, and loss of function is associated with low bone mineral density (BMD) and volume. However, it is unclear whether these variants impact bone strength in ADPKD patients. Here, we examined BMD in ADPKD after kidney transplantation (KTx). This retrospective observational study retrieved data from adult patients who received a KTx over the past 15 years. Patients with available dual-energy X-ray absorptiometry (DXA) of the hip and/or lumbar spine (LS) post-transplant were included. ADPKD patients (n = 340) were matched 1:1 by age (±2 years) at KTx and sex with non-diabetic non-ADPKD patients (n = 340). Patients with ADPKD had slightly higher BMD and T-scores at the right total hip (TH) as compared to non-ADPKD patients [BMD: 0.951 vs. 0.897, p < 0.001; T-score: −0.62 vs. -0.99, p < 0.001] and at left TH [BMD: 0.960 vs. 0.893, p < 0.001; T-score: −0.60 vs. -1.08, p < 0.001], respectively. Similar results were found at the right femoral neck (FN) between ADPKD and non-ADPKD [BMD: 0.887 vs. 0.848, p = 0.001; T-score: −1.20 vs. -1.41, p = 0.01] and at left FN [BMD: 0.885 vs. 0.840, p < 0.001; T-score: −1.16 vs. -1.46, p = 0.001]. At the LS level, ADPKD had a similar BMD and lower T-score compared to non-ADPKD [BMD: 1.120 vs. 1.126, p = 0.93; T-score: −0.66 vs. -0.23, p = 0.008]. After adjusting for preemptive KTx, ADPKD patients continued to have higher BMD T-scores in TH and FN. Our findings indicate that BMD by DXA is higher in patients with ADPKD compared to non-ADPKD patients after transplantation in sites where cortical but not trabecular bone is predominant. The clinical benefit of the preserved cortical bone BMD in patients with ADPKD needs to be explored in future studies.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of multiple kidney cysts that leads to growth in total kidney volume (TKV) and progression to kidney failure. Venglustat is a glucosylceramide synthase inhibitor that has been shown to inhibit cyst growth and reduce kidney failure in preclinical models of ADPKD.

The failure of the polycystins (PCs) to function in primary cilia is thought to be responsible for autosomal dominant polycystic kidney disease (ADPKD). Primary cilia integrate multiple cellular signaling pathways, including calcium, cAMP, Wnt, and Hedgehog, which control cell proliferation and differentiation. It has been proposed that mutated PCs result in reduced intracellular calcium, which in turn upregulates cAMP, protein kinase A (PKA) signaling, and subsequently other proliferative signaling pathways. However, the role of PKA in ADPKD has not been directly ascertained in vivo, although the expression of the main regulatory subunit of PKA in cilia and other compartments (PKA-RIα, encoded by PRKAR1A) is increased in a mouse model orthologous to ADPKD. Therefore, we generated a kidney-specific knockout of Prkar1ato examine the consequences of constitutive upregulation of PKA on wild-type and Pkd1hypomorphic (Pkd1RC) backgrounds. Kidney-specific loss of Prkar1ainduced renal cystic disease and markedly aggravated cystogenesis in the Pkd1RCmodels. In both settings, it was accompanied by upregulation of Src, Ras, MAPK/ERK, mTOR, CREB, STAT3, Pax2 and Wnt signaling. On the other hand, Gli3 repressor activity was enhanced, possibly contributing to hydronephrosis and impaired glomerulogenesis in some animals. To assess the relevance of these observations in humans we looked for and found evidence for kidney and liver cystic phenotypes in the Carney complex, a tumoral syndrome caused by mutations in PRKAR1A. These observations expand our understanding of the pathogenesis of ADPKD and demonstrate the importance of PRKAR1Ahighlighting PKA as a therapeutic target in ADPKD.

Polycystic kidney disease (PKD) involves progressive hepatorenal cyst expansion and fibrosis, frequently leading to end-stage renal disease. Increased vasopressin and cAMP signaling, dysregulated calcium homeostasis, and hypertension play major roles in PKD progression. The guanylyl cyclase A agonist, B-type natriuretic peptide (BNP), stimulates cGMP and shows anti-fibrotic, anti-hypertensive, and vasopressin-suppressive effects, potentially counteracting PKD pathogenesis. Here, we assessed the impacts of guanylyl cyclase A activation on PKD progression in a rat model of PKD. Sustained BNP production significantly reduced kidney weight, renal cystic indexes and fibrosis, in concert with suppressed hepatic cystogenesis in vivo. In vitro, BNP decreased cystic epithelial cell proliferation, suppressed fibrotic gene expression, and increased intracellular calcium. Together, our data demonstrate multifaceted effects of sustained activation of guanylyl cyclase A on polycystic kidney and liver disease. Thus, targeting the guanylyl cyclase A-cGMP axis may provide a novel therapeutic strategy for hepatorenal fibrocystic diseases.

Background: Autosomal dominant polycystic kidney disease (ADPKD) commonly results in end-stage renal disease (ESRD), yet a long-term treatment that is well tolerated is still lacking. In a small randomized trial in children and adolescents pravastatin administration for 3 years was associated with reduced renal cyst growth, but no large trial has tested the effect of statins in adults. Methods: We performed a post-hoc analysis of the HALT PKD trials to compare outcomes of participants who never used statins with those who used statin for at least 3 years. Because statins were not randomly allocated, we used propensity score models with inverse probability of treatment weighting to account for imbalances between the groups. For subjects in Study A (preserved renal function, n=438) relevant outcomes were percent change in total kidney and liver volume and the rate of decline in estimated glomerular filtration rate (eGFR); for those in Study B (reduced renal function, n=352) we compared time to the composite endpoint of death, ESRD or 50% decline in eGFR. Follow-up was 5-8 years. Results: There was no difference in any outcome between the 2 groups. However, limitations of this analysis are the small number of statin users in Study A, different statin drugs and doses used, non-randomized allocation and advanced disease stage in Study B. Conclusion: Although this post-hoc analysis of the HALT PKD trials does not demonstrate a benefit of statin therapy, conclusions remain preliminary. A larger randomized trial in young people with ADPKD is necessary to answer the question whether statins can slow renal cyst growth and preserve kidney function.

The CRISP study of polycystic kidney disease (PKD) found that urinary sodium excretion associated with the rate of total kidney volume increase. Whether sodium restriction slows the progression of Autosomal Dominant PKD (ADPKD) is not known. To evaluate this we conducted a post hoc analysis of the HALT-PKD clinical trials of renin-angiotensin blockade in patients with ADPKD. Linear mixed models examined whether dietary sodium affected rates of total kidney volume or change in estimated glomerular filtration rate (eGFR) in patients with an eGFR over 60 ml/min/1.73 m2(Study A) or the risk for a composite endpoint of 50% reduction in eGFR, end-stage renal disease or death, or the rate of eGFR decline in patients with an eGFR 25–60 ml/min/1.73 m2(Study B) all in patients initiated on an under100 mEq sodium diet. During the trial urinary sodium excretion significantly declined by an average of 0.25 and 0.41 mEq/24 hour per month in studies A and B, respectively. In Study A, averaged and time varying urinary sodium excretions were significantly associated with kidney growth (0.43%/year and 0.09%/year, respectively, for each 18 mEq urinary sodium excretion). Averaged urinary sodium excretion was not significantly associated with faster eGFR decline (–0.07 ml/min/1.73m2/year for each 18 mEq urinary sodium excretion). In Study B, the averaged but not time-varying urinary sodium excretion significantly associated with increased risk for the composite endpoint (hazard ratio 1.08 for each 18 mEq urinary sodium excretion) and a significantly faster eGFR decline (–0.09 ml/min/1.73m2/year for each mEq 18 mEq urinary sodium excretion). Thus, sodium restriction is beneficial in the management of ADPKD.

Kidney pain is a common complication in patients with autosomal dominant polycystic kidney disease (ADPKD), and data from the TEMPO 3:4 trial suggested that tolvaptan, a vasopressin V2 receptor antagonist, may have a positive effect on kidney pain in this patient group. Because pain is difficult to measure, the incidence of kidney pain leading to objective medical interventions was used in the present study to assess pain.

Substrate integrated circuits (SIC) have attracted much attention in the last years because of their great potential of low cost, easy manufacturing, integration in a circuit board, and higher-quality factor than planar circuits. A first suite of SIC where the waves propagate through dielectric have been first developed, based on the well-known substrate integrated waveguide (SIW) and related technological implementations. One step further has been made with a new suite of empty substrate integrated waveguides, where the waves propagate through air, thus reducing the associated losses. This is the case of the empty substrate integrated waveguide (ESIW) or the air-filled substrate integrated waveguide (air-filled SIW). However, all these SIC are Hplane structures, so classical Hplane solutions in rectangular waveguides have already been mapped to most of these new SIC. In this paper a novel Eplane empty substrate integrated waveguide (ESIW-E) is presented. This structure allows to easily map classical Eplane solutions in rectangular waveguide to this new substrate integrated solution. It is similar to the ESIW, although more layers are needed to build the structure. A wideband transition (covering the frequency range between 33 GHz and 50 GHz) from microstrip to ESIW-E is designed and manufactured. Measurements are successfully compared with simulation, proving the validity of this new SIC. A broadband high-frequency phase shifter (for operation from 35 GHz to 47 GHz) is successfully implemented in ESIW-E, thus proving the good performance of this new SIC in a practical application. First Eplane device in empty substrate integrated waveguideLow reflection transition from microstrip to Eplane empty substrate integrated waveguideHigh-performance and high-frequency phase shifter in Eplane empty substrate integrated waveguide

Tolvaptan is associated with risk of drug-induced liver injury when used to treat autosomal dominant polycystic kidney disease (ADPKD). After this risk was described based on the clinical trials TEMPO 3:4 and TEMPO 4:4, additional data from the REPRISE trial and a long-term extension of TEMPO 4:4, REPRISE, and other tolvaptan trials in ADPKD have become available. To further characterize the hepatic safety profile of tolvaptan, an analysis of the expanded dataset was conducted.

New image-derived biomarkers for patients affected by autosomal dominant polycystic kidney disease are needed to improve current clinical management. The measurement of total kidney volume (TKV) provides critical information for clinicians to drive care decisions. However, patients with similar TKV may present with very different phenotypes, often requiring subjective decisions based on other factors (e.g., appearance of healthy kidney parenchyma, a few cysts contributing significantly to overall TKV, etc.). In this study, we describe a new technique to individually segment cysts and quantify biometric parameters including cyst volume, cyst number, parenchyma volume, and cyst parenchyma surface area. Using data from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study the utility of these new parameters was explored, both quantitatively as well as visually. Total cyst number and cyst parenchyma surface area showed superior prediction of the slope of estimated glomerular filtration rate decline, kidney failure and chronic kidney disease stages 3A, 3B, and 4, compared to TKV. In addition, presentations such as a few large cysts contributing significantly to overall kidney volume were shown to be much better stratified in terms of outcome predictions. Thus, these new image biomarkers, which can be obtained automatically, will have great utility in future studies and clinical care for patients affected by autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive renal cyst formation that leads to kidney failure. Tolvaptan, a vasopressin 2 receptor (V2R) antagonist, is the only drug approved to treat ADPKD patients with rapid disease progression. The use of tolvaptan is limited by reduced tolerability from aquaretic effects and potential hepatotoxicity. Thus, the search for more effective drugs to slow down the progression of ADPKD is urgent and challenging. Drug repurposing is a strategy for identifying new clinical indications for approved or investigational medications. Drug repurposing is increasingly becoming an attractive proposition due to its cost- and time-efficiencies and known pharmacokinetic and safety profiles. In this review, we focus on the repurposing approaches to identify suitable drug candidates to treat ADPKD and prioritization and implementation of candidates with high probability of success. Identification of drug candidates through understanding of disease pathogenesis and signaling pathways is highlighted.