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Ketogenic metabolic therapy (KMT) is a medical nutrition therapy to address certain health and disease conditions. It is increasingly used for many non-communicable diseases that are rooted in abnormal metabolic health. Since chronic kidney disease (CKD) is commonly caused by overnutrition leading to hyperglycemia, insulin resistance and diabetes mellitus, the carbohydrate restriction inherent in KMT may offer a therapeutic option. Numerous studies have found that various forms of KMT are safe for individuals with CKD and may lead to improvement of renal function. This is in contrast to the current standard pharmacological approach to CKD that only slows the relentless progression towards renal failure. Kidney care providers, including physicians and dietitians, are usually not aware of non-standard dietary interventions, including KMT, and often criticize KMT due to common misconceptions and uncertainty about the underlying science, including the common misconception that KMT must involve high protein or meat consumption. This review article discusses the rationales for using KMT, including plant-dominant KMT, for treatment of CKD, clarifies common misconceptions, summarizes the results of clinical studies and discusses why KMT is emerging as an effective medical nutrition therapy (MNT) to consider for patients with kidney disease. KMT, including its plant-dominant versions, can expand a practitioners kidney health toolbox and will likely become a first-line therapy for CKD in certain CKD-associated conditions such as obesity, metabolic syndrome and polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and causes significant morbidity, ultimately leading to kidney failure. PKD pathogenesis is characterized by complex and dynamic alterations in multiple cell types during disease progression, hampering a deeper understanding of disease mechanism and the development of therapeutic approaches. Here, we generate a single-nucleus multimodal atlas of an orthologous mouse PKD model at early, mid, and late timepoints, consisting of 125,434 single-nucleus transcriptomic and epigenetic multiomes. We catalog differentially expressed genes and activated epigenetic regions in each cell type during PKD progression, characterizing cell-type-specific responses to Pkd1 deletion. We describe heterogeneous, atypical collecting duct cells as well as proximal tubular cells that constitute cyst epithelia in PKD. The transcriptional regulation of the cyst lining cell marker GPRC5A is conserved between mouse and human PKD cystic epithelia, suggesting shared gene regulatory pathways. Our single-nucleus multiomic analysis of mouse PKD provides a foundation to understand the earliest changes molecular deregulation in a mouse model of PKD at a single-cell resolution. [ABSTRACT FROM AUTHOR]

The editorial in "Frontiers in Endocrinology" discusses the role of Hepatocyte nuclear factor 4 alpha (HNF4a) as a master regulator of liver-specific transcription, with implications for various human diseases. The article covers the evolutionary origins of HNF4a, mutations linked to diabetes, and the structure of the protein. Research on HNF4a's role in liver regeneration, metabolism, and intestines is highlighted, along with potential future research directions. The article emphasizes the importance of HNF4a in various tissues and its potential therapeutic implications. [Extracted from the article]

Background: Prenatal ultrasound findings of fetal bilateral echogenic kidneys accompanied by oligohydramnios can be highly stressful for both pregnant women and physicians. The diversity of underlying causes makes it challenging to confirm a prenatal diagnosis, predict postnatal outcomes, and counsel regarding recurrence risks in future pregnancies. Case Presentation: We report two cases of abnormal fetal echogenic kidneys with oligohydramnios detected in the early third trimester. Autosomal recessive polycystic kidney disease (ARPKD), a rare genetic syndrome, was initially suspected in both cases. However, postnatal diagnoses differed: the first case was confirmed as glomerulocystic kidney disease (GCKD) through renal pathology, while the second case was diagnosed as ARPKD with a compound heterozygous likely pathogenic PKHD1 mutation. Conclusion: Prenatal diagnosis of fetal echogenic kidneys with oligohydramnios should prioritize accurate diagnosis. Given the differences in the clinical spectrum, GCKD should be considered a differential diagnosis for this condition, particularly ARPKD. This study highlights the importance and benefits of molecular diagnosis and postnatal renal pathology for precise diagnosis and effective counseling. [ABSTRACT FROM AUTHOR]

Polycystin-1 (PC1) is the protein product of the PKD1 gene whose mutation causes autosomal dominant Polycystic Kidney Disease (ADPKD). PC1 is an atypical G protein-coupled receptor (GPCR) with an autocatalytic GAIN domain that cleaves PC1 into extracellular N-terminal and membrane-embedded C-terminal (CTF) fragments. Recently, activation of PC1 CTF signaling was shown to be regulated by a stalk tethered agonist (TA), resembling the mechanism observed for adhesion GPCRs. Here, synthetic peptides of the first 9-(p9), 17-(p17), and 21-residues (p21) of the PC1 stalk TA were shown to re-activate signaling by a stalkless CTF mutant in human cell culture assays. Novel Peptide Gaussian accelerated molecular dynamics (Pep-GaMD) simulations elucidated binding conformations of p9, p17, and p21 and revealed multiple specific binding regions to the stalkless CTF. Peptide agonists binding to the TOP domain of PC1 induced close TOP-putative pore loop interactions, a characteristic feature of stalk TA-mediated PC1 CTF activation. Additional sequence coevolution analyses showed the peptide binding regions were consistent with covarying residue pairs identified between the TOP domain and the stalk TA. These insights into the structural dynamic mechanism of PC1 activation by TA peptide agonists provide an in-depth understanding that will facilitate the development of therapeutics targeting PC1 for ADPKD treatment. [ABSTRACT FROM AUTHOR]

Background: Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are major genetic polycystic kidney diseases that can progress to end-stage kidney disease (ESKD). Longitudinal data on the clinical characteristics associated with clinical outcomes in polycystic kidney disease (PKD), including the development of ESKD and cardiovascular disease (CVD) are lacking in Japan. To address this unmet need the authors are establishing a novel, web-based, Nationwide Cohort Registry Study—the Japanese Registry of PKD (JRP). Methods: The JRP is a prospective cohort study for ADPKD (aim to recruit n = 1000 patients), and both a retrospective and prospective study for ARPKD (aim to recruit n = 100). In the prospective registry, patients will be followed-up for 10 years every 6 months and 12 months for patients with ADPKD and ARPKD, respectively. Data collection will be recorded on Research Electronic Data Capture (REDCap) starting on April 1, 2024, with recruitment ending on March 31, 2029. (jRCT 1030230618). Results: Data to be collected include: baseline data, demographics, diagnostic and genetic information, radiological and laboratory findings, and therapeutic interventions. During follow-up, clinical events such as development of ESKD, hospitalization, occurrence of extra kidney complications including CVD events, and death will be recorded, as well as patient-reported health-related quality of life for patients with ADPKD. Conclusions: The JRP is the first nationwide registry study for patients with ADPKD and ARPKD in Japan, providing researchers with opportunities to advance knowledge and treatments for ADPKD and ARPKD, and to inform disease management and future clinical practice. [ABSTRACT FROM AUTHOR]

The HNF1B gene, located on chromosome 17q12, encodes a transcription factor essential for the development of several organs. It regulates the expression of multiple genes in renal, pancreatic, hepatic, neurological, and genitourinary tissues during prenatal and postnatal development, influencing processes such as nephrogenesis, cellular polarity, tight junction formation, cilia development, ion transport in the renal tubule, and renal metabolism. Mutations that alter the function of Hnf1b deregulate those processes, leading to various pathologies characterized by both renal and extrarenal manifestations. The main renal diseases that develop are polycystic kidney disease, hypoplastic or dysplastic kidneys, structural abnormalities, Congenital Anomalies of the Kidney and Urinary Tract (CAKUT), and electrolyte imbalances such as hyperuricemia and hypomagnesemia. Extrarenal manifestations include Maturity-Onset Diabetes of the Young (MODY), hypertransaminasemia, genital and urinary tract malformations, Autism Spectrum Disorder (ASD), and other neurodevelopmental disorders. Patients with HNF1B alterations typically carry either punctual mutations or a monoallelic microdeletion in the 17q12 region. Future research on the molecular mechanisms and genotype–phenotype correlations in HNF1B-related conditions will enhance our understanding, leading to improved clinical management, genetic counseling, monitoring, and patient care. [ABSTRACT FROM AUTHOR]

Understanding chronic kidney disease (CKD) through the lens of evolutionary biology highlights the mismatch between our Paleolithic-optimized genes and modern diets, which led to the dramatically increased prevalence of CKD in modern societies. In particular, the Standard American Diet (SAD), high in carbohydrates and ultra-processed foods, causes conditions like type 2 diabetes (T2D), chronic inflammation, and hypertension, leading to CKD. Autosomal dominant polycystic kidney disease (ADPKD), a genetic form of CKD, is characterized by progressive renal cystogenesis that leads to renal failure. This review challenges the fatalistic view of ADPKD as solely a genetic disease. We argue that, just like non-genetic CKD, modern dietary practices, lifestyle, and environmental exposures initiate and accelerate ADPKD progression. Evidence shows that carbohydrate overconsumption, hyperglycemia, and insulin resistance significantly impact renal health. Additionally, factors like dehydration, electrolyte imbalances, nephrotoxin exposure, gastrointestinal dysbiosis, and renal microcrystal formation exacerbate ADPKD. Conversely, carbohydrate restriction, ketogenic metabolic therapy (KMT), and antagonizing the lithogenic risk show promise in slowing ADPKD progression. Addressing disease triggers through dietary modifications and lifestyle changes offers a conservative, non-pharmacological strategy for disease modification in ADPKD. This comprehensive review underscores the urgency of integrating diet and lifestyle factors into the clinical management of ADPKD to mitigate disease progression, improve patient outcomes, and offer therapeutic choices that can be implemented worldwide at low or no cost to healthcare payers and patients. [ABSTRACT FROM AUTHOR]

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 m2 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/1.73m2. EGFR declined by 3.7 mL/min/1.73m2 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. [ABSTRACT FROM AUTHOR]

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary kidney disease, characterized by enlarged kidneys with numerous cysts, high blood pressure, and a variety of extrarenal complications. This disease is a significant cause of renal failure and requires accurate differentiation from other cystic kidney diseases, especially when family history does not clearly indicate ADPKD. This is crucial due to differences in prognosis, treatment, and familial implications. Advanced molecular genetics and imaging techniques are employed to diagnose and assess the prognosis of patients and their families. Case presentation: The case study revolves around three patients from the same family—two sisters and one daughter—referred to a nephrology department for ADPKD management. The initial proband, a 42-year-old woman, experienced abdominal discomfort leading to an ultrasound that suggested ADPKD. However, MRI findings indicated standard-sized kidneys with bilateral parapelvic cysts, and no genetic markers for ADPKD were found. Her sister, presenting with controlled hypertension and similar ultrasound findings, also had her initial ADPKD diagnosis refuted by MRI and genetic testing, which revealed no significant mutations. The daughter, however, exhibited a different scenario with enlarged kidneys and multiple cysts characteristic of early-stage ADPKD. Genetic testing confirmed a deleterious PKD1 mutation, suggesting a de novo mutation, as her father showed no signs of the disease. Conclusion: This study highlights the complexity and necessity of thorough diagnostic processes in suspected ADPKD cases to prevent misdiagnosis. The initial symptoms and imaging might misleadingly suggest ADPKD, as seen in the cases of the two older patients. Still, further detailed imaging and genetic analyses revealed no ADPKD, preventing inappropriate treatment and stress. In contrast, the younger patient's distinctive clinical and genetic profile confirmed ADPKD, illustrating the variability within even closely related individuals. Such detailed assessments are crucial in guiding correct treatment decisions and providing accurate familial counseling, emphasizing the importance of considering a broader spectrum of renal cystic disorders before confirming a diagnosis of ADPKD. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions Serum, liver and urinary bile acids are increased, and hepatic transport protein levels are decreased in a non‐clinical model of polycystic kidney disease. Similar changes in patients with autosomal dominant polycystic kidney disease (ADPKD) may predispose them to drug‐induced liver injury (DILI) and hepatic drug–drug interactions (DDIs). Systemic coproporphyrin‐I (CP‐I), an endogenous biomarker for hepatic OATP1B function and MRP2 substrate, is used to evaluate OATP1B‐mediated DDI risk in humans. In this clinical observational cohort‐comparison study, bile acid profiles and CP‐I concentrations in healthy volunteers and patients with ADPKD were compared.Serum and urine samples from healthy volunteers (n = 16) and patients with ADPKD (n = 8) were collected. Serum bile acids, and serum and urine CP‐I concentrations, were quantified by ultra‐performance liquid chromatography tandem mass spectrometry (UPLC‐MS/MS).Patients with ADPKD exhibited increased serum concentrations of total (1.3‐fold) and taurine‐conjugated (2.8‐fold) bile acids compared to healthy volunteers. Specifically, serum concentrations of six bile acids known to be more hydrophobic/hepatotoxic (glycochenodeoxycholate, taurochenodeoxycholate, taurodeoxycholate, lithocholate, glycolithocholate and taurolithocholate) were increased (1.5‐, 2.9‐, 2.8‐, 1.6‐, 1.7‐ and 2.7‐fold, respectively) in patients with ADPKD. Furthermore, serum CP‐I concentrations were elevated and the renal clearance of CP‐I was reduced in patients with ADPKD compared to healthy volunteers.Increased exposure to bile acids may increase susceptibility to DILI in some patients with ADPKD. Furthermore, the observed increase in serum CP‐I concentrations could be attributed, in part, to impaired OATP1B function in patients with ADPKD, which could increase the risk of DDIs involving OATP1B substrates compared to healthy volunteers. [ABSTRACT FROM AUTHOR]

Background: Helsmoortel-Van der Aa syndrome was officially documented in 2014. Helsmoortel-Van der Aa syndrome is an extremely rare complex neurodegenerative disorder characterized by reduced intellectual capacity, motor dysfunction, facial dysmorphism, impaired development, and an increased predisposition to autism spectrum disorder. In addition, many patients also present with neuropsychiatric disorders, including attention deficit hyperactivity disorder, anxiety disorders, and various behavioral abnormalities. Helsmoortel-Van der Aa syndrome is challenging to identify solely on the basis of symptoms, and genetic investigations, including exome sequencing, may facilitate diagnosis. Case presentation: We report a case of 13-year-old Saudi patient who presented with dysmorphic features as illustrated in Fig. 1, severe mental retardation, autism spectrum disorder, and attention deficit hyperactivity disorder. Initial genetic testing was unremarkable; thus, a clinical exome analysis was performed to identify the genetic basis of the condition. Conclusions: Clinical exome analysis indicated an autosomal dominant Helsmoortel-Van der Aa syndrome with a likely pathogenic de novo variant within the activity-dependent neuroprotector homeobox (ADNP) gene not previously reported in Helsmoortel-Van der Aa syndrome. The patient had a right-sided solitary kidney and polycystic ovaries, conditions that were not previously associated with HVDAS. [ABSTRACT FROM AUTHOR]

Background/aim: Autosomal recessive polycystic kidney disease is an inherited kidney disease. This study aims to detect rare and common DNA variants of the PKHD1 gene using next-generation sequencing (NGS) and to classify them in terms of being pathogenic according to The American College of Medical Genetics and Genomics. Materials and methods: NGS analysis was performed on the DNA of 304 patients who were referred to Ege University Molecular Medicine Laboratory with suspected polycystic kidney disease. Results: As a result, a total of 82 different DNA variants, 16 of which were novel, were detected. The breakdown of the variants found is as follows: 73 (89.02%) were missense variants, six (7.32%) nonsense variants, two (2.44%) frameshift deletions, and one (1.22%) nonframeshift deletion. According to The American College of Medical Genetics and Genomics classification of these variants, 26 were benign (Class 5), two were likely benign (Class 4), 36 were of uncertain significance (Class 3), and nine were likely pathogenic (Class 2), nine of which are pathogenic variants (Class 1). Heterozygosity was found in 39 (63.9%) patients, homozygosity in six (9.8%) patients, compound heterozygosity in 12 (19.7%) patients, and complex genotype in four (6.6%) patients in which variants in Class 1, Class 2 and Class 3 were determined according to ACMG classification. When the exon distributions of the DNA variants detected in the PKHD1 gene were analyzed, the most common exons of the DNA variant are exon 32 (n = 9), exon 58 (n = 8), exon 67 (n = 6), exon 61 (n = 5), 30 exons (n = 4). Conclusion: This fast and economical molecular diagnostic approach will provide a reliable prenatal diagnostic option, enabling definitive disease diagnosis and the identification of carriers. [ABSTRACT FROM AUTHOR]

Polycystic kidney disease (PKD), a disease characterized by the enlargement of the kidney through cystic growth is the fourth leading cause of end-stage kidney disease world-wide. Transient receptor potential Vanilloid 4 (TRPV4), a calcium-permeable TRP, channel participates in kidney cell physiology and since TRPV4 forms complexes with another channel whose malfunction is associated to PKD, TRPP2 (or PKD2), we sought to determine whether patients with PKD, exhibit previously unknown mutations in TRPV4. Here, we report the presence of mutations in the TRPV4 gene in patients diagnosed with PKD and determine that they produce gain-of-function (GOF). Mutations in the sequence of the TRPV4 gene have been associated to a broad spectrum of neuropathies and skeletal dysplasias but not PKD, and their biophysical effects on channel function have not been elucidated. We identified and examined the functional behavior of a novel E6K mutant and of the previously known S94L and A217S mutant TRVP4 channels. The A217S mutation has been associated to mixed neuropathy and/or skeletal dysplasia phenotypes, however, the PKD carriers of these variants had not been diagnosed with these reported clinical manifestations. The presence of certain mutations in TRPV4 may influence the progression and severity of PKD through GOF mechanisms. PKD patients carrying TRVP4 mutations are putatively more likely to require dialysis or renal transplant as compared to those without these mutations. Graphical Abstract Abstract graph showing a schematic representation of a wild-type TRPV4 channel compared to the increased activity of a mutant TRPV4 channel carrying one of the two TRPV4 mutations located in the amino-terminal domain and found in a patient cohort diagnosed with polycystic kidney disease.Abstract graph showing a schematic representation of a wild-type TRPV4 channel compared to the increased activity of a mutant TRPV4 channel carrying one of the two TRPV4 mutations located in the amino-terminal domain and found in a patient cohort diagnosed with polycystic kidney disease. [ABSTRACT FROM AUTHOR]

Background: Despite its severity, there has been a lack of adequate study on autosomal dominant polycystic kidney disease (ADPKD) in Ethiopia. This study assessed the clinical profile and determinant factors contributing to renal disease progression. Methods: A retrospective study was conducted on 114 patients for 6 years in Addis Ababa. Patients with ADPKD who had follow-up visits at two health centers were included. Results: The mean age at diagnosis was 42.7 ± 12.7 years, with 43% reporting a positive family history of ADPKD. Approximately 22 patients (20%) developed end-stage renal disease, and 12 patients died. The mean estimated glomerular filtration rate at the initial visit was 72.4 mL/min/1.73 m2. The key risk factors associated with disease progression included younger age at diagnosis [adjusted Odds Ratio (aOR): 0.92, 95% CI: 0.87–0.98; p = 0.007], male gender (aOR: 4.5, 95% CI: 1.3–15.95, p = 0.017), higher baseline systolic blood pressure (aOR: 1.05, 95% CI: 1.01–1.10, p = 0.026), and the presence of comorbidities (aOR: 3.95, 95% CI: 1.10–14.33, p = 0.037). The progression of renal disease in ADPKD patients significantly correlates with age at diagnosis, gender, presence of comorbidities, and higher baseline systolic blood pressure. Conclusions: These findings underscore the importance of early detection and management of hypertension and comorbidities in ADPKD patients to mitigate disease progression and improve treatment outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUND: Secondary hyperparathyroidism (SHPT) is one of the common complications of end-stage renal disease-uremia, and is mainly manifested as parathyroid hyperplasia and abnormal secretion of parathyroid hormone (PTH). OBJECTIVE: To investigate the value and advantages of contrast-enhanced ultrasound (CEUS) in evaluating the survival of autografts after parathyroidectomy + parathyroid autotransplantation. METHODS: In this study, 125 patients with renal failure due to polycystic kidney disease, chronic nephritis, diabetic nephropathy, lupus nephritis, and atherosclerotic nephropathy were enrolled as the participants and each of them had 4 secondary hyperactive parathyroid glands and underwent parathyroid autotransplantation. One parathyroid gland was taken from each patient and equally divided into 4 parts and placed in the subcutaneous fat of one forearm for transplantation. CEUS was performed 14 days after the transplantation to observe the micro blood supply of the graft and assess the survival and secretory function of the transplanted parathyroid. The grafts were divided into the partial survival group and the total survival group based on the enhancement characteristics. The survival of the grafts was determined by comparing the parathyroid hormone level in bilateral elbow cephalic veins 1 month after surgery. RESULTS: Among the 125 patients, 112 had linear or punctate enhancement of 2–4 parathyroid glands 14 days after surgery, and 13 patients had linear or punctate enhancement of 0–1 parathyroid gland. There were statistically significant differences in the perfusion pattern, enhancement uniformity, and parathyroid hormone levels in the cephalic veins at the elbow on both the graft and non-graft sides among all groups (P < 0.05). CONCLUSION: Compared to the detection of the difference in the parathyroid hormone level in the cephalic vein of bilateral elbows 1 month after surgery, CEUS can reflect the parathyroid survival after transplantation more quickly and accurately 2 weeks later, and provide a more rapid and agile non-invasive clinical diagnosis method. [ABSTRACT FROM AUTHOR]

• Polycystic kidney disease is a common hereditary etiology of kidney failure. • In certain clinical circumstances, a pretransplant nephrectomy is indicated. • Pre-transplant nephrectomy is not associated with mortality and other long-term complications. Polycystic kidney disease (PKD) is the most common hereditary kidney disorder. In most patients, the disease progresses to end stage kidney disease, which is treated preferably by kidney transplantation. In certain clinical circumstances, a pretransplant nephrectomy is indicated. Data regarding long-term outcomes of pretransplant nephrectomy are limited. In this study, we aimed to compare patient and graft survival, as well as other long-term outcomes of kidney transplantation, between patients with PKD who had a pretransplant nephrectomy and those who have not. A retrospective analysis of 112 adult kidney transplant recipients with PKD, 36 (32.14%) of which underwent a pretransplant nephrectomy. In a mean follow-up period of 79 and 129 months (for patients who underwent nephrectomy and patients who did not, respectively), no significant differences were found in patient and graft survival, after adjustment to age and donor type. In addition, rate of hospitalizations, urinary tract infections requiring hospitalization, diabetes mellitus, and erythrocytosis post-transplant were similar in both cohorts. Pretransplant nephrectomy in patients with PKD is not associated with increased risk of mortality and other long-term complications following kidney transplantation. [ABSTRACT FROM AUTHOR]

Osteopontin (OPN) is a multi‐functional glycoprotein that coordinates the innate immune response, prevents nanocrystal formation in renal tubule fluid, and is a biomarker for kidney injury. OPN expression is markedly increased in cystic epithelial cells of polycystic kidney disease (PKD) kidneys; however, its role in PKD progression remains unclear. We investigated the in vitro effects of recombinant OPN on the proliferation of tubular epithelial cells from PKD and normal human kidneys and in vivo effects of OPN deletion on kidney cyst formation, fibrosis, and mineral metabolism in pcy/pcy mice, a non‐orthologous model of autosomal‐dominant PKD. In vitro studies revealed that OPN enhanced the proliferation of PKD cells but had no effect on normal kidney cells. Deletion of OPN in pcy/pcy mice significantly reduced kidney cyst burden; however, this was accompanied by increased fibrosis and no change in kidney function. The loss of OPN had no effect on kidney macrophage numbers, cyst epithelial cell proliferation, or apoptosis. Furthermore, there was no difference in kidney mineral deposition or mineral metabolism parameters between pcy/pcy mice with and without OPN expression. Global deletion of OPN reduced kidney cyst burden, while paradoxically exacerbating kidney fibrosis in mice with cystic kidney disease. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is characterized by a steady decline in kidney function and affects roughly 10% of the world's population. This review focuses on the critical function of cyclic adenosine monophosphate (cAMP) signaling in CKD, specifically how it influences both protective and pathogenic processes in the kidney. cAMP, a critical secondary messenger, controls a variety of cellular functions, including transcription, metabolism, mitochondrial homeostasis, cell proliferation, and apoptosis. Its compartmentalization inside cellular microdomains ensures accurate signaling. In kidney physiology, cAMP is required for hormone-regulated activities, particularly in the collecting duct, where it promotes water reabsorption through vasopressin signaling. Several illnesses, including Fabry disease, renal cell carcinoma, nephrogenic diabetes insipidus, Bartter syndrome, Liddle syndrome, diabetic nephropathy, autosomal dominant polycystic kidney disease, and renal tubular acidosis, have been linked to dysfunction in the cAMP system. Both cAMP analogs and phosphodiesterase inhibitors have the potential to improve kidney function and reduce kidney damage. Future research should focus on developing targeted PDE inhibitors for the treatment of CKD. [ABSTRACT FROM AUTHOR]

Glomerular kidney diseases typically begin insidiously and can progress to end stage kidney failure. Early onset of therapy can slow down disease progression. Early diagnosis is required to ensure such timely therapy. The goal of our study was to evaluate protein biomarkers (BMs) for common nephropathies that have been described for children with Alport syndrome. Nineteen candidate BMs were determined by commercial ELISA in children with congenital anomalies of the kidneys and urogenital tract, inflammatory kidney injury, or diabetes mellitus. It is particularly essential to search for kidney disease BMs in children because they are a crucial target group that likely exhibits early disease stages and in which misleading diseases unrelated to the kidney are rare. Only minor differences in blood between affected individuals and controls were found. However, in urine, several biomarker candidates alone or in combination seemed to be promising indicators of renal injury in early disease stages. The BMs of highest sensitivity and specificity were collagen type XIII, hyaluronan-binding protein 2, and complement C4-binding protein. These proteins are unrelated to inflammation markers or to risk factors for and signs of renal failure. In conclusion, our study evaluated several strong candidates for screening for early stages of kidney diseases and can help to establish early nephroprotective regimens. [ABSTRACT FROM AUTHOR]

Polycystic kidney disease (PKD) is a common hereditary kidney disease. Although PKD occurrence is associated with certain gene mutations, its onset regulatory mechanisms are still not well understood. Here, we first report that the key enzyme geranylgeranyl diphosphate synthase (GGPPS) is specifically expressed in renal tubular epithelial cells of mouse kidneys. We aimed to explore the role of GGPPS in PKD. In this study, we established a Ggppsfl/fl:Cdh16cre mouse model and compared its phenotype with that of wild‐type mice. A Ggpps‐downregulation HK2 cell model was also used to further determine the role of GGPPS. We found that GGPPS was specifically expressed in renal tubular epithelial cells of mouse kidneys. Its expression also increased with age. Low GGPPS expression was observed in human ADPKD tissues. In the Ggppsfl/fl:Cdh16cre mouse model, Ggpps deletion in renal tubular epithelial cells induced the occurrence and development of renal tubule cystic dilation and caused the death of mice after birth due to abnormal renal function. Enhanced proliferation of cyst‐lining epithelial cells was also observed after the knockout of Ggpps. These processes were related to the increased rate of Rheb on membrane/cytoplasm and hyperactivation of mTORC1 signaling. In conclusion, the deficiency of GGPPS in kidney tubules induced the formation of renal cysts. It may play a critical role in PKD pathophysiology. A novel therapeutic strategy could be designed according to this work. [ABSTRACT FROM AUTHOR]

Objective: To reaffirm the value of a joint obstetric and renal clinic on obstetric outcomes in patients with high‐risk pregnancies due to chronic kidney disease (CKD). Methods: This was a retrospective cohort study of patients who attended the clinic between 2005 and December 2021. The hospital is a regional tertiary unit for renal medicine and a maternal medicine hub. The data included all women with pre‐existing renal conditions who were cared for in a dedicated renal and obstetric clinic. Datasets were extracted from hospital notes, the renal database, clinical data and maternity electronic health records. The data analyzed included pre‐existing renal conditions, biochemical parameters related to the renal condition, pregnancy outcomes included miscarriages, gestation, mode of delivery, postpartum hemorrhage (PPH), loss, birth weight and neonatal admission. Results: The results were as follows: Lupus nephritis: four term deliveries; three had pre‐eclampsia; two PPH and two miscarriages. Four estimated glomerular filtration rates (eGFRs) returned to baseline levels within 12 months. With regard to IgA nephropathy there were five live births, four term deliveries, two pre‐eclampsia (PE) and five cesarean sections (CS). All eGFRs returned to baseline within 12 months. With regard to patients with adult polycystic kidney disease (APKD), there were six live births, two had pre‐eclampsia and there were five term vaginal deliveries. Conclusion: Patients with lupus nephritis, APKD, and IgA demonstrated a higher incidence of adverse pregnancy outcomes as compared with our local pregnant population. Our findings reflect those of larger studies and support the role of combined renal/obstetric clinics. More research and larger scale studies are needed into specific CKD conditions and their outcomes. Synopsis: The obstetric patients with renal disease that were included in our data had a higher incidence of adverse pregnancy outcomes than the local pregnant population. [ABSTRACT FROM AUTHOR]

Cystic kidney diseases encompass a range of genetic disorders in which the primary cilia of the cells are affected and thereby cysts form as a result. There are an increasing range of cystic renal diseases recognized due to the advances in genomics. The most common genetic kidney condition is autosomal dominant polycystic kidney disease (ADPKD). ADPKD leads to renal failure in adulthood. In children, hypertension is common and if treated, may slow down renal decline. The most common cystic kidney disease causing renal failure in children is autosomal recessive polycystic kidney disease (ARPKD). ARPKD also affects the liver. These conditions often have extra-renal features which also need to be addressed. Until recently, treatments were mainly supportive but now it is possible to slow down development of cyst formation and renal decline in ADPKD. This raises hope for treatment for other cystic renal conditions as more genes are identified and underlying mechanisms defined. [ABSTRACT FROM AUTHOR]

Renal ciliopathies are a group of genetic disorders that affect the function of the primary cilium in the kidney, as well as other organs. Since primary cilia are important for regulation of cell signaling pathways, ciliary dysfunction results in a range of clinical manifestations, including renal failure, cyst formation, and hypertension. We summarize the current understanding of the pathophysiological and pathological features of renal ciliopathies in childhood, including autosomal dominant and recessive polycystic kidney disease, nephronophthisis, and Bardet-Biedl syndrome, as well as skeletal dysplasia associated renal ciliopathies. The genetic basis of these disorders is now well-established in many cases, with mutations in a large number of cilia-related genes such as PKD1, PKD2, BBS, MKS, and NPHP being responsible for the majority of cases. Renal ciliopathies are broadly characterized by development of interstitial fibrosis and formation of multiple renal cysts which gradually enlarge and replace normal renal tissue, with each condition demonstrating subtle differences in the degree, location, and age-related development of cysts and fibrosis. Presentation varies from prenatal diagnosis of congenital multisystem syndromes to an asymptomatic childhood with development of complications in later adulthood and therefore clinicopathological correlation is important, including increasing use of targeted genetic testing or whole genome sequencing, allowing greater understanding of genetic pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

Aim: Is there a change in the circulatory system in fetuses with renal disease in the prenatal period to make hemodynamic assessments. In addition, fetal cardiac functions in the same patients will be studied in detail using fetal echocardiography. Material and Method: Thirty-one fetuses with renal disease were included in the study; 4 with polycystic kidneys, 4 with bilateral hydronephrosis, 12 with unilateral hydronephrosis, and 28 with pelvicalyceal ectasia. In the control group, there were 30 fetuses of the same gestational week without renal disease. The circulatory system and hemodynamic status were examined in detail by fetal echocardiography in both groups. Results: High umbilical artery pulsatility index (PI) values were observed in 2 fetuses with bilateral hydronephrosis and 2 fetuses with unilateral hydronephrosis. The PI values of the middle cerebral artery were high in 2 fetuses with bilateral hydronephrosis and 2 cases with isolated pelvicalyceal ectasia. When the right and left myocardial performance index values of fetuses with renal disease were compared with normal fetuses, no significant results were observed, but the tricuspid valve pulse Doppler was abnormal in fetuses with fetal kidney disease. In addition, the right spherical index was higher in fetuses with renal disease than in the control group. Conclusion: Although there is no functional change, morphologic findings of right ventricular overload can be observed in fetuses with fetal renal disease. [ABSTRACT FROM AUTHOR]

A 68-year-old man on hemodialysis treatment for end-stage kidney disease secondary to autosomal dominant polycystic kidney disease (ADPKD) complained of right ankle pain that impaired walking ability two weeks after the initiation of intravenous levofloxacin as a treatment for concomitant liver cyst infection. A systemic workup led us to conclude that our patient had a fluoroquinolone-associated tendon injury. Such a disease condition has been recognized as a serious adverse event resulting from the receipt of fluoroquinolones in various clinical settings. Fluoroquinolones have received focus as standard therapeutic agents for liver and/or renal cyst infection because of their lipophilic properties that lead to good penetration into infected cysts. However, reports on fluoroquinolone-associated tendinopathy in patients with ADPKD associated with cyst infection are sparse. We believe the current report illustrates the pitfalls associated with managing patients with ADPKD who are subjected to the administration of fluoroquinolones due to infectious complications. [ABSTRACT FROM AUTHOR]

Introduction: Chronic kidney disease (CKD) etiology varies greatly between developed and developing countries. In addition, differences in underlying pathogenesis and therapeutic options affect the progression towards advanced-CKD. This meta-analysis aims to identify the etiology of advanced-CKD in Southeast Asia. Methods: A systematic search in four electronic-databases and complementary search on national kidney registries and repository libraries was conducted until July 20, 2023. The risk of bias was assessed using Newcastle–Ottawa Scale for observational studies and Version-2 of Cochrane for intervention studies. A random-effects model was used to estimate pooled prevalence. The protocol is registered in the International Prospective Register of Systematic Reviews PROSPERO; Registration ID:CRD42022300786. Results: We analyzed 81 studies involving 32,834 subjects. The pooled prevalence of advanced-CKD etiologies are diabetic kidney disease (DKD) 29.2% (95%CI 23.88–34.78), glomerulonephritis 20.0% (95%CI 16.84–23.38), hypertension 16.8% (95%CI 14.05–19.70), other 8.6% (95%CI 6.97–10.47), unknown 7.5% (95%CI 4.32–11.50), and polycystic kidney disease 0.7% (95%CI 0.40–1.16). We found a significant increase in DKD prevalence from 21% (9.2%, 95%CI 0.00–33.01) to 30% (95%CI 24.59–35.97) before and after the year 2000. Among upper-middle-income and high-income countries, DKD is the most prevalent (26.8%, 95%CI 21.42–32.60 and 38.9%, 95%CI 29.33–48.79, respectively), while glomerulonephritis is common in lower-middle-income countries (33.8%, 95%CI 15.62–54.81). Conclusion: The leading cause of advanced-CKD in Southeast Asia is DKD, with a substantial proportion of glomerulonephritis. An efficient screening program targeting high-risk populations (diabetes mellitus and glomerulonephritis) is needed, with the aim to delay CKD progression. [ABSTRACT FROM AUTHOR]

Renal fibrosis (RF) is a typical pathological presentation of end‐stage chronic kidney disease (CKD) and autosomal dominant polycystic kidney disease (ADPKD). However, the precise regulatory mechanisms governing this re‐expression process remain unclear. Differentially expressed microRNAs (miRNAs) associated with RF were screened by microarray analysis using the Gene Expression Omnibus (GEO) database. The miRNAs upstream of the genes in question were predicted using the miRWalk database. The miRNAs involved in the two GEO data sets were intersected to identify key miRNAs; their regulatory pathways were investigated using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Subsequently, the effects and the underlying mechanisms of target miRNA on RF were examined in a unilateral ureteral obstruction (UUO)‐induced mice renal fibrotic model and a transforming growth factor‐β1 (TGF‐β1)‐induced tubular epithelium (HK‐2) fibrotic cell model. In total, 109 and 32 differentially expressed miRNAs were identified in the GSE133530 and GSE80247 data sets, respectively. GREM1 was identified as a hub gene, where its 2196 upstream miRNAs were predicted; miR‐574‐5p was found to be downregulated and closely related to fibrosis after data set intersection and enrichment analyses, thus was selected for further investigation. A differential expression heatmap (GSE162794) showed that miR‐542‐5p was downregulated. The expression of GREM1 mRNA was upregulated, whereas that of miR‐542‐5p was downregulated in UUO mice and fibrotic HK‐2 cells as compared with the relevant controls. The binding site of miR‐542‐5p was predicted at the 3'UTR region of GREM1 and was confirmed by subsequent dual luciferase reporter gene assay. Western blot analysis showed that Gremlin‐1 and Fibronectin were significantly upregulated after induction of TGF‐β1; when miR‐542‐5p was overexpressed or GREM1 mRNA was interfered, the upregulations of Gremlin‐1 and Fibronectin were significantly reduced. Our research demonstrates that miR‐542‐5p plays a critical role in the progression of RF, and thus may be a promising therapeutic target for CKD and ADPKD. [ABSTRACT FROM AUTHOR]

We analyzed the impact of nine previously identified missense PKD1 variants from our studies, including c.6928G > A p.G2310R, c.8809G > A p.E2937K, c.2899 T > C p.W967R, c.6284A > G p.D2095G, c.6644G > A p.R2215Q, c.7810G > A p.D2604N, c.11249G > C p.R3750P, c.1001C > T p.T334M, and c.3101A > G p.N1034S on RNA structures and PC1 protein structure dynamics utilizing computational tools. RNA structure analysis was done using short RNA snippets of 41 nucleotides with the variant position at the 21st nucleotide, ensuring 20 bases on both sides. The secondary structures of these RNA snippets were predicted using RNAstructure. Structural changes of the mutants compared to the wild type were analyzed using the MutaRNA webserver. Molecular dynamics (MD) simulation of PC1 wild-type and mutant protein regions were performed using GROMACS 2018 (GROMOS96 54a7 force field). Findings revealed that five variants including c.8809G > A (p.E2937K), c.11249G > C (p.R3750P), c.3101A > G (p.N1034S), c.6928G > A (p.G2310R), c.6644G > A (p.R2215Q) exhibited major alterations in RNA structures and thereby their interactions with other proteins or RNAs affecting protein structure dynamics. While certain variants have minimal impact on RNA conformations, their observed alterations in MD simulations indicate impact on protein structure dynamics highlighting the importance of evaluating the functional consequences of genetic variants by considering both RNA and protein levels. The study also emphasizes that each missense variant exerts a unique impact on RNA stability, and protein structure dynamics, potentially contributing to the heterogeneous clinical manifestations and progression observed in Autosomal Dominant Polycystic Kidney Disease (ADPKD) patients offering a novel perspective in this direction. Thus, the utility of studying the structure dynamics through computational tools can help in prioritizing the variants for their functional implications, understanding the molecular mechanisms underlying variability in ADPKD presentation and developing targeted therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: The Covid-19 pandemic greatly affected those with chronic diseases, impacting healthcare access and healthcare seeking behaviors. The impact of the pandemic on adults with Autosomal Dominant Polycystic Kidney Disease (ADPKD) has not been investigated. Methods: Participants were recruited from a cohort of 239 ADPKD patients enrolled in a longitudinal study at the University of Maryland. Patients on renal replacement therapy were excluded. N = 66 patients participated in a phone questionnaire from June 2022-December 2022 about ADPKD-related complications, concern about contracting Covid-19, healthcare-seeking behaviors, and telehealth utilization before and after March 2020. Results: N = 34 (51.5%) of participants reported a positive Covid-19 test result. N = 29 (44%) expressed high concern of contracting Covid-19. Those who avoided medical care at least once (N = 17, 25.8%) had similar demographics and ADPKD severity to those who did not, but reported greater telehealth utilization (88.2% vs. 42.9%, p = 0.002), greater use of non-prescribed medication for Covid-19 treatment or prevention (35.3% vs. 8.2%, p = 0.01), and were more likely to contract Covid-19 (76.5% vs. 42.9%, p = 0.02). Among the N = 53 who reported very good or excellent ADPKD disease management pre-pandemic, N = 47(89%) reported no significant change during the pandemic. Conclusions: In this highly educated, high-income cohort with a mean age of 46.1 years, most people reported well-managed ADPKD prior to the pandemic. This may explain why less than half of participants expressed high concern for contracting Covid-19. Overall, there was no significant pandemic-related decline in self-reported ADPKD management. This was likely due to this cohort's excellent access to, and uptake of, telehealth services. Notably, 1 in 4 participants reported healthcare avoidant behavior, the effect of which may only be seen years from now. Future studies should investigate potential impacts of avoidant behaviors, as well as expand investigation to a more diverse cohort whose care may not have been as easily transitioned to telehealth. [ABSTRACT FROM AUTHOR]

Background: Pathogenic variants in the Polycystic Kidney Disease 2 (PKD2) gene are associated with Autosomal Dominant Polycystic Kidney Disease (ADPKD) in approximately 30% of cases. In recent years, the high-throughput sequencing techniques have significantly increased the number of variants identified in affected patients. Here, we described the peculiar effect of a PKD2 splicing variant, the c.1717-2A>G, identified in an Italian male patient with ADPKD. This variant led to the unusual and rare skipping of two consecutive exons, causing a large in-frame deletion. Methods: The genetic evaluation of the patient was performed using the Next-Generation Sequencing (NGS) assay Clinical Exome Solution® (SOPHiA Genetics). Bioinformatics analysis was performed using the SOPHiA DDM platform (SOPHiA Genetics). Prediction of pathogenicity was carried out by integrating several in silico tools. RNA evaluation was performed to test the effect of the variant on the PKD2 splicing using a Reverse-Transcription PCR coupled with cDNA sequencing. Results: NGS revealed the presence of the PKD2 c.1717-2A>G variant that lies in the canonical splice site of intron 7. This rare variant was predicted to have a significant impact on the splicing, proved by the RNA-based analysis. We identified the presence of a transcript characterised by the simultaneous skipping of exons 8 and 9, with a retained reading frame and the merging of exons 7–10. Conclusions: We described for the first time a dual-exon skip event related to the presence of a single-base substitution in the PKD2 gene in an ADPKD-affected patient. We assumed that the molecular basis of such a rare mechanism lies in the specific order of intron removal. The finding represents novel evidence of an alternative and unusual splicing mechanism in the PKD2 gene, adding insights to the pathogenesis of the ADPKD. [ABSTRACT FROM AUTHOR]

Non-tumorous kidney diseases include a variety of conditions affecting both the structure and function of the kidneys, thereby causing a range of health-related problems. Positron emission tomography/computed tomography (PET/CT) has emerged as a potential diagnostic tool, offering a multifaceted approach to evaluating non-tumorous kidney diseases. Its clinical significance extends beyond its conventional role in cancer imaging, enabling a comprehensive assessment of renal structure and function. This review explores the diverse applications of PET/CT imaging in the evaluation of non-cancerous kidney diseases. It examines PET/CT's role in assessing acute kidney injuries, including acute pyelonephritis and other forms of nephritis, as well as chronic conditions such as immune complex-mediated glomerulonephritis and chronic kidney disease. Additionally, the review delves into PET/CT's utility in evaluating complications in renal transplant recipients, identifying renal histiocytosis and detecting renal amyloidosis. The current review aims to promote further research and technological advancements to popularize PET/CT's clinical utility in diagnosing and treating non-tumorous kidney diseases. [ABSTRACT FROM AUTHOR]

AbstractIntroductionAimsMethodologyResultsConclusionIntracranial aneurysms (IA) are a common complication of autosomal dominant polycystic kidney disease (ADPKD). Screening protocols that exist for IA in ADPKD patients are an important component of disease monitoring to enable appropriate preventative measures and precautions to avoid IA rupture with its associated morbidly and mortality.The aims of this review are to analyse the different types of screening protocols that exist by referencing the lead time between IA diagnosis and rupture in ADPKD patients, the purpose and importance of screening, the types of imaging modalities used, and patient outcomes. We will also consider cost-effectiveness and its relation in establishing a screening protocol as this is an important factor.A literature search was conducted in April 2022 using PubMed, BMJ electronic databases, Dynamed, NICE guidelines and Cochrane databases for articles published between 1990 and 2022 with special interest in IA, ADPKD and screening protocols. The only exclusion criteria were patients who were diagnosed with ADPKD <30 years of age.Our findings suggest that if a patient with ADPKD presents with either a positive family history of IA and/or cerebrovascular events and/or is above 40 years of age, then they should have a magnetic resonance angiography (MRA) scan every 5 years to monitor IA formation and growth with annual follow-ups. This may contribute to decreased patient morbidity and mortality in ADPKD-positive patients.While there is some evidence proving that screening protocols decrease the morbidity and mortality of ADPKD patients, none have been recommended. The screening protocol suggested in this review should be used as a guideline for future studies that will try and establish a national or international guidelines that can be used by nephrologists and neurosurgeons worldwide. [ABSTRACT FROM AUTHOR]

Kidney cysts in humans are mainly caused by inheritable polycystic kidney disease. Although they are a regular finding in laboratory mice, their occurrence upon dissection has not been systematically investigated, yet. Therefore, the aim of this report was to investigate on prevalence, phenotype and aetiology of spontaneously occurring kidney cysts in mice by retrospectively analysing the laboratory-receipt tables of the in-house laboratory of a central animal facility in North Rhine-Westphalia, Germany, years 2009–2019. A percentage of 0.4% of dissected mice displayed kidney cysts, with more male than female animals affected and average age equal to that of all dissected animals. Preliminary report in half of the cases was distended abdomen, and a few individuals displayed additional pathologic alterations of kidneys, most commonly dilated renal pelvis, or extrarenal comorbidities. Kidney cysts occurred independently of a renal phenotype of the transgenic strain or presence of infectious agents in health monitoring. To conclude, kidney cysts were characterized as harmless for affected mice but, as inheritability is suggested according with the literature, affected animals should be excluded from breeding. [ABSTRACT FROM AUTHOR]

Introduction The DAPA-CKD study showed a protective effect of dapagliflozin on kidney function in chronic kidney disease (CKD) patients with and without diabetes mellitus. Although dapagliflozin is expected to be effective also in CKD patients with autosomal dominant polycystic kidney disease (ADPKD), its efficacy and safety in this population remain unknown because ADPKD was an exclusion criterion in the DAPA-CKD study. Therefore, we evaluated the effects of dapagliflozin in CKD patients with ADPKD. Methods We performed a retrospective observational study of seven patients with ADPKD treated with dapagliflozin at Toranomon Hospital, Tokyo, Japan. We analyzed changes in estimated glomerular filtration rate (eGFR) slope and annual height-corrected total kidney volume before and after starting dapagliflozin treatment. Results The median observation period after starting dapagliflozin was 20 months. Four patients received concomitant tolvaptan. The eGFR slope before and after initiation of dapagliflozin could be calculated in six patients and improved in all of them except the one who did not receive a renin-angiotensin system (RAS) inhibitor. Annual height-corrected total kidney volume increased in all patients. Concurrent tolvaptan treatment had no effect. Conclusion In CKD patients with ADPKD, dapagliflozin may increase kidney volume but may have a protective effect on kidney function when used concomitantly with RAS inhibitors. [ABSTRACT FROM AUTHOR]

Polycystin-2 (PC2) is mutated in ~15% of patients with autosomal dominant polycystic kidney disease (ADPKD). PC2 belongs to the family of transient receptor potential (TRP) channels and can function as a homotetramer. We investigated whether three disease-associated mutations (F629S, C632R, or R638C) localized in the channel’s pore loop alter ion channel properties of human PC2 expressed in Xenopus laevis oocytes. Expression of wild-type (WT) PC2 typically resulted in small but measurable Na+ inward currents in the absence of extracellular divalent cations. These currents were no longer observed when individual pore mutations were introduced in WT PC2. Similarly, Na+ inward currents mediated by the F604P gain-of-function (GOF) PC2 construct (PC2 F604P) were abolished by each of the three pore mutations. In contrast, when the mutations were introduced in another GOF construct, PC2 L677A N681A, only C632R had a complete lossof-function effect, whereas significant residual Na+ inward currents were observed with F629S (~15%) and R638C (~30%). Importantly, the R638C mutation also abolished the Ca2+ permeability of PC2 L677A N681A and altered its monovalent cation selectivity. To elucidate the molecular mechanisms by which the R638C mutation affects channel function, molecular dynamics (MD) simulations were used in combination with functional experiments and site-directed mutagenesis. Our findings suggest that R638C stabilizes ionic interactions between Na+ ions and the selectivity filter residue D643. This probably explains the reduced monovalent cation conductance of the mutant channel. In summary, our data support the concept that altered ion channel properties of PC2 contribute to the pathogenesis of ADPKD. [ABSTRACT FROM AUTHOR]

While significant advances have been made in understanding renal pathophysiology, less is known about the role of glycosphingolipid (GSL) metabolism in driving organ dysfunction. Here, we used a small molecule inhibitor of glucosylceramide synthase to modulate GSL levels in three mouse models of distinct renal pathologies: Alport syndrome (Col4a3 KO), polycystic kidney disease (Nek8jck), and steroid-resistant nephrotic syndrome (Nphs2 cKO). At the tissue level, we identified a core immune-enriched transcriptional signature that was shared across models and enriched in human polycystic kidney disease. Single nuclei analysis identified robust transcriptional changes across multiple kidney cell types, including epithelial and immune lineages. To further explore the role of GSL modulation in macrophage biology, we performed in vitro studies with homeostatic and inflammatory bone marrow-derived macrophages. Cumulatively, this study provides a comprehensive overview of renal dysfunction and the effect of GSL modulation on kidney-derived cells in the setting of renal dysfunction. This study identifies shared immune-related gene signatures across kidney cell types in three distinct mouse models of renal disease and examines the role of glycosphingolipid metabolism in renal dysfunction. [ABSTRACT FROM AUTHOR]

Incidental findings are unrelated to a patient's complaint, found on diagnostic imaging, such as point-of-care ultrasound (POCUS). Incidental findings represent potential harms to patients and may lead to increased patient anxiety and health care costs related to downstream testing and surveillance. In this study, we aimed to calculate the rate of incidental renal cysts found by POCUS. Further, we hoped to describe how emergency physicians relay the findings to patients. Lastly, we hoped to examine if patients suffered harms in the 12 months following identification of an incidental renal cyst. From our single-center, academic emergency department (ED), we reviewed renal POCUS images from 1000 consecutive adult ED patients to determine if there was a renal cyst. Next, we performed manual chart review to determine if patients were informed of the incidental renal cyst or suffered any patient harms. We found the prevalence of renal cysts to be 6.5% (95% confidence interval: 4.9%–8.4%). Those with cysts were more likely to be older compared to those without (63 ± 14 vs. 49 ± 15 years of age). Only 8% of patients had evidence that they were informed of their incidental renal cyst. No patients received a biopsy or were diagnosed with renal cell carcinoma or polycystic kidney disease. Incidental renal cysts are common and are more likely to be found in older adults. In our study, physicians infrequently informed patients of their incidental finding. [ABSTRACT FROM AUTHOR]

This document provides concise summaries of various studies on surgical robotics, specifically focusing on different procedures and their outcomes. The studies cover a range of topics, including knee arthroplasty, anterior resection, inguinal hernia surgery, sacrocolpopexy, bladder diverticulectomy, and rectal cancer resections. The summaries highlight the findings of each study, such as cost comparisons, shorter hospital stays, fewer complications, and good patient satisfaction. The document also includes summaries of studies on robotic-assisted hernia repair surgery and the preservation of arteries and veins during robotic prostate surgery. Overall, the studies emphasize the benefits of robotic-assisted procedures and the importance of collaboration and comprehensive care in optimizing patient outcomes. [Extracted from the article]

Background: Autosomal dominant tubulointerstitial kidney disease (ADTKD) results from mutations in various genes, including REN, UMOD, MUC1, and HNF1B. ADTKD due to REN mutations (ADTKD-REN) is often characterized as a proteinopathy that triggers the endoplasmic reticulum stress (ERS) cascade, potentially sharing similarities with ADTKD-UMOD and ADTKD-MUC1 at the cellular level. This study, inspired by a patient harboring a W17R mutation, investigates ERS activation by this mutation alongside two other renin variants, W10R and L381P. Methods: We established stable cell lines expressing both wild-type and mutated renin forms (W17R, W10R, and L381P). Using luciferase reporter assays, RT-qPCR, and confocal microscopy, we evaluated ERS activation, determined the cellular localization of the renin variants, and characterized the mitochondrial network in the W17R line. Results: The L381P line exhibited ERS activation, including transcriptional upregulation of MANF and CRELD2. No ERS activation was observed in the W17R line, while the W10R line exhibited intermediate characteristics. Notably, the W17R variant was misrouted to the mitochondria resulting in changes of the mitochondrial network organisation. Conclusions: ERS activation is not a universal response to different renin mutations in ADTKD-REN. The pathogenesis of the W17R mutation may involve mitochondrial dysfunction rather than the ER pathway, albeit further research is needed to substantiate this hypothesis fully. Testing CRELD2 and MANF as targeted therapy markers for a specific subgroup of ADTKD-REN patients is recommended. Additionally, fludrocortisone treatment has shown efficacy in stabilizing the renal function of our patient over a four-year period without significant side effects. [ABSTRACT FROM AUTHOR]

This document contains summaries of various articles related to nephrology. The articles cover a range of topics including dialysis, kidney disease, liver cirrhosis, transplantation, and patient perspectives. The summaries provide insights into different aspects of nephrology and can be useful for researchers and healthcare professionals in the field. The articles emphasize the need for further research, improved patient care, and addressing barriers to access and adherence. Overall, the document offers a culturally sensitive and respectful overview of nephrology research. [Extracted from the article]

and treatment options, genetic factors, and the use of organoids as models for studying kidney diseases. The articles highlight the importance of accurate diagnosis, family planning, and identifying potential therapeutic targets for conditions such as autoimmune diseases, Alport syndrome, acute kidney injury, and chronic kidney disease. The research also emphasizes the need for further data collection, education, and policies to improve outcomes and prevent death in patients with kidney-related conditions. [Extracted from the article]

Background: Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) has been suggested as a useful imaging method for diagnosing cyst infections in patients with autosomal dominant polycystic kidney disease (ADPKD). The aim of this article is to provide evidence-based data in this setting. Methods: A systematic literature review (exploring several bibliographic databases) and a bivariate meta-analysis were carried out to calculate the pooled diagnostic performance of [18F]FDG PET/CT in diagnosing probable cyst infection in ADPKD. Results: Ten studies (282 PET/CT scans and 249 patients) were included in the analysis. The pooled sensitivity and specificity of [18F]FDG PET/CT in this setting were 84.6% (95% confidence interval: 75.4–90.7) and 94.9% (95% confidence interval: 72.6–99.2), respectively, without statistical heterogeneity or significant publication bias. [18F]FDG PET/CT significantly changed patient management in more than half of ADPKD patients with suspected cyst infection. Conclusions: [18F]FDG PET/CT has high performance in diagnosing probable cyst infections in ADPKD patients with an impact on management in the majority of patients. Although more studies are warranted, the provided evidence-based data are an important step towards the integration of [18F]FDG PET/CT in clinical and diagnostic guidelines on probable cyst infection in ADPKD patients. [ABSTRACT FROM AUTHOR]

Mechanotransduction is an evolutionary conserved and essential physiological process enabling cells to sense and convert mechanical stimuli into intracellular electrochemical events. Transient receptor potential (TRP) channels have been implicated in numerous mechanotransduction processes, including cancer cell migration, bone mineralization, and sensing blood flow. However, limited evidence supports TRP channels acting as primary mechanotransducers – those that directly sense and convert the external stimuli into an intracellular signal. Most evidence is congruent with TRP channels instead acting as molecular amplifiers responding downstream of the activation of a primary mechanotransducer (such as PIEZO1 or PIEZO2), forming mechanosensory modules. Here, we discuss the evidence supporting TRP channels as primary mechanotransducers and alternative models whereby TRP channels together with primary mechanotransducers could contribute to mechanosignalling. Transient receptor potential (TRP) channels are implicated in a wide array of mechanotransduction processes. However, a question remains whether TRP channels directly sense mechanical force, thus acting as primary mechanotransducers. We use several recent examples to demonstrate the difficulty in definitively ascribing mechanosensitivity to TRP channel subfamilies. Ultimately, despite being implicated in an ever-growing list of mechanosignalling events in most cases limited robust or reproducible evidence supports the contention that TRP channels act as primary transducers of mechanical forces. They either (i) possess unique and as yet unspecified structural or local requirements for mechanosensitivity; or (ii) act as mechanoamplifiers responding downstream of the activation of a primary mechanotransducer that could include Ca2+-permeable mechanosensitive (MS) channels or other potentially unidentified mechanosensors. [ABSTRACT FROM AUTHOR]

The kidney plays a pivotal role in regulating calcium levels within the body. Approximately 98% of the filtered calcium is reabsorbed in the nephron, and this process is tightly controlled to maintain calcium homeostasis, which is required to facilitate optimal bone mineralization, preserve serum calcium levels within a narrow range, and support intracellular signalling mechanisms. The maintenance of these functions is attributed to a delicate balance achieved by various calcium channels, transporters, and calcium-binding proteins in renal cells. Perturbation of this balance due to deficiency or dysfunction of calcium channels and calcium-binding proteins can lead to severe complications. For example, polycystic kidney disease is linked to aberrant calcium transport and signalling. Furthermore, dysregulation of calcium levels can promote the formation of kidney stones. This Review provides an updated description of the key aspects of calcium handling in the kidney, focusing on the function of various calcium channels and the physiological stimuli that control these channels or are communicated through them. A discussion of the role of calcium as an intracellular second messenger and the pathophysiology of renal calcium dysregulation, as well as a summary of gaps in knowledge and future prospects, are also included. Calcium reabsorption along the nephron is essential for calcium homeostasis and whole-body electrolyte balance. Here, Staruschenko et al. highlight signalling pathways and molecules involved in renal calcium handling in health and disease, and discuss progress in the integration of systems-level and molecular understanding of calcium transport and regulation. Key points: The kidney has an essential role in the maintenance of serum calcium levels owing to its careful regulation of reabsorption along the nephron, which contributes to whole-body calcium balance. Physiologically relevant mechanisms that control calcium channels in the kidney include endocrine and paracrine signals and physical factors such as fluid flow. Tight control of calcium influx and intracellular calcium levels maintains intracellular calcium concentrations within the physiological range, despite acute and chronic variation in calcium intake. Failure to reabsorb calcium from renal tubules results in hypercalciuria and an increased risk of kidney stones. Aberrant calcium signalling in particular renal cell types is a hallmark of renal diseases such as polycystic kidney disease and focal segmental glomerulosclerosis. [ABSTRACT FROM AUTHOR]

Background. Polycystic kidney disease is a cystic genetic disease. There are two forms: an autosomal dominant one, more common and typical of adults, and an autosomal recessive one, rarer and present in childhood. The autosomal dominant form is caused by genetic mutations of the PKD1 gene in 85% of cases and of PKD2 in 10-15% of cases. Case Report. We reported a case of 56-year-old woman with ADPKD, who had a kidney transplant and who was hospitalized for respiratory failure from Covid 19 disease. She was intubated, sedated and dialyzed, treated with antibiotics, immunosuppressants, diuretics and heparin. CT scan of the abdomen showed multiple cysts of various sizes in the liver and multiple cysts in the kidneys. The patient died after 20 days because she was unresponsive to therapy. The autopsy showed milky ascitic fluid in the abdomen, massive gastric haemorrhage, intestinal fungal plaques, hepatic and renal polycystosis. The kidneys measured a total of 27 cm with a total weight of about 9 kg. The liver parenchyma appeared cavernous with multiple cysts. The kidney cysts contained bloody liquid. Conclusions. The case demonstrates how important it is in these subjects to evaluate not only the kidneys but also the liver which could present polycystosis and cause liver failure, affecting the severity of the pathology and death. This data is important to emphasize in the clinical management of these patients a close monitoring of liver function also from a preventative perspective in life. [ABSTRACT FROM AUTHOR]

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disorder characterized by the formation of numerous fluid-filled cysts in the kidneys, leading to progressive renal failure and various extrarenal complications, including hypertension. This review explores the genetic basis of ADPKD, including emerging evidence of epigenetic mechanisms in modulating gene expression and disease progression in ADPKD. Furthermore, it proposes to examine the pathological characteristics of this condition at the nephrological, cardiovascular, nutritional, and psychological levels, emphasizing that the follow-up of patients with ADPKD should be multidisciplinary from a young pediatric age. [ABSTRACT FROM AUTHOR]

Kidney cysts and tumors often are identified during imaging for unrelated issues. Kidney cysts can be attributable to heritable polycystic kidney diseases. These cysts are rare in children. In adults, they affect approximately 50% of individuals older than 50 years. Kidney cysts are categorized on imaging using the Bosniak Classification of Cystic Renal Masses, which determines the likelihood that cysts are malignant or benign. Asymptomatic Bosniak class I and II cysts require no further evaluation or follow-up; however, symptomatic large simple cysts might require treatment. Bosniak class III and IV cysts might be malignant and require excision. Kidney tumors also occur in children and adults. In children, the most common is Wilms tumor, but after age 10 years renal cell carcinoma (RCC) is more common. In adults, kidney tumors may be malignant or benign. RCC accounts for 85% of kidney tumors in adults, often with metastatic disease. In patients with kidney tumors, biopsy typically is avoided to prevent spread of malignant cells. Tumors that appear suspicious for cancer on imaging are managed directly, which can include total or partial nephrectomy, ablation therapy, and adjuvant therapies, along with chemotherapy and radiotherapy depending on tumor stage. For some patients, evaluation may involve consideration of genetic testing for hereditary cancer syndromes. Patients with these syndromes should undergo periodic screening for RCC. [ABSTRACT FROM AUTHOR]

Abstract Background Prenatal ultrasound findings of fetal bilateral echogenic kidneys accompanied by oligohydramnios can be highly stressful for both pregnant women and physicians. The diversity of underlying causes makes it challenging to confirm a prenatal diagnosis, predict postnatal outcomes, and counsel regarding recurrence risks in future pregnancies. Case Presentation We report two cases of abnormal fetal echogenic kidneys with oligohydramnios detected in the early third trimester. Autosomal recessive polycystic kidney disease (ARPKD), a rare genetic syndrome, was initially suspected in both cases. However, postnatal diagnoses differed: the first case was confirmed as glomerulocystic kidney disease (GCKD) through renal pathology, while the second case was diagnosed as ARPKD with a compound heterozygous likely pathogenic PKHD1 mutation. Conclusion Prenatal diagnosis of fetal echogenic kidneys with oligohydramnios should prioritize accurate diagnosis. Given the differences in the clinical spectrum, GCKD should be considered a differential diagnosis for this condition, particularly ARPKD. This study highlights the importance and benefits of molecular diagnosis and postnatal renal pathology for precise diagnosis and effective counseling.