Genetics of cystogenesis in base-edited human organoids reveal therapeutic strategies for polycystic kidney disease.

In polycystic kidney disease (PKD), microscopic tubules expand into macroscopic cysts. Among the world's most common genetic disorders, PKD is inherited via heterozygous loss-of-function mutations but is theorized to require additional loss of function. To test this, we establish human pluripotent stem cells in allelic series representing four common nonsense mutations, using CRISPR base editing. When differentiated into kidney organoids, homozygous mutants spontaneously form cysts, whereas heterozygous mutants (original or base corrected) express no phenotype. Using these, we identify eukaryotic ribosomal selective glycosides (ERSGs) as PKD therapeutics enabling ribosomal readthrough of these same nonsense mutations. Two different ERSGs not only prevent cyst initiation but also limit growth of pre-formed cysts by partially restoring polycystin expression. Furthermore, glycosides accumulate in cyst epithelia in organoids and mice. Our findings define the human polycystin threshold as a surmountable drug target for pharmacological or gene therapy interventions, with relevance for understanding disease mechanisms and future clinical trials.

Inspiring Tactics with the Improvement of Mitophagy and Redox Balance for the Development of Innovative Treatment against Polycystic Kidney Disease.

Polycystic kidney disease (PKD) is the most common genetic form of chronic kidney disease (CKD), and it involves the development of multiple kidney cysts. Not enough medical breakthroughs have been made against PKD, a condition which features regional hypoxia and activation of the hypoxia-inducible factor (HIF) pathway. The following pathology of CKD can severely instigate kidney damage and/or renal failure. Significant evidence verifies an imperative role for mitophagy in normal kidney physiology and the pathology of CKD and/or PKD. Mitophagy serves as important component of mitochondrial quality control by removing impaired/dysfunctional mitochondria from the cell to warrant redox homeostasis and sustain cell viability. Interestingly, treatment with the peroxisome proliferator-activated receptor-α (PPAR-α) agonist could reduce the pathology of PDK and might improve the renal function of the disease via the modulation of mitophagy, as well as the condition of gut microbiome. Suitable modulation of mitophagy might be a favorable tactic for the prevention and/or treatment of kidney diseases such as PKD and CKD.

Vascular Dysfunction in Polycystic Kidney Disease: A Mini-Review.

Polycystic kidney disease (PKD) is one of the most common hereditary kidney diseases, which is characterized by progressive cyst growth and secondary hypertension. In addition to cystogenesis and renal abnormalities, patients with PKD can develop vascular abnormalities and cardiovascular complications. Progressive cyst growth substantially alters renal structure and culminates into end-stage renal disease. There remains no cure beyond renal transplantation, and treatment options remain largely limited to chronic renal replacement therapy. In addition to end-stage renal disease, patients with PKD also present with hypertension and cardiovascular disease, yet the timing and interactions between the cardiovascular and renal effects of PKD progression are understudied. Here, we review the vascular dysfunction found in clinical and preclinical models of PKD, including the clinical manifestations and relationship to hypertension, stroke, and related cardiovascular diseases. Finally, our discussion also highlights the critical questions and emerging areas in vascular research in PKD.

Experimental Models of Polycystic Kidney Disease: Applications and Therapeutic Testing.

Polycystic kidney diseases (PKDs) are genetic disorders characterized by the formation and expansion of numerous fluid-filled renal cysts, damaging normal parenchyma and often leading to kidney failure. Although PKDs comprise a broad range of different diseases, with substantial genetic and phenotypic heterogeneity, an association with primary cilia represents a common theme. Great strides have been made in the identification of causative genes, furthering our understanding of the genetic complexity and disease mechanisms, but only one therapy so far has shown success in clinical trials and advanced to US Food and Drug Administration approval. A key step in understanding disease pathogenesis and testing potential therapeutics is developing orthologous experimental models that accurately recapitulate the human phenotype. This has been particularly important for PKDs because cellular models have been of limited value; however, the advent of organoid usage has expanded capabilities in this area but does not negate the need for whole-organism models where renal function can be assessed. Animal model generation is further complicated in the most common disease type, autosomal dominant PKD, by homozygous lethality and a very limited cystic phenotype in heterozygotes while for autosomal recessive PKD, mouse models have a delayed and modest kidney disease, in contrast to humans. However, for autosomal dominant PKD, the use of conditional/inducible and dosage models have resulted in some of the best disease models in nephrology. These have been used to help understand pathogenesis, to facilitate genetic interaction studies, and to perform preclinical testing. Whereas for autosomal recessive PKD, using alternative species and digenic models has partially overcome these deficiencies. Here, we review the experimental models that are currently available and most valuable for therapeutic testing in PKD, their applications, success in preclinical trials, advantages and limitations, and where further improvements are needed.

Endovascular treatment of intrarenal aneurysms bleeding and angiomyolipomas in a patient with tuberous sclerosis and polycystic kidney disease.

Tuberous sclerosis complex (TSC) and autosomal dominant polycystic kidney disease (ADPKD) are conditions related to renal failure that can rarely occur in association as a contiguous gene syndrome. Angiomyolipomas (AMLs) are renal tumors strongly related to TSC that may rupture and cause life-threatening bleedings. We present a patient with TSC, ADPKD, and renal AMLs with persistent hematuria requiring blood transfusion. The persistent hematuria was successfully treated through endovascular embolization, a minimally invasive nephron sparing technique.

Relationship between disease awareness and severity of kidney disease in autosomal dominant polycystic kidney disease patients.

INTRODUCTION: Polycystic kidney disease (PKD) is responsible for 5%-10% of end-stage renal disease. We examined the relationship between renal and extrarenal findings, disease severity, and the level of consciousness of PKD patients. METHODS: Patients were asked to answer the questionnaire about PKD. Disease severity was determined according to estimated glomerular filtration rate, and disease awareness was assessed by adapting the Disease Perception Scale to PKD. Awareness of patients was evaluated comparatively with chronic kidney disease stage, age, region, and symptoms. RESULTS: One out of five patients does not know that this disease is inherited. Mean awareness scores of the patients decreased significantly with increasing age. Awareness scores were significantly higher in patients with flank pain, hematuria, and urinary tract stones. CONCLUSION: Although PKD is the most common hereditary kidney disease, the rate of patients' knowledge on this subject is low. Increased awareness might lead to better treatment in those patients.

Polycystic Kidney/Liver Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder that leads to chronic kidney disease and end-stage kidney disease (ESKD). Polycystic liver disease (PCLD) is the most common extrarenal manifestation of ADPKD. Though isolated PCLD and PCLD due to ADPKD are genetically distinct, they follow a similar clinical course of hepatomegaly from multiple cysts with preserved liver function. Tolvaptan use in ADPKD can slow down the deterioration of renal function and growth of cysts. Somatostatin analogs can slow the growth of polycystic livers but the effect is short-lived. The only curative therapy for PCLD is liver transplantation. Renal transplantation can significantly improve survival in patients with ESKD due to ADPKD.

Renal plasticity revealed through reversal of polycystic kidney disease in mice.

Initiation of cyst formation in autosomal dominant polycystic kidney disease (ADPKD) occurs when kidney tubule cells are rendered null for either PKD1 or PKD2 by somatic 'second hit' mutations. Subsequent cyst progression remodels the organ through changes in tubule cell shape, proliferation and secretion. The kidney develops inflammation and fibrosis. We constructed a mouse model in which adult inactivation of either Pkd gene can be followed by reactivation of the gene at a later time. Using this model, we show that re-expression of Pkd genes in cystic kidneys results in rapid reversal of ADPKD. Cyst cell proliferation is reduced, autophagy is activated and cystic tubules with expanded lumina lined by squamoid cells revert to normal lumina lined by cuboidal cells. Increases in inflammation, extracellular matrix deposition and myofibroblast activation are reversed, and the kidneys become smaller. We conclude that phenotypic features of ADPKD are reversible and that the kidney has an unexpected capacity for plasticity controlled at least in part by ADPKD gene function.

What are the information needs and concerns of individuals with Polycystic Kidney Disease? Results of an online survey using Facebook and social listening analysis.

BACKGROUND: Polycystic Kidney Disease (PKD) is a hereditary disorder that has no cure and can result in end stage kidney failure. Searching for health information online and via social media is a common phenomenon in many medical conditions. However, no recent studies have documented the information needs, online behaviours, and concerns of people with PKD. The aim of this study was to explore the information needs of individuals with PKD and their carers by documenting (i) the information needs (ii) online information health seeking behaviours (iii) the perceived challenges of living with PKD and (iv) dietary concerns. METHODS: A 17-item survey was constructed by undertaking a social listening analysis. This survey was then distributed via PKD related social media groups on Facebook. Seven groups distributed the survey with permission from the group owners. Open free text survey questions were analysed thematically using content analysis. RESULTS: A total of 536 respondents completed the online survey (70.9 % female, 77 % aged 35-70, 70.2 % diagnosed more than 10 years ago). The major information need expressed by participants with PKD was for dietary information. Information regarding medications, medical management and symptom control were also desired. The overarching themes arising from the free text responses to the major challenge of living with PKD included 'learning to navigate dietary ambiguities'; 'managing social, psychological and emotional needs'; and 'accepting an uncertain future'. In addition to a strong desire for practical and specific dietary information, participants expressed a need for more online information pertaining to management of fatigue, pain, complications and how to manage mental health. Online peer support was also highly regarded and desired. CONCLUSIONS: This study provides contemporary insights into the type of information desired by people with PKD. The results indicated that there was a strong desire for unambiguous information and guidance from health professionals to facilitate self-management, alleviate concerns, and address the complexities of living with Polycystic Kidney Disease. While diet is an important and frequently expressed need, there also remains a large demand for information on how to support psychological needs, and on medical management in order to support treatment decision making. Future work is required to develop specific, actionable and evidence-based resources for patients that are available online and through health professionals. Increased access to renal dietitians, peer support and additional training for health professionals could also improve patient-centered care and support self-management.

Development of Glycerol-Rose Bengal-Polidocanol (GRP) foam for enhanced sclerosis of a cyst for cystic diseases.

Polycystic kidney disease (PKD) is a common genetic disorder that results in a proliferating and enlarging cyst and ultimately leads to loss of kidney function. Because an enlarged cyst is a primary factor for limited kidney function, the large cyst is surgically removed by laparoscopic deroofing or sclerosant. This a relatively nascent treatment method entails complications and sometimes fail due to the cyst fluid refilling and infection. This study proposes using a more stable and effective polidocanol foam with glycerol and Rose Bengal (GRP form) to prevent cyst regeneration and irritation, which is caused by the required body movement during the treatment. Specifically, the foam retention time and viscosity were increased by adding glycerol up to 10% (w/v). The GRP form inhibited cellular proliferation and disrupted cellular junctions, e-cadherin, and cyst formation, demonstrated by the LDH, Live and Dead, and re-plating culture assays. The GRP foam was shown to be a safe and effective treatment as a commercial grade polidocanol foam form by an in vivo study in which subcutaneously injected mice injected with commercial 3% polidocanol, and the GRP foam showed no difference in inflammation. Thus, this study provides an advanced polidocanol form by adding glycerol and Rose-Bengal to help existing sclerotherapy.

Renal cystic diseases during the perinatal and neonatal period.

Renal cystic diseases are a clinically and genetically diverse group of renal diseases that can manifest in utero, infancy, or throughout childhood and adulthood. These diseases may be unilateral or bilateral with a single cyst or multiple cysts, or with increased echogenicity of the renal cortex without macroscopic cysts. Certain cystic renal diseases are life-threatening, with many developing chronic kidney and hepatic disease if not recognized early enough. Therefore, due to the prevalence and life-altering complications of this specific group of diseases in vulnerable populations, it is crucial for clinicians and healthcare providers to have an overall understanding of cystic diseases and how to pre-emptively detect and manage these conditions. In this review, we discuss in detail the epidemiology, genetics and pathophysiology, diagnosis, presentation, and management of numerous genetic and sporadic renal cystic diseases, such as polycystic kidney disease, multicystic dysplastic kidney, and calyceal diverticula, with an emphasis on prenatal care and pregnancy counseling.

Intraperitoneal Pressure in Polycystic and Non-Polycystic Kidney Disease Patients, Treated by Peritoneal Dialysis.

INTRODUCTION: Intraperitoneal volume (IPV) should be individualized and aimed to maintain an intraperitoneal pressure (IPP) lower than 17 cm H2O. IPP is very variable, given its relation with body size. However, it is not yet fully understood which anthropometric variable mostly affects IPP and the relation between IPP and organomegaly in polycystic kidney disease (PKD) patients is not known. OBJECTIVES: The aim of the present study was to analyse the relation between antropometric variables and IPP in a large cohort of peritoneal dialysis (PD) patients and to identify if a relation between nephromegaly and IPP exists in PKD patients. METHODS: IPP was measured in PD patients and data was retrospectively collected. In PKD patients, total kidney volumes were measured in CT scans, and normalized with height (hTKV). RESULTS: Seventy-seven patients were included in the study, 18% affected by PKD. Mean IPP was 14.9 ± 2.9 cm H2O and it showed significant positive correlation with body mass index (BMI; ρ = 0.42, p < 0.001). No correlation was found between IPP and absolute IPV; conversely, IPP has a significant inverse correlation with IPV normalized with BMI and body surface area (ρ -0.38, p = 0.001 and ρ -0.25, p = 0.02, -respectively). Patients with IPP >17 cm H2O have significant larger BMI and lower IPV/BMI compared to those with IPP <17 cm H2O (29 ± 3.6 vs. 26 ± 4 kg/m2, p < 0.05 and 97 ± 15.5 vs. 109 ± 22 mL/kg/m2, p < 0.05). PKD patients have a wide variability in hTKV (range 645-3,787 mL/m2) and it showed a significant correlation with IPP/IPV (ρ = 0.6, p < 0.05). CONCLUSIONS: Patients with larger BMI have greater IPP, irrespectively to IPV. In PKD patients, hTKV correlate with IPP/IPV ratio. However, given the wide range of distribution of hTKV, increased IPP cannot be presumed because of pre-existing polycystic kidney, but need to be quantified.

Simultaneous bilateral femoral neck fractures in a dialysis-dependent patient: case report and literature review.

BACKGROUND: Simultaneous bilateral femoral neck fractures are extremely rare without obvious injury. Herein, we report the case of a patient on dialysis presenting with bilateral femoral neck fractures, which is a condition with high complication and mortality rates according to a review of the pertinent literature. CASE PRESENTATION: We report the case a 47-year-old female with a history of 8 years of haemodialysis due to polycystic kidney disease who presented with bilateral hip pain during walking. The clinical history and results of physical and radiographic examinations of this patient are shown. Single-stage bilateral hemiarthroplasty was performed after a multidisciplinary team consultation. Three days after the operation, she could ambulate with a walker. The woman gradually regained her previous ability to walk over 6 months after surgery. CONCLUSIONS: A multidisciplinary team consultation for perioperative management is necessary and effective in patients on dialysis. Early diagnosis with prompt surgical treatment could lead to favourable recovery.

Therapeutic effect of high-efficiency online hemodiafiltration for recurrent restless legs syndrome in dialysis patients.

Two dialysis patients developed recurrent restless legs syndrome. The clinical courses and the association between the α1-microglobulin removal rate and the therapeutic effects of hemodiafiltration were analyzed. Case 1: a middle-aged woman was switched from predilution online hemodiafiltration to hemodialysis, following which the α1-microglobulin removal rate decreased from 39.1 to 29.9%. A month later, the severe restless legs syndrome occurred. The treatment was then switched to high-efficiency hemodiafiltration and 2 weeks later, these symptoms were resolved. The α1-microglobulin removal rate increased to 41.9%. Her symptoms recurred 5 years later with severity; thus, the hemodiafiltration treatment conditions were changed. Under revised conditions, the α1-microglobulin removal rate was 42.6%, and her symptoms were alleviated. Continuation of high-efficiency hemodiafiltration led to the resolution of the syndrome at 1 month after recurrence. Case 2: a middle-aged man on hemodialysis developed the restless legs syndrome in the second year of treatment. The α1-microglobulin removal rate was 23.8%. After switching to a month-long high-efficiency hemodiafiltration with a removal rate of ≥ 40%, his symptoms were resolved. However, the syndrome recurred after a year with severity. The symptoms were alleviated using various measures. The hemodiafilters were changed, and hemodiafiltration with an α1-microglobulin removal rate of ≥ 40% was continued; 2 months later, his symptoms resolved. High-efficiency online hemodiafiltration is an effective therapeutic strategy for restless legs syndrome in dialysis patients. We found, for the first time, that target removal efficiency is an α1-microglobulin removal rate of 40% or higher.

[Clinical practice guidelines for polycystic kidney diseases].

Polycystic kidney disease (PKD) is a group of hereditary kidney diseases caused by genetic mutations. Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are the two main forms of PKD. The pathological features of PKD include progressive enlargement of renal cysts and destruction of kidney structure, which may eventually lead to end-stage renal disease (ESRD). As a result, the lives of PKD patients can only be sustained by dialysis or kidney transplantation. On the basis of basic research, clinical studies and guidelines issued for PKD at home and abroad, and by combining with the reality of Chinese PKD patients, this guideline has summarized the key points for the genetic counseling and clinical treatment of PKD, with an aim to improve the understanding and standardized diagnosis and treatment for such disorders.