Severity of polycystic kidney disease revealed by multiparametric MRI.

PURPOSE: We aimed to compare multiple MRI parameters, including relaxation rates ( R 1 $$ {R}_1 $$ , R 2 $$ {R}_2 $$ , and R 1 ρ $$ {R}_{1\rho } $$ ), ADC from diffusion weighted imaging, pool size ratio (PSR) from quantitative magnetization transfer, and measures of exchange from spin-lock imaging ( S ρ $$ {S}_{\rho } $$ ), for assessing and predicting the severity of polycystic kidney disease (PKD) over time. METHODS: Pcy/Pcy mice with CD1 strain, a mouse model of autosomal dominant PKD, were imaged at 5, 9, and 26 wk of age using a 7T MRI system. Twelve-week normal CD1 mice were used as controls. Post-mortem paraffin tissue sections were stained using hematoxylin and eosin and picrosirius red to identify histological changes. RESULTS: Histology detected segmental cyst formation in the early stage (week 5) and progression of PKD over time in Pcy kidneys. In T 2 $$ {T}_2 $$ -weighted images, small cysts appeared locally in cystic kidneys in week 5 and gradually extended to the whole cortex and outer stripe of outer medulla region from week 5 to week 26. Regional PSR, R 1 $$ {R}_1 $$ , R 2 $$ {R}_2 $$ , and R 1 ρ $$ {R}_{1\rho } $$ decreased consistently over time compared to normal kidneys, with significant changes detected in week 5. Among all the MRI measures, R 2 $$ {R}_2 $$ and R 1 ρ $$ {R}_{1\rho } $$ allow highest detectability to PKD, while PSR and R 1 $$ {R}_1 $$ have highest correlation with pathological indices of PKD. Using optimum MRI parameters as regressors, multiple linear regression provides reliable prediction of PKD progression. CONCLUSION: R 2 $$ {R}_2 $$ , R 1 $$ {R}_1 $$ , and PSR are sensitive indicators of the presence of PKD. Multiparametric MRI allows a comprehensive analysis of renal changes caused by cyst formation and expansion.

Establishing a Core Outcome Set for Autosomal Dominant Polycystic Kidney Disease: Report of the Standardized Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD) Consensus Workshop.

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

Ciliopathies and the Kidney: A Review.

Primary cilia are specialized sensory organelles that protrude from the apical surface of most cell types. During the past 2 decades, they have been found to play important roles in tissue development and signal transduction, with mutations in ciliary-associated proteins resulting in a group of diseases collectively known as ciliopathies. Many of these mutations manifest as renal ciliopathies, characterized by kidney dysfunction resulting from aberrant cilia or ciliary functions. This group of overlapping and genetically heterogeneous diseases includes polycystic kidney disease, nephronophthisis, and Bardet-Biedl syndrome as the main focus of this review. Renal ciliopathies are characterized by the presence of kidney cysts that develop due to uncontrolled epithelial cell proliferation, growth, and polarity, downstream of dysregulated ciliary-dependent signaling. Due to cystic-associated kidney injury and systemic inflammation, cases result in kidney failure requiring dialysis and transplantation. Of the handful of pharmacologic treatments available, none are curative. It is important to determine the molecular mechanisms that underlie the involvement of the primary cilium in cyst initiation, expansion, and progression for the development of novel and efficacious treatments. This review updates research progress in defining key genes and molecules central to ciliogenesis and renal ciliopathies.

Diagnosis and Management of Renal Cystic Disease of the Newborn: Core Curriculum 2021.

Renal cystic disease encompasses a large variety of illnesses with various phenotypic expressions that can manifest in utero, in infancy, and in childhood. These diseases may be unilateral or bilateral and present with single or multiple cysts. Various cystic diseases may also progress to chronic kidney disease (CKD), including kidney failure, and hepatic disease, thus potentially being life threatening. The prevalence and serious complications of CKD in the pediatric population make it vital that health care providers detect these conditions early and provide effective management. This installment of AJKD's Core Curriculum in Nephrology discusses various genetic and sporadic kidney cystic diseases, including multicystic dysplastic kidney, nephronophthisis, cystic dysplasia, hepatocyte nuclear factor 1-ß (HNF1-ß) nephropathy, Bardet-Biedl syndrome, Meckel-Gruber syndrome, Zellweger syndrome, calyceal diverticulum, autosomal recessive polycystic kidney disease (ARPKD), and autosomal dominant polycystic kidney disease (ADPKD). This article discusses the epidemiology, genetics and pathophysiology, diagnosis, presentation, and management for each of these renal cystic diseases, with particular attention to prenatal care and pregnancy counseling.

Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system.

To explore the approaches and diagnostic yield of genetic testing for renal disease in children, we describe the genotype and phenotype of the national cohort of children with renal disease from 13 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system (Chinese Children Genetic Kidney Disease Database, CCGKDD). Genetic diagnosis was confirmed in 42.1% of our cohort of 1001 pediatric patients with clinical suspicion of a genetic renal disease. Of the 106 distinct monogenetic disorders detected, 15 accounted for 60.7% of genetic diagnoses. The diagnostic yield was 29.1% in steroid resistant nephritic syndrome (SRNS), 61.4% in cystic renal disease, 17.0% in congenital anomalies of the kidney and urinary tract (CAKUT), 62.3% in renal tubular disease/renal calcinosis, and 23.9% for chronic kidney disease (CKD) 3 to 5 stage with unknown origin. Genetic approaches of target gene sequence (TGS), singleton whole-exome sequencing (WES) and trio-WES were performed with diagnostic rates of 44.8%, 36.2%, and 42.6%, respectively. The early use of trio-WES could improve the diagnostic rate especially in renal tubular disease and calcinosis. We report the genetic spectrum of Chinese children with renal disease. Establishment of the CCGKDD will improve the genetic work on renal disease.

Loss of zinc finger MYND-type containing 10 (zmynd10) affects cilia integrity and axonemal localization of dynein arms, resulting in ciliary dysmotility, polycystic kidney and scoliosis in medaka (Oryzias latipes).

Cilia and flagella are hair-like organelles that project from the cell surface and play important roles in motility and sensory perception. Motility defects in cilia and flagella lead to primary ciliary dyskinesia (PCD), a rare human disease. Recently zinc finger MYND-type containing 10 (ZMYND10) was identified in humans as a PCD-associated gene. In this study, we use medaka fish as a model to characterize the precise functions of zmynd10. In medaka, zmynd10 is exclusively expressed in cells with motile cilia. Embryos with zmynd10 Morpholino knockdown exhibited a left-right (LR) defect associated with loss of motility in Kupffer's vesicle (KV) cilia. This immotility was caused by loss of the outer dynein arms, which is a characteristic ultrastructural phenotype in PCD. In addition, KV cilia in zmynd10 knockdown embryos had a swollen and wavy morphology. Together, these results suggest that zmynd10 is a multi-functional protein that has independent roles in axonemal localization of dynein arms and in formation and/or maintenance of cilia. The C-terminal region of zmynd10 has a MYND-type zinc finger domain (zf-MYND) that is important for its function. Our rescue experiment showed that the zmynd10-ΔC truncated protein, which lacks zf-MYND, was still partially functional, suggesting that zmynd10 has another functional domain besides zf-MYND. To analyze the later stages of development, we generated a zmynd10 knockout mutant using transcription activator-like effector nuclease (TALEN) technology. Adult mutants exhibited sperm dysmotility, scoliosis and progressive polycystic kidney.

CRISPR Gene Editing in the Kidney.

CRISPR is a nuclease guidance system that enables rapid and efficient gene editing of specific DNA sequences within genomes. We review applications of CRISPR for the study and treatment of kidney disease. CRISPR enables functional experiments in cell lines and model organisms to validate candidate genes arising from genetic studies. CRISPR has furthermore been used to establish the first models of genetic disease in human kidney organoids derived from pluripotent stem cells. These gene-edited organoids are providing new insight into the cellular mechanisms of polycystic kidney disease and nephrotic syndrome. CRISPR-engineered cell therapies are currently in clinical trials for cancers and immunologic syndromes, an approach that may be applicable to inflammatory conditions such as lupus nephritis. Use of CRISPR in large domestic species such as pigs raises the possibility of farming kidneys for transplantation to alleviate the shortage of donor organs. However, significant challenges remain, including how to effectively deliver CRISPR to kidneys and how to control gene editing events within the genome. Thorough testing of CRISPR in preclinical models will be critical to the safe and efficacious translation of this powerful young technology into therapies.

The C-terminal tail of polycystin-1 regulates complement factor B expression by signal transducer and activator of transcription 1.

Inhibition of the overactivated alternative complement pathway in autosomal dominant polycystic kidney disease (ADPKD) retards disease progression in animal models; however, it remains unknown how complement factor B (CFB) is upregulated in ADPKD. Here, we showed that the overexpression of CFB in cystic kidneys is associated with increased JAK2/STAT1 activity and enhanced expression of the polycystin-1 C-terminal tail (PC1-CTT). Overexpression or blockage of STAT1 increased or decreased CFB expression and CFB promoter activity. Moreover, overexpression of PC1-CTT induced JAK2/STAT1 activation and CFB upregulation in renal tubular epithelial cells. Furthermore, PC1-CTT overexpression increased human CFB promoter activity, whereas dominant negative STAT1 plasmids or mutation of putative STAT1 responsive elements decreased PC1-CTT-induced CFB promoter activity. The effect of CFB on macrophage differentiation was tested on a mouse macrophage cell line. Bioactive CFB dose dependently promoted macrophage M2 phenotype conversion. In addition, conditioned media from renal epithelial cells promoted macrophage M2 phenotype conversion which was blocked by STAT1 inhibition in a dose-dependent manner. Conditioned media from PC1-CTT-transfected renal epithelial cells further promoted macrophage M2 phenotype conversion, which was suppressed by fludarabine or a CFB antibody. In addition, we show that NF-κB acts downstream of PC1-CTT and may partly mediate PC1-CTT-induced CFB expression. In conclusion, our study reveals possible mechanisms of CFB upregulation in ADPKD and a novel role of PC1-CTT in ADPKD-associated inflammation. Furthermore, our study suggests that targeting STAT1 may be a new strategy to prevent inflammation in the kidney of patients with ADPKD.

A retrospective analysis of mortality in captive pygmy hippopotamus (Choeropsis liberiensis) from 1912 to 2014.

The pygmy hippopotamus (Choeropsis liberiensis) is an IUCN Red List Endangered species (CITES Appendix II) that has been housed in zoological collections since 1912. As wild populations continue to decline throughout the species' range, successful ex situ breeding and management, including an understanding of morbidity and mortality, are of utmost importance. This study is the first comprehensive review of mortality data from the captive population since 1982 and significantly expands on previous analyses. We solicited necropsy reports from 129/187 zoological institutions worldwide that currently or previously held pygmy hippos and received data for 404 animals (177 ♂, 220 ♀, 7 undermined sex), representing 43% of pygmy hippos that have died in captivity. Mortality in neonates was primarily due to perinatal causes (51.8%-stillbirth, failure to thrive, weakness, poor suckling reflex, maternal neglect) or parent-inflicted trauma (28%). Common causes of mortality in adult and geriatric animals included cardiovascular disease (16%), degenerative musculoskeletal conditions (10%), obstructive gastrointestinal disease (9%), and renal insufficiency (13%), sometimes associated with advanced polycystic kidney disease (PKD). Although not the direct cause of mortality, a number of adult and geriatric pygmy hippos were also overweight to obese. Infectious causes of mortality in included leptospirosis and encephalomyocarditis virus, the latter usually presenting as acute death due to cardiovascular demise. This comprehensive overview presents a useful guide for recommendations in preventative veterinary care and for improved husbandry and management of pygmy hippos in captivity. Zoo Biol. 35:556-569, 2016. © 2016 Wiley Periodicals, Inc.

ADAM17 promotes proliferation of collecting duct kidney epithelial cells through ERK activation and increased glycolysis in polycystic kidney disease.

Polycystic kidney disease (PKD) is a common genetic disorder leading to cyst formation in the kidneys and other organs that ultimately results in kidney failure and death. Currently, there is no therapy for slowing down or stopping the progression of PKD. In this study, we identified the disintegrin metalloenzyme 17 (ADAM17) as a key regulator of cell proliferation in kidney tissues of conditional knockout Ift88(-/-) mice and collecting duct epithelial cells from Ift88°(rpk) mice, animal models of autosomal recessive polycystic kidney disease (ARPKD). Using Western blotting, an enzyme activity assay, and a growth factor-shedding assay in the presence or absence of the specific ADAM17 inhibitor TMI-005, we show that increased expression and activation of ADAM17 in the cystic kidney and in collecting duct epithelial cells originating from the Ift88°(rpk) mice (designated as PKD cells) lead to constitutive shedding of several growth factors, including heparin-binding EGF-like growth factor (HB-EGF), amphiregulin, and transforming growth factor-α (TGF-α). Increased growth factor shedding induces activation of the EGFR/MAPK/ERK pathway and maintains higher cell proliferation rate in PKD cells compared with control cells. PKD cells also displayed increased lactate formation and extracellular acidification indicative of aerobic glycolysis (Warburg effect), which was blocked by ADAM17 inhibition. We propose that ADAM17 is a key promoter of cellular proliferation in PKD cells by activating the EGFR/ERK axis and a proproliferative glycolytic phenotype.

Rationale and design of the DIPAK 1 study: a randomized controlled clinical trial assessing the efficacy of lanreotide to Halt disease progression in autosomal dominant polycystic kidney disease.

BACKGROUND: There are limited therapeutic options to slow the progression of autosomal dominant polycystic kidney disease (ADPKD). Recent clinical studies indicate that somatostatin analogues are promising for treating polycystic liver disease and potentially also for the kidney phenotype. We report on the design of the DIPAK 1 (Developing Interventions to Halt Progression of ADPKD 1) Study, which will examine the efficacy of the somatostatin analogue lanreotide on preservation of kidney function in ADPKD. STUDY DESIGN: The DIPAK 1 Study is an investigator-driven, randomized, multicenter, controlled, clinical trial. SETTING & PARTICIPANTS: We plan to enroll 300 individuals with ADPKD and estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m(2) who are aged 18-60 years. INTERVENTION: Patients will be randomly assigned (1:1) to standard care or lanreotide, 120 mg, subcutaneously every 28 days for 120 weeks, in addition to standard care. OUTCOMES: Main study outcome is the slope through serial eGFR measurements starting at week 12 until end of treatment for lanreotide versus standard care. Secondary outcome parameters include change in eGFR from pretreatment versus 12 weeks after treatment cessation, change in kidney volume, change in liver volume, and change in quality of life. MEASUREMENTS: Blood and urine will be collected and questionnaires will be filled in following a fixed scheme. Magnetic resonance imaging will be performed for assessment of kidney and liver volume. RESULTS: Assuming an average change in eGFR of 5.2 ± 4.3 (SD) mL/min/1.73 m(2) per year in untreated patients, 150 patients are needed in each group to detect a 30% reduction in the rate of kidney function loss between treatment groups with 80% power, 2-sided α = 0.05, and 20% protocol violators and/or dropouts. LIMITATIONS: The design is an open randomized controlled trial and measurement of our primary end point does not begin at randomization. CONCLUSIONS: The DIPAK 1 Study will show whether subcutaneous administration of lanreotide every 4 weeks attenuates disease progression in patients with ADPKD.

A Rare Case of Renal Angiomyolipoma and Polycystic Kidney Disease in a Patient with Tuberous Sclerosis.

Renal angiomyolipoma (AML) is a rare benign tumor that follows an autosomal dominant inheritance pattern. Its association with polycystic kidney disease is uncommon, with only a handful of cases documented in the literature. The growth of lesions to a significant size may lead to life-threatening complications. We report a case of a 32-year-old female who presented with a palpable mass and bilateral flank pain. Following clinical assessment and CT examination, the patient underwent a left radical nephrectomy. The resected mass measured 9.3 x 8.2 x 7.5 cm, and the subsequent histopathological examination confirmed the diagnosis as renal AML.

Pedigree Analysis of Polycystic Kidney Disease Patients: Bangladeshi Perspective.

Background: Polycystic kidney disease (PKD), an inheritance disorder which is the fourth leading cause of the end-stage renal disease. The inheritance pattern can be diagnosed and confirmed by pedigree analysis. The aim of the present research was to determine the type and frequency of PKD using pedigree analysis. Materials and Methods: The present research was designed as a cross-sectional descriptive study. Thirty-eight adult Bangladeshi PKD patients were recruited using a selection checklist from the Department of Nephrology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh. Data were collected using a data collection sheet after taking informed written consent. The pedigree was drawn using the genetic pedigree chart creation software f-tree V4.0.6. The percentage frequencies of different types of pedigree were calculated using the Statistical Package for the Social Sciences software, version 23. Results: A total of 24 (63.20%) had a positive family history and 36.80% (14) had no positive family history. All of the patients with a positive family history had vertical transmission; male and female were equally inheriting the gene. Out of these 24 patients, 4.17% (one), 8.33% (two), and 16.67% (four) had a homozygous/heterozygous state, skip generation, and male to male transmission, respectively. Conclusions: Pedigree analysis of PKD patients showed an increased value in early diagnosis and better management and prognosis of the disease.

Scar Epilepsy as a Complication of Subarachnoid Hemorrhage in a Patient With Adult Polycystic Kidney Disease: A Case Report.

Polycystic kidney disease (PKD) is the most common hereditary disorder of kidneys. In adults, PKD1 gene mutation almost always signifies its subtype, autosomal dominant polycystic kidney disease (ADPKD), or adult polycystic kidney disease. ADPKD is a multisystemic disorder giving rise to renal and extra-renal manifestations. The renal shutdown is the most feared renal complication while the development of intracranial aneurysms is considered the most lethal extra-renal feature. This can be attributed to the increased risk of rupture associated with aneurysms leading to a condition called subarachnoid hemorrhage (SAH). While being notorious for the subtle situations SAH often leads to, its association with the onset of seizures is a matter of high clinical significance. We present a patient with a kidney disorder (ADPKD) that has led to the onset of epilepsy. Five years after the diagnosis of ADPKD, he developed an aneurysm in the right internal carotid artery, for which he was treated conservatively. After four months, he presented with the onset of symptoms of SAH, which was confirmed by computed tomography angiography. Clipping was unable to be performed, and the patient was treated conservatively, this time as well. Recently, the patient presented with the onset of generalized tonic-clonic seizures, unable to be controlled with single anti-epileptics. He was stabilized by dual intravenous antiepileptics but on further workup, he was found to have a recurrence of a berry aneurysm for which he was referred to a neurosurgeon for a clipping procedure to be performed. The operation was successful, but the patient was still found to be an epileptic for which he was discharged with a long-term course of double anti-epileptics.

Inactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse.

Nephronophthisis (NPHP) is a ciliopathy characterized by renal fibrosis and cyst formation, and accounts for a significant portion of end stage renal disease in children and young adults. Currently, no targeted therapy is available for this disease. INVS/NPHP2 is one of the over 25 NPHP genes identified to date. In mouse, global knockout of Invs leads to renal fibrosis and cysts. However, the precise contribution of different cell types and the relationship between epithelial cysts and interstitial fibrosis remains undefined. Here, we generated and characterized cell-type-specific knockout mouse models of Invs, investigated the impact of removing cilia genetically on phenotype severity in Invs mutants and evaluated the impact of the histone deacetylase inhibitor valproic acid (VPA) on Invs mutants. Epithelial-specific knockout of Invs in Invsflox/flox;Cdh16-Cre mutant mice resulted in renal cyst formation and severe stromal fibrosis, while Invsflox/flox;Foxd1-Cre mice, where Invs is deleted in stromal cells, displayed no observable phenotypes up to the young adult stage, highlighting a significant role of epithelial-stromal crosstalk. Further, increased cell proliferation and myofibroblast activation occurred early during disease progression and preceded detectable cyst formation in the Invsflox/flox;Cdh16-Cre kidney. Moreover, concomitant removal of cilia partially suppressed the phenotypes of the Invsflox/flox;Cdh16-Cre mutant kidney, supporting a significant interaction of cilia and Invs function in vivo. Finally, VPA reduced cyst burden, decreased cell proliferation and ameliorated kidney function decline in Invs mutant mice. Our results reveal the critical role of renal epithelial cilia in NPHP and suggest the possibility of repurposing VPA for NPHP treatment.

One of the most common causes of kidney failure in children and young adults is nephronophthisis. This genetic disease causes cysts and tissue scarring in the kidneys, leading to excessive urine production and extreme tiredness. Unfortunately, there is no targeted therapy available for this condition. Scientists do not fully understand how genetic mutations lead to these symptoms. Previous research in mice showed that blocking the gene for a protein called INVS recreated signs similar to nephronophthisis. However, it is not clear how the different cell types in the kidneys are involved. Previous results suggest that cilia, the hair-like projections on the surface of cells, could be involved in developing cysts in nephronophthisis. To understand how the disease is driven, Li, Xu et al. created a range of genetically modified mice with INVS missing in different cell types. When INVS was removed from cells that line the kidney tubules, the mice developed scarring and cysts. By contrast, there were no symptoms when connective tissue cells were lacking INVS. When Li, Xu et al. removed the cilia from the cells, it helped to reduce the negative impact of the loss of INVS. In addition, a drug called valproic acid reduced the cysts and tissue scarring, and slowed kidney decline in the mutant mice, suggesting the possibility of repurposing this drug for nephronophthisis treatment. These results could help researchers to study other conditions that are influenced by the health of cilia. Future work on nephronophthisis will be needed to understand how INVS causes the disease and the mechanism for the benefits of valproic acid.

Polycystic kidney disease increases the stoke incidence in Taiwan: A retrospective population-based cohort study using National Health Insurance Database.

BACKGROUND: Few studies documented incidence rates of different types of stroke among patients with polycystic kidney disease (PKD). METHODS: We conducted a retrospective cohort study based on the National Health Insurance (NHI) Database of Taiwan. The PKD cohort comprised patients aged≥20 years diagnosed with PKD using inpatient claims from 1998 to 2011, excluding prior stroke. The reference cohort was established by inpatients without PKD using 1:4 frequency-matched with age, gender, and baseline comorbidities. The two cohorts were followed-up until stroke hospitalization, death, withdrawal from the NHI program, or the end of 2012. To account for competing risks of death, we used multivariable competing risks regression models to estimate sub-distribution hazard ratio (SHR) adjusted for age, gender, baseline comorbidities and end stage renal disease. RESULTS: 7837 PKD patients and 31,211 reference subjects were followed up through 2012. A total of 955 cases of stroke were identified in the PKD cohort, including 441 ischemic stroke (IS), 289 intracranial hemorrhage (ICH), 73 subarachnoid hemorrhage (SAH) and 232 other stroke. The incidence rates of overall stroke, IS, ICH, and SAH were 21.3, 10.2, 6.8, and 1.7 per 1000 person-years, respectively. The SHR for overall stroke was 1.39 [95% confidence interval (CI) 1.28-1.50]. SAH had the highest SHR, 4.55 [95% CI 3.26-6.37], followed by ICH (1.84), other stroke (1.24), and IS (1.22). CONCLUSION: This study illustrated the incidence rates of stroke among inpatient of PKD. The PKD patients had a significantly increased risk of all kinds of stroke after adjusting baseline comorbidities.

Real clinical experience after one year of treatment with tolvaptan in patients with autosomal dominant polycystic kidney disease.

Background: Tolvaptan (TV) is the first vasopressin-receptor antagonist approved for the treatment of autosomal dominant polycystic kidney disease (ADPKD). No publications report TV experience in real clinical practice during the first year of treatment. Methods: A prospective study of an initial cohort of 220 rapidly progressing patients treated with TV for 12 months. The tolerability of TV, the evolution of the estimated glomerular filtration rate (eGFR), analytical parameters, and blood pressure were analyzed. Results: A total of 163 patients (78.2%) received TV for 1 year. The main causes of treatment withdrawal were the aquaretic effects (11%), eGFR deterioration (5%), and hepatic toxicity (2.3%). eGFR decreased significantly after 1 month of treatment without further changes. The decrease in eGFR in the first month was higher in patients with an initially higher eGFR. The eGFR drop during the first year of treatment with TV was lower than that reported by patients in the 2 years prior to TV treatment (-1.7 ± 7.6 vs. -4.4 ± 4.8 mL/min, p = 0.003). Serum sodium and uric acid concentrations increased, and morning urinary osmolality decreased in the first month, with no further changes. Blood pressure decreased significantly without changes in antihypertensive medication. Conclusion: TV treatment is well tolerated by most patients. Liver toxicity is very rare and self-limited. TV reduces eGFR in the first month without showing further changes during the first year of treatment. Patients with a higher starting eGFR will suffer a greater initial drop, with a longer recovery. We suggest using the eGFR observed after a month of treatment as the reference for future comparisons and calculating the rate of eGFR decline in patients undergoing TV treatment.

Genetic Architecture of Childhood Kidney and Urological Diseases in China.

Kidney disease is manifested in a wide variety of phenotypes, many of which have an important hereditary component. To delineate the genotypic and phenotypic spectrum of pediatric nephropathy, a multicenter registration system is being implemented based on the Chinese Children Genetic Kidney Disease Database (CCGKDD). In this study, all the patients with kidney and urological diseases were recruited from 2014 to 2020. Genetic analysis was conducted using exome sequencing for families with multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early-onset or extrarenal features. The genetic diagnosis was confirmed in 883 of 2256 (39.1%) patients from 23 provinces in China. Phenotypic profiles showed that the primary diagnosis included steroid-resistant nephrotic syndrome (SRNS, 23.5%), glomerulonephritis (GN, 32.2%), congenital anomalies of the kidney and urinary tract (CAKUT, 21.2%), cystic renal disease (3.9%), renal calcinosis/stone (3.6%), tubulopathy (9.7%), and chronic kidney disease of unknown etiology (CKDu, 5.8%). The pathogenic variants of 105 monogenetic disorders were identified. Ten distinct genomic disorders were identified as pathogenic copy number variants (CNVs) in 11 patients. The diagnostic yield differed by subgroups, and was highest in those with cystic renal disease (66.3%), followed by tubulopathy (58.4%), GN (57.7%), CKDu (43.5%), SRNS (29.2%), renal calcinosis /stone (29.3%) and CAKUT (8.6%). Reverse phenotyping permitted correct identification in 40 cases with clinical reassessment and unexpected genetic conditions. We present the results of the largest cohort of children with kidney disease in China where diagnostic exome sequencing was performed. Our data demonstrate the utility of family-based exome sequencing, and indicate that the combined analysis of genotype and phenotype based on the national patient registry is pivotal to the genetic diagnosis of kidney disease. Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-021-00014-1.

Role of oxygen and the HIF-pathway in polycystic kidney disease.

Kidney cyst growth in ADPKD is associated with regional hypoxia, presumably due to a mismatch between enlarged cysts and the peritubular capillary blood supply and compression of peritubular capillaries in cyst walls. Regional hypoxia leads to activation of hypoxia-inducible transcription factors, with the two main HIF isoforms, HIF-1 and HIF-2 expressed in cyst epithelia and pericystic interstitial cells, respectively. While HIF-2 activation is linked to EPO production, mitigating the anemia that normally accompanies chronic kidney disease, HIF-1 promotes cyst growth. HIF-dependent cyst growth is primarily due to an increase in chloride-dependent fluid secretion into the cyst lumen. However, given the broad spectrum of HIF-target genes, additional HIF-mediated pathways may also contribute to cyst progression. Furthermore, hypoxia can influence cyst growth through the generation of reactive oxygen species. Since cyst expansion aggravates regional hypoxia, a feedforward loop is established that accelerates cyst expansion and disease progression. Inhibiting the HIF pathway and/or HIF target genes that are of particular relevance for HIF-dependent cyst fluid secretion may therefore represent novel therapeutic approaches to retard the progression of APDKD.

A Large Database Analysis of Rates of Aneurysm Screening, Elective Treatment, and Subarachnoid Hemorrhage in Patients With Polycystic Kidney Disease.

BACKGROUND: Professional societies provide conflicting guidelines on aneurysm screening in patients with polycystic kidney disease (PKD), and the rate of subarachnoid hemorrhage (SAH) is poorly understood. OBJECTIVE: To evaluate screening, elective treatment, and the rate of SAH in patients with known PKD. METHODS: We examined longitudinally linked claims data from a large private insurer, identifying screening, elective treatment, aneurysmal subarachnoid hemorrhage (aSAH) and secured aneurysmal SAH (saSAH) in 2004 to 2014 amongst patients with known PKD. RESULTS: We identified 20 704 patients diagnosed with PKD. Among patients with an initial PKD diagnosis, 51/446 (15.9%) underwent angiographic screening within 2 yr. Forty aneurysms were treated electively in 48 868 yr at risk in PKD patients (82/100K patient yr, 95% confidence interval [CI] 60-112) vs 24 elective treatments in 349 861 yr at risk in age- and sex-matched controls (7/100K patient yr, 95% CI 5-10, P < .0001). Eleven admissions for aSAH were identified in PKD patients (23/100K patient yr, 95% CI 13-41) and 22 admissions for aSAH in controls (6/100K patient yr, 95% CI 4-10), giving an incidence rate ratio (IRR) of 3.6 (95% CI 1.7-7.4, P < .0001) and a comorbidity-adjusted IRR of 3.1 (95% CI 1.4-6.9). The incidence of saSAH was proportionally even higher in PKD patients than controls, 16 vs 2/100K patient years, IRR 9.5 (95% CI 3.3-27.5, P < .0001). CONCLUSION: Screening in PKD is performed only selectively, though resulting rates of elective treatment were over 10× those of controls. Despite screening and treatment, the rate of SAH remains significantly elevated over that of controls.