Podocyte-Parietal Epithelial Cell Interdependence in Glomerular Development and Disease
PECs are thought to contribute to disease progression and severity, and the interdependence between these two cell-types during development and in various manifestations of kidney pathology is the primary focus of this review.
KEY FINDINGS: PECs are thought to contribute to disease progression and severity, and the interdependence between these two cell-types during development and in various manifestations of kidney pathology is the primary focus of this review.
BACKGROUND: Podocytes and parietal epithelial cells (PECs) are among the few principal cell types within the kidney glomerulus, the former serving as a crucial constituent of the kidney filtration barrier and the latter representing a supporting epithelial layer that adorns the inner wall of Bowman's capsule.
DETAILS: Podocytes and PECs share a circumscript developmental lineage that only begins to diverge during the S-shaped body stage of nephron formation - occurring immediately before the emergence of the fully mature nephron. These two cell-types therefore share a highly conserved gene expression program, evidenced by recently discovered intermediate cell types occupying a distinct spatio-temporal gene expression zone between podocytes and PECs. In addition to their homeostatic functions, podocytes and PECs also have roles in kidney pathogenesis. Rapid podocyte loss in diseases such as Rapidly Progressive Glomerulonephritis (RPGN) and collapsing and cellular subtypes of Focal Segmental Glomerulosclerosis (FSGS) is closely allied with PEC proliferation and migration towards the capillary tuft - resulting in the formation of crescents and pseudo-crescents.
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Source: Bronstein, R., Pace, J., Gowthaman, Y., et al. (2023). Podocyte-Parietal Epithelial Cell Interdependence in Glomerular Development and Disease. Journal of the American Society of Nephrology . 2023; 10.1681/ASN.104. Published: February 16, 2023. DOI: 10.1681/ASN.0000000000000104.
Increasing Threat of Spread of Antimicrobial-resistant Fungus in Healthcare Facilities
C. auris case counts may also have increased because of enhanced efforts to detect cases, including increased colonization screening, a test to see if someone has the fungus somewhere on their body but does not have an infection or symptoms of infection.
KEY FINDINGS: C. auris case counts have increased for many reasons, including poor general infection prevention and control (IPC) practices in healthcare facilities. Case counts may also have increased because of enhanced efforts to detect cases, including increased colonization screening, a test to see if someone has the fungus somewhere on their body but does not have an infection or symptoms of infection. The timing of this increase and findings from public health investigations suggest C. auris spread may have worsened due to strain on healthcare and public health systems during the COVID-19 pandemic.
BACKGROUND: Candida auris (C. auris), an emerging fungus considered an urgent antimicrobial resistance (AR) threat, spread at an alarming rate in U.S. healthcare facilities in 2020-2021, according to data from the Centers for Disease Control and Prevention (CDC) published in the Annals of Internal Medicine. Equally concerning was a tripling in 2021 of the number of cases that were resistant to echinocandins, the antifungal medicine most recommended for treatment of C. auris infections. In general, C. auris is not a threat to healthy people. People who are very sick, have invasive medical devices, or have long or frequent stays in healthcare facilities are at increased risk for acquiring C. auris. CDC has deemed C. auris as an urgent AR threat, because it is often resistant to multiple antifungal drugs, spreads easily in healthcare facilities, and can cause severe infections with high death rates.
DETAILS: "The rapid rise and geographic spread of cases is concerning and emphasizes the need for continued surveillance, expanded lab capacity, quicker diagnostic tests, and adherence to proven infection prevention and control," said CDC epidemiologist Dr. Meghan Lyman, lead author of the paper.
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As further explained in the article, C. auris has spread in the United States since it was first reported in 2016, with a total of 3,270 clinical cases (in which infection is present) and 7,413 screening cases (in which the fungus is detected but not causing infection) reported through December 31, 2021. Clinical cases have increased each year since 2016, with the most rapid rise occurring during 2020-2021. CDC has continued to see an increase in case counts for 2022. During 2019-2021, 17 states identified their first C. auris case ever. Nationwide, clinical cases rose from 476 in 2019 to 1,471 in 2021. Screening cases tripled from 2020 to 2021, for a total of 4,041. Screening is important to prevent spread by identifying patients carrying the fungus so that infection prevention controls can be used.
The CDC's Antimicrobial Resistance Laboratory Network, which provides nationwide lab capacity to rapidly detect antimicrobial resistance and inform local responses to prevent spread and protect people, provided some of the data for this report. CDC worked to significantly strengthen laboratory capacity, including in state, territorial, and local health departments, through supplemental funding supported by the American Rescue Plan Act. These efforts include increasing susceptibility testing capacity for C. auris from seven Regional Labs to more than 26 labs nationwide.
CDC continues to work with state, local, and territorial health departments and other partners to address this emerging threat to public health. Review more information on C. auris, the Antimicrobial Resistance Threats Report that identified C. auris as an urgent threat in the United States, or the WHO fungal priority pathogen list that identifies C. auris as a priority globally.
Copyright © CDC. All rights reserved.
Source: Increasing Threat of Spread of Antimicrobial-resistant Fungus in Healthcare Facilities. Centers for Disease Control and Prevention. 2023; 320. Published: March 20, 2023. https://www.cdc.gov/media/releases/2023/p0320-cauris.html.
Tolvaptan for Children and Adolescents with Autosomal Dominant Polycystic Kidney Disease
Tolvaptan exhibited pharmacodynamic activity in pediatric ADPKD. Aquaretic effects were manageable, with few discontinuations.
Summary
Randomized Controlled Trial
[Posted 25/Jan/2023]
AUDIENCE: Nephrology, Internal Medicine, Pediatric
KEY FINDINGS: Tolvaptan exhibited pharmacodynamic activity in pediatric ADPKD. Aquaretic effects were manageable, with few discontinuations.
BACKGROUND: Tolvaptan slows expansion of kidney volume and kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD). Progression during childhood could be treated before irreversible kidney damage occurs, but trial data are lacking. We evaluated the safety and efficacy of tolvaptan in children/adolescents with ADPKD.
DETAILS: This was the 1-year, randomized, double-blind, portion of a phase 3b, two-part trial being conducted at 20 academic pediatric nephrology centers. Key eligibility criteria were ADPKD and eGFR >=60 ml/min per 1.73 m2. Participants aged 12-17 years were the target group (group 1, enrollment goal n>=60); participants aged 4-11 years could additionally enroll (group 2, anticipated enrollment approximately 40). Treatments were tolvaptan or placebo titrated by body weight and tolerability. Coprimary end points, change from baseline in spot urine osmolality and specific gravity at week 1, assessed inhibition of antidiuretic hormone activity. The key secondary end point was change in height-adjusted total kidney volume (htTKV) to month 12 in group 1. Additional end points were safety/tolerability and quality of life. Statistical comparisons were exploratory and post hoc. Among the 91 randomized (group 1, n=66; group 2, n=25), least squares (LS) mean reduction (±SEM) in spot urine osmolality at week 1 was greater with tolvaptan (-390 [28] mOsm/kg) than placebo (-90 [29] mOsm/kg; P<0.001), as was LS mean reduction in specific gravity (-0.009 [0.001] versus -0.002 [0.001]; P0.001). In group 1, the 12-month htTKV increase was 2.6% with tolvaptan and 5.8% with placebo (P>0.05). For tolvaptan and placebo, respectively, 65% and 16% of subjects experienced aquaretic adverse events, and 2% and 0% experienced hypernatremia. There were no elevated transaminases or drug-induced liver injuries. Four participants discontinued tolvaptan, and three discontinued placebo. Quality-of-life assessments remained stable.
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Source: Mekahli, D., Guay-Woodford, L., Cadnapaphornchai, M. A., et al. (2022). Tolvaptan for Children and Adolescents with Autosomal Dominant Polycystic Kidney Disease: Randomized Controlled Trial. Clinical Journal of the American Society of Nephrology. 2023; 18(1): 36-46. Published: January, 2023. DOI: 10.2215/CJN.0000000000000022.
Study of Purine Derivatives and Their Relation To Renal Disorders In Patients With Psoriasis
The findings suggest that apremilast was a safe and efficacious add-on treatment in recalcitrant dermatomyositis, with an overall response rate of 87.5% and associations with downregulation of multiple inflammatory pathways.
KEY FINDINGS: Pso, being a hyperproliferative disease, is associated with hyperuricemia, which has a harmful effect on kidney function. The related PDs may be unique serological biomarkers for patients with Pso who are at high risk of developing renal abnormalities, especially with higher severity scores.
BACKGROUND: Psoriasis (Pso) is a chronic proliferative skin condition associated with hyperuricemia that may impair renal function.
DETAILS: This case–control study comprises 30 psoriatic patients and 30 age- and sex-matched healthy controls. The enzyme-linked immunosorbent assay (ELISA) was used to assess serum xanthine oxidase (XO) and urine albumin levels. Serum uric acid (SUA) and urinary creatinine were measured using the colorimetric method. There was a rise in the related PDs levels in patients with Pso compared to controls, as evidenced by the enhanced SUA levels (p 0.001) and XO levels (p 0.001). The presence of the related PDs in the serum was linked to the severity of Pso, and there was also a connection between the related PDs levels in the blood and indicators of renal dysfunction. Moreover, SUA and urinary albumin creatinine ratio (UACR) were found to be significantly correlated (r = 0.371 and p = 0.044), as were XO and UACR (r = 0.422 and p = 0.020). In psoriatic patients with itching and palmoplantar affection, mean SUA levels were considerably more significant than those in other instances ( < p = 0.005 and p = 0.018, respectively).
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Copyright © John Wiley & Sons, Inc. All rights reserved.
Source: Bazid, H. A. S., Shoeib, M. A., El-Saued, S., et al. (2022). Study of Purine Derivatives And Their Relation To Renal Disorders In Patients With Psoriasis. International Journal of Dermatology. 2023; 62(1): 73-78. Published: January, 2023. DOI: 10.1111/ijd.16343.
Chronic Diseases and Comorbidities In Adults With and Without Intellectual Disabilities
This study identified a younger onset of chronic illness and a higher prevalence of multiple comorbidities among people with ID in general practice than those without ID. This underlines the complexity of people with ID and chronic diseases in general practice.
Summary
Comparative Cross-Sectional Study In Dutch General Practice
[Posted 2/Jan/2023]
AUDIENCE: Family Medicine, Neurology
KEY FINDINGS: This study identified a younger onset of chronic illness and a higher prevalence of multiple comorbidities among people with ID in general practice than those without ID. This underlines the complexity of people with ID and chronic diseases in general practice. As this study confirmed the earlier onset of chronic diseases and comorbidities, it is recommended to acknowledge these age differences when following chronic disease guidelines.
BACKGROUND: Chronic disease and comorbidity patterns in people with intellectual disabilities (ID) are more complex than in the general population. However, incomplete understanding of these differences limits care providers in addressing them. Aim of this study is to compare chronic disease and comorbidity patterns in chronically ill patients with and without ID in Dutch general practice.
DETAILS: In this population-based study, a multi-regional primary care database of 2018 was combined with national population data to improve identification of adults with ID. Prevalence was calculated using Poisson regression to estimate prevalence ratios and 95% confidence intervals for the highest-impact chronic diseases (ischemic heart disease (IHD), cerebrovascular disease (CVD), diabetes mellitus (DM), and chronic obstructive pulmonary disease (COPD)) and comorbidities. Information from 18,114 people with ID and 1,093,995 people without ID was available. When considering age and sex, CVD (PR = 1.1), DM (PR = 1.6), and COPD (PR = 1.5) times more prevalent in people with than without ID. At younger age, people with ID more often had a chronic disease and multiple comorbidities. Males with ID most often had a chronic disease and multiple comorbidities. Comorbidities of circulatory nature were most common.
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Copyright © Oxford University Press. All rights reserved.
Source: van den Bemd, M., Schalk, B. W. M., Bischoff, E. W. M. A., et al. (2022). Chronic Diseases and Comorbidities In Adults With and Without Intellectual Disabilities: Comparative Cross-Sectional Study In Dutch General Practice. Family Practice. 2022; 39 (6): 1056-1062. Published: December, 2022. DOI: 10.1093/fampra/cmac042.
Close Association between Altered Urine-Urothelium Barrier and TLS Formation in the Renal Pelvis during Nephritis
Immune responses to infections, autoimmune responses, or allergic responses may trigger TLS development.
KEY FINDINGS: TLS formation in the RP is possible and altered urine-urothelium barrier-based UTALS formation may represent a novel mechanism underlying the pathogenesis of chronic nephritis, regardless of urinary tract infection.
BACKGROUND: Kidneys with chronic inflammation develop tertiary lymphoid structures (TLSs). Infectious pyelonephritis is characterized by renal pelvis (RP) inflammation. However, the pathologic features of TLSs, including their formation and association with non-infectious nephritis, are unclear.
DETAILS: RPs from humans and mice that were healthy or had non-infectious chronic nephritis were analyzed for TLS development, and the mechanism of TLS formation investigated using urothelium or lymphoid structure cultures. Regardless of infection, TLSs in the RP, termed urinary tract-associated lymphoid structures (UTALSs), formed in humans and mice with chronic nephritis. Moreover, urine played a unique role in UTALS formation. Specifically, we identified urinary IFN-y as a candidate factor affecting urothelial barrier integrity because it alters occludin expression. In a nephritis mouse model, urine leaked from the lumen of the RP into the parenchyma. In addition, urine immunologically stimulated UTALS-forming cells via cytokine (IFN-γ, TNF-α) and chemokine (CXCL9, CXCL13) production. CXCL9 and CXCL13 were expressed in UTALS stromal cells and urine stimulation specifically induced CXCL13 in cultured fibroblasts. Characteristically, type XVII collagen (BP180), a candidate autoantigen of bullous pemphigoid, was ectopically localized in the urothelium covering UTALSs and associated with UTALS development by stimulating CXCL9 or IL-22 induction via the TNF-α/FOS/JUN pathway. Notably, UTALS development indices were positively correlated with chronic nephritis development.
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Source: Ichii, O., Hosotani, M., Masum, M. A., et al. (2022). Close Association between Altered Urine-Urothelium Barrier and Tertiary Lymphoid Structure Formation in the Renal Pelvis during Nephritis. JASN. 2022; 33(1). Published: January, 2022. DOI: 10.1681/ASN.2021040575.
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