[Posted 28/Feb/2023]

AUDIENCE: Nephrology, Internal Medicine

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.

Copyright © American Society of Nephrology. All rights reserved.

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.

[Posted 23/May/2023]

AUDIENCE: Nephrology, Internal Medicine

KEY FINDINGS: Protein carbamylation, a nonenzymatic post-translational protein modification partially driven by elevated blood urea levels, associates with mortality and adverse outcomes in patients with ESKD on dialysis. However, little is known about carbamylation's relationship to clinical outcomes in the much larger population of patients with earlier stages of CKD. In this prospective observational cohort study of 3111 individuals with CKD stages 2-4, higher levels of carbamylated albumin (a marker of protein carbamylation burden) were associated with a greater risk of developing ESKD and other significant adverse clinical outcomes. These findings indicate that protein carbamylation is an independent risk factor for CKD progression. They suggest that further study of therapeutic interventions to prevent or reduce carbamylation is warranted.

BACKGROUND: Protein carbamylation, a post-translational protein modification partially driven by elevated blood urea levels, associates with adverse outcomes in ESKD. However, little is known about protein carbamylation's relationship to clinical outcomes in the much larger population of patients with earlier stages of CKD.

DETAILS: To test associations between protein carbamylation and the primary outcome of progression to ESKD, authors measured baseline serum carbamylated albumin (C-Alb) in 3111 patients with CKD stages 2-4 enrolled in the prospective observational Chronic Renal Insufficiency Cohort study. The mean age of study participants was 59 years (SD 10.8); 1358 (43.7%) were female, and 1334 (42.9%) were White. The mean eGFR at the time of C-Alb assessment was 41.8 (16.4) ml/minute per 1.73 m², and the median C-Alb value was 7.8 mmol/mol (interquartile range, 5.8-10.7). During an average of 7.9 (4.1) years of follow-up, 981 (31.5%) individuals developed ESKD. In multivariable adjusted Cox models, higher C-Alb (continuous or quartiles) independently associated with an increased risk of ESKD. For example, compared with quartile 1 (C-Alb <=5.80 mmol/mol), those in quartile 4 (C-Alb >10.71 mmol/mol) had a greater risk for ESKD (adjusted hazard ratio, 2.29; 95% confidence interval, 1.75 to 2.99), and the ESKD incidence rate per 1000 patient-years increased from 15.7 to 88.5 from quartile 1 to quartile 4. The results remained significant across numerous subgroup analyses, when treating death as a competing event, and using different assessments of eGFR.

Copyright © American Society of Nephrology. All rights reserved.

Source: Kalim, S., Zhgao, S., Tang, M., et al. (2023). Protein Carbamylation and the Risk of ESKD in Patients with CKD.. Journal of the American Society of Nephrology. 2023; 34(5): 876-885. Published: May, 2023. DOI: 10.1681/ASN.0000000000000078.

[Posted 8/May/2023]

AUDIENCE: Surgery, Internal Medicine, Nephrology

KEY FINDINGS: Using the largest cohort of adult kidney transplant recipients with IDD to date, the study team found that rates of evaluation and transplant were lower despite yielding equivalent outcomes. These data support consideration of adults with IDD for kidney transplant and underscore the urgent need for antidiscrimination initiatives to promote the receipt of equitable care for this population.

BACKGROUND: Improving equity in organ transplant access for people with intellectual and developmental disabilities (IDD) is a topic of social discourse in mainstream media, state legislation, and national legislation. However, few studies have compared evaluation rates, transplant rates, and outcomes among adults with and without IDD. Aim of this study was to compare rates of kidney transplant and transplant-specific outcomes between propensity–score matched groups of adults with end-stage kidney disease (ESKD [also referred to as end-stage renal disease (ESRD)]) with and without co-occurring IDD.

DETAILS: This retrospective cohort study included all Medicare inpatient and outpatient standard analytical files from 2013 through 2020. A total of 1,413,655 adult Medicare beneficiaries with ESKD were identified. Propensity–score matching was used to balance cohorts based on age, sex, race, follow-up duration, and Charlson Comorbidity Index. The matched cohorts consisted of 21,384 adults with ESKD (10,692 of whom had IDD) and 1258 kidney transplant recipients (629 of whom had IDD). Data were analyzed between June 1, 2022, and August 1, 2022. Of the 21,384 propensity–score matched adults with ESKD, the median (IQR) age was 55 (43-65) years, 39.2% were male, 27.4% were Black, 64.1% were White, and 8.5% identified as another race or ethnicity. After propensity score matching within the ESKD cohort, 633 patients with IDD (5.9%) received a kidney transplant compared with 1367 of adults without IDD (12.8%). Adults with IDD were 54% less likely than matched peers without IDD to be evaluated for transplant (odds ratio, 0.46; 95% CI, 0.43-0.50) and 62% less likely to receive a kidney transplant (odds ratio, 0.38; 95% CI, 0.34-0.42). Among matched cohorts of kidney transplant recipients, rates of perioperative complications, readmission, and graft failure were similar for adults with and without IDD.

Copyright © This is an open access article distributed under the terms of the CC-BY License. © 2023 Hand BN et al. JAMA Surgery.

Source: Hand, B. N., Hyer, J. M., Schenk, A., et al. (2023). Comparing Kidney Transplant Rates and Outcomes Among Adults With and Without Intellectual and Developmental Disabilities. JAMA Surg.. 2023; 158(4): 386-392. Published: April, 2023. DOI: 10.1001/jamasurg.2022.7753.

Findings From the Cardiovascular and Metabolic Disease Etiology Research Center–High Risk (CMERC-HI) Study

[Posted 28/Apr/2023]

AUDIENCE: Nephrology, Internal Medicine

KEY FINDINGS: Short-term BPV is associated with the development of a composite kidney disease outcome in hypertensive patients.

BACKGROUND: The association between short-term blood pressure variability (BPV) and kidney outcomes is poorly understood. This study evaluated the association between short-term BPV and kidney disease outcomes in people with hypertension.

DETAILS: The Cardiovascular and Metabolic Disease Etiology Research Center–High Risk (CMERC-HI) Study is a prospective observational cohort study comprising patients at a high risk of developing CVD who do not have symptomatic CVD at baseline. The cohort included 3,259 individuals who met the inclusion criteria from December 2013 to June 2018. The CMERC-HI study design and detailed methods have been described elsewhere and are depicted in the Item S1. During a median follow-up of 5.4 [4.1-6.5] years, 271 events of the composite kidney disease outcome occurred (46.5 per 1,000 person-years). Multivariable Cox analysis revealed that the highest SBP-ARV and DBP-ARV tertiles were associated with a higher risk of the composite kidney disease outcome than the lowest tertiles, independent of the 24-hour SBP or DBP levels (HR, 1.64 [95% CI, 1.16-2.33], and 1.60 [95% CI, 1.15-2.24] for SBP-ARV and DBP-ARV, respectively). These associations were consistent when SBP-ARV and DBP-ARV were treated as continuous variables (HR per 1.0-unit greater SBP-ARV, 1.03 [95% CI, 1.01-1.06]; HR per 1.0-unit greater DBP-ARV, 1.04 [95% CI, 1.01-1.08]). These associations were consistent, irrespective of subgroups (age, sex, 24-hour SBP or DBP, and moderate albuminuria). However, other measures of short-term BPV including SD, coefficient of variation, and dipping patterns were not associated with the composite kidney disease outcome.

Copyright © Elsevier Ltd. All rights reserved.

Source: Jhee, J. H., Oh, D., Seo, J., et al. (2023). Short-term Blood Pressure Variability and Incident CKD in Patients With Hypertension: Findings From the Cardiovascular and Metabolic Disease Etiology Research Center–High Risk (CMERC-HI) Study. Am J Kidney Dis. 2023; 81(4): 384-393. Published: April, 2023. DOI: 10.1053/j.ajkd.2022.08.017.

[Posted 24/Mar/2023]

AUDIENCE: Infectious Disease, Internal Medicine

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.

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.

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.

Copyright © American Society of Nephrology. All rights reserved.

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.