Kidney360最新文献

Our understanding of the pathogenesis of uremic pruritus (also known as Chronic Kidney Disease - associated pruritus (CKD-aP)) remains elusive. While multiple discrete changes in the immuno-chemical milieu of the skin of patients with CKD-aP have been described, a coherent theory of mechanism is absent. This article proposes a theoretical model of mechanism. It concentrates on the initiation phase of CKD-aP and its three parts: 1) Genesis, triggered by first precipitants; 2) Cascade of cytokine release that follows and the cross-talking of multiple skin cells with each other and afferent nerve fibers and 3) Enhancement. The limitation of the model will be described and ideas for future research proposed. Implications for management shall be examined.

Background: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia in chronic kidney disease (CKD). This study investigated safety and efficacy of once-daily and 3-times-weekly dosing in patients with dialysis-dependent (DD)-CKD compared with darbepoetin alfa (DA).

Methods: This phase 3b, randomized (1:1:1; vadadustat once-daily [starting dose: 300 or 450 mg], vadadustat 3-times-weekly [starting dose: 600 or 750 mg], DA), open-label, active-controlled, noninferiority trial included conversion (weeks 0-20) and maintenance (weeks 20-52) periods. Primary and secondary efficacy endpoints were mean change in hemoglobin from baseline during the primary (PEP, weeks 20-26) and secondary (SEP, weeks 46-52) evaluation periods. Other endpoints included proportion of patients requiring ESA rescue (hemoglobin <9.5 g/dL or with increases in dose ≥50% or ≥100% in DA group). Safety endpoints included treatment-emergent adverse events (TEAEs) and serious AEs (SAEs).

Results: Least squares (LS) mean treatment difference between vadadustat once-daily and DA from baseline to PEP was -0.27 g/dL (95% CI, -0.55 to 0.01); the lower bound met the noninferiority threshold (-0.75 g/dL). The LS mean treatment difference between vadadustat 3-times-weekly and DA from baseline to PEP was -0.53 g/dL (95% CI, -0.80 to -0.25), which did not meet the lower bound noninferiority threshold. The LS mean change from baseline to the SEP between DA and vadadustat once-daily was -0.40 (95% CI, -0.79 to -0.02), and for vadadustat 3-times-weekly was -0.42 (95% CI, -0.81 to -0.02). Proportion of patients who received ESA rescue during weeks 2-52 was higher in the DA group than vadadustat groups. Similar TEAEs and treatment-emergent SAEs were observed across groups.

Conclusions: Vadadustat once-daily, but not 3-times-weekly, was noninferior to DA in the correction and maintenance of hemoglobin in patients with DD-CKD converted from an ESA; safety profiles were similar across groups.

Trial registration: EudraCT 2019-004851-36/ClinicalTrials.gov identifier: NCT04313153.

Background: Immunoglobulin A nephropathy often requires kidney replacement therapy because of its refractoriness and because corticosteroids pose infection risks. However, mesenchymal stem cells offer clinical benefits because of their regenerative and immunomodulatory properties. This prospective clinical trial assessed the safety and tolerability of adipose-derived mesenchymal stem cell therapy and evaluated its therapeutic efficacy.

Methods: This phase 1 study included adult patients with refractory immunoglobulin A nephropathy that was difficult to treat with traditional therapies. Adipose-derived mesenchymal stem cell therapy comprising one intravenous dose of 1 × 108 cells was administered to three to six patients in cohort 1. The same intravenous dose was administered twice with a 2-week interval to six patients in cohort 2. Heparin was administered simultaneously. This study continued for 52 weeks, and the primary endpoints were safety and tolerability during the 6-week period after treatment administration. Secondary endpoints included adverse events and efficacy measures such as clinical remission, partial remission, urine protein remission, hematuria remission, time to remission, changes in the urine protein and hematuria levels, and changes in the estimated glomerular filtration rate.

Results: The three patients in cohort 1 and six patients in cohort 2 who received adipose-derived mesenchymal stem cell therapy achieved the primary endpoints. No severe adverse clinical events were observed. Therefore, the safety and tolerability of adipose-derived mesenchymal stem cells were confirmed. Improvements such as significantly decreased kidney damage markers and urinary protein levels were observed immediately after adipose-derived mesenchymal stem cell administration.

Conclusions: The safety and tolerability of adipose-derived mesenchymal stem cells are acceptable for patients with immunoglobulin A nephropathy.

Trial registration: This trial was registered with the Japan Registry of Clinical Trials (jRCT2043200002; registration date: April 14, 2020) and ClinicalTrials.gov (NCT04342325; registration date: April 13, 2020).

Like other multicellular organisms, the fruit fly Drosophila melanogaster must maintain homeostasis of the internal milieu, including the maintenance of constant ion and water concentrations. In mammals, the WNK-SPAK/OSR1 (With No Lysine (K)- Ste20-proline/alanine rich kinase/oxidative stress response 1) kinase cascade is an important regulator of epithelial ion transport in the kidney. This pathway regulates SLC12 family cotransporters, including sodium-potassium-2-chloride (NKCC), sodium chloride (NCC) and potassium chloride (KCC) cotransporters. The WNK-SPAK/OSR1 kinase cascade also regulates epithelial ion transport via regulation of the Drosophila NKCC in the Malpighian tubule, the renal epithelium of the fly. Studies in Drosophila have contributed to the understanding of multiple regulators of WNK pathway signaling, including intracellular chloride and potassium, the scaffold protein Mo25, hypertonic stress, hydrostatic pressure, and macromolecular crowding. These will be discussed, together with implications for mammalian kidney function and blood pressure control.

Molecular targeted therapy has revolutionized cancer treatment by significantly improving the patient survival compared to standard conventional chemotherapies. The use of these drugs targets specific molecules or targets which block growth and spread of cancer cells. Many of these therapies have been approved for use with remarkable success in breast, leukemia colorectal, lung and ovarian cancers. The advantage over conventional chemotherapy is its ability to deliver drug effectively with high specificity while being less toxic. Although known as "targeted," many of these agents lack specificity and selectivity, and they tend to inhibit multiple targets including those in the kidneys. The side effects usually arise because of dysregulation of targets of the inhibited molecule in normal tissue. The "off target" effects are caused by drug binding to unintended targets. The "on target" effects are associated with inhibition towards the pathway reflecting inappropriate inhibition or activation of the intended drug target. Early detection and correct management of kidney toxicities is crucial to preserve kidney functions. The knowledge of these toxicities helps guide optimal and continued utilization of these potent therapies. This review summarizes the different types of molecular targeted therapies used in treatment of cancer, the incidence, severity and pattern of nephrotoxicity caused by them, with their plausible mechanism and proposed treatment recommendations.

Background: Dialysis-dependent pediatric patients and their families face significant biopsychosocial burdens and low health-related quality of life. Palliative care consultations can alleviate some degree of suffering for patients and families but remain underutilized within pediatric nephrology. Little is known about how providers, nurses, and caregivers perceive palliative care integration into the multidisciplinary care of dialysis-dependent pediatric patients.

Methods: This study surveyed pediatric nephrology providers (physicians and advanced practice providers), inpatient pediatric nephrology bedside nurses, and caregivers of dialysis-dependent pediatric patients at a freestanding tertiary care children's hospital in Dallas, Texas. Participants completed a survey regarding knowledge about, experiences with, and perceptions of palliative care in pediatric nephrology.

Results: 10 providers, 20 nurses, and 18 caregivers completed the survey. Although 80% of providers and all nurses agreed that palliative care would benefit dialysis-dependent pediatric patients, most believed that palliative care is not as important in pediatric nephrology as it should be. 70% of providers and 45% of nurses believed that they understand the scope of palliative care. 90% of providers and all nurses desired more palliative care education. Of the 22% of caregivers whose child had already received palliative care services, all found the consultation to be helpful. Many providers and nurses worried that a palliative care consultation would signal to families that the nephrology team would be giving up on their child and that their child is approaching the end of life. However, no caregivers thought that a consultation would mean that the nephrology team would be giving up on their child and only 6% worried that it would indicate that their child is approaching the end of life.

Conclusions: These data support further palliative care education for pediatric nephrology providers and nurses and more robust and systematic involvement of subspecialty palliative care for dialysis-dependent pediatric patients.

Background: Despite offering several advantages to patients and healthcare systems, utilization of home dialysis modalities (HDM) remains low, particularly among racial and ethnic minorities, and those with increased sociodemographic stress. Providers' apprehension towards adverse outcomes and home dialysis failure remains a barrier to HDM referral. We investigated the relationship sociodemographic factors have on HDM use and technique failure.

Methods: We performed a retrospective cohort study of adult incident ESRD patients over a six-year period at the University of Rochester to evaluate the association between demographic factors, social deprivation index (SDI), and co-morbidity burden on HDM utilization and technique failure. Person-time incidence rates were calculated to compare outcome variables, and rates were compared using a Poisson Rate Ratio Test. A univariate Cox regression was used to examine predictors impacting technique failure.

Results: Of the 873 patients, 102 started dialysis with HDM, 79 patients converted to HDM, and 692 remained on in-center hemodialysis (ICHD). Age, race, and SDI scores were significantly different between patients starting on ICHD, peritoneal dialysis (PD) and home hemodialysis (HHD) with no significant difference in comorbidity burden. Black patients represented 32% of the overall cohort, but only 16% of the initial home dialysis population. Compared to those that remained on ICHD, individuals converting from ICHD to HDM were younger and had significantly different SDI scores. SDI was not associated with HDM technique failure.

Conclusions: Historically underrepresented racial populations are less represented in those starting home dialysis, however there was no racial difference in the group transitioning to HDM after initiating ICHD. Social deprivation scores were higher in those on ICHD compared to PD. Neither social deprivation nor race predicted success on home therapy. These findings demonstrate a disparity in initial modality, and a disconnect between sociodemographic factors associated with home dialysis use and those predicting HDM technique failure.

Background: Circulating extracellular vesicles (EVs) carry protected cargoes of nucleic acids, proteins, and metabolites. Here we identified and validated the surface proteins and enzymatic activity of chymase, angiotensin converting enzymes 1 (ACE) and 2 (ACE2), and neprilysin (NEP) in EVs isolated from the blood and urine of primary hypertensive patients.

Methods: Peripheral venous blood and spot urine from 34 hypertensive patients were processed to isolate plasma and urinary EVs. Immuno-gold labeling and transmission electron microscopy validated the presence of the exosomal marker protein CD63 on the surface of plasma and urinary EVs. Flow cytometry characterized plasma and urinary EVs for CD63, CD9, and CD81 surface markers. In addition, exosomal CD63, TSG101, and Alix were analyzed in urine by Western blotting. Urinary EVs did not express the endoplasmic reticulum protein calnexin and Golgi protein GM130. Chymase, ACE, ACE2, and NEP activities on 125I substrates ─ angiotensin-(1-12) [Ang-(1‒12)] and angiotensin II (Ang II) ─ [1 nmol/L each] were quantified by HPLC. Data were analyzed based on whether the patient's blood pressure was controlled (Group I: <140/80 mm Hg) or not controlled (Group II: ≥ 140/80 mm Hg).

Results: Chymase activity on Ang-(1‒12) was significantly higher in plasma and urinary EVs than in ACE, ACE2, and NEP. In addition, chymase activity in urine EVs was more than 3-fold higher than in plasma EVs. Chymase activity increased in plasma and urine EVs retrieved from Group II patients. No comparable differences were found in the enzymatic activities of ACE, ACE2, and NEP urinary EVs between Group I and Group II.

Conclusion: These studies reveal a differential enzymatic activity of renin angiotensin system enzymes in plasma and urine EVs isolated from hypertensive patients. Demonstrating a comparatively high chymase enzymatic activity in EVs expands a previously documented finding of increased plasma Ang-(1‒12) in hypertensive patients.

Traditional medical Artificial Intelligence models, approved for clinical use, restrict themselves to single-modal data e.g. images only, limiting their applicability in the complex, multimodal environment of medical diagnosis and treatment. Multimodal Transformer Models in healthcare can effectively process and interpret diverse data forms such as text, images, and structured data. They have demonstrated impressive performance on standard benchmarks like USLME question banks and continue to improve with scale. However, the adoption of these advanced AI models is not without challenges. While multimodal deep learning models like Transformers offer promising advancements in healthcare, their integration requires careful consideration of the accompanying ethical and environmental challenges.