Idiopathic collapsing glomerulopathy is associated with APOL1 high-risk genotypes or Mendelian variants in most affected individuals in a highly admixed population.

Collapsing glomerulopathy (CG) is most often associated with fast progression to kidney failure with an incidence apparently higher in Brazil than in other countries. However, the reason for this occurrence is unknown. To better understand this, we performed an integrated analysis of clinical, histological, therapeutic, causative genetic and genetic ancestry data in a highly genetically admixed cohort of 70 children and adult patients with idiopathic CG (ICG). The disease onset occurred at 23 (interquartile range: 17-31) years and approximately half of patients progressed to chronic kidney disease requiring kidney replacement therapy (CKD-KRT) 36 months after diagnosis. Causative genetic bases, assessed by targeted-gene panel or whole-exome sequencing, were identified in 58.6% of patients. Among these cases, 80.5% harbored APOL1 high-risk genotypes (HRG) and 19.5% causative Mendelian variants (MV). Self-reported non-White patients more frequently had HRG. MV was an independent risk factor for progression to CKD-KRT by 36 months and the end of follow-up, while remission was an independent protective factor. All patients with HRG manifested CG at 9-44 years of age, whereas in those with APOL1 low-risk genotype, the disease arose throughout life. HRGs were associated with higher proportion of African genetic ancestry. Novel causative MVs were identified in COL4A5, COQ2 and PLCE1 and previously described causative MVs were identified in MYH9, TRPC6, COQ2, COL4A3 and TTC21B. Three patients displayed HRG combined with a variant of uncertain significance (ITGB4, LAMA5 or PTPRO). MVs were associated with worse kidney prognosis. Thus, our data reveal that the genetic status plays a major role in ICG pathogenesis, accounting for more than half of cases in a highly admixed Brazilian population.

Volume replacement is associated with a diminished osmolar effect of mannitol in patients with acute brain injury.

INTRODUCTION: Animal experiments recently demonstrated that replacing urinary loses with crystalloid diminishes the therapeutic effect of mannitol by reducing the increase in osmolality. We aimed to investigate whether this effect is similarly seen in in brain-injured patients by studying the association between total body fluid balance (TBB) and the osmolar response to mannitol. METHODS: We performed a retrospective cohort study of adult patients with acute brain injury between 2015 and 2021 who received ≥ 2 doses of mannitol within 8 hours and no intercurrent concentrated saline solution. We analyzed the association between the change in TBB (∆TBB) and change in osmolality (∆Osm) before and after mannitol in a linear model, both as univariate and after adjustment for common confounding factors. RESULTS: Of 6,145 patients who received mannitol, 155 patients met inclusion criteria (mean age 60 ± 17 years, 48% male, 83% white). The mean total mannitol dose was 2 ± 0.5 g/kg and the mean change in plasma osmolality was 7.9 ± 7.1 mOsm/kg. Each 1 L increase in ∆TBB was associated with a change of -1.1 mOsm/L in ∆Osm (95% CI [-2.2, -0.02], p = 0.045). The magnitude of association was similar to that of total mannitol dose and remained consistent in an adjusted model and after excluding outliers. CONCLUSIONS: In patients with acute brain injury, a positive TBB is associated with a diminished mannitol-induced increase in plasma osmolality. Future prospective studies are needed to confirm these findings and their influence on the therapeutic effect of mannitol.

Gli1+ Pericyte Loss Induces Capillary Rarefaction and Proximal Tubular Injury.

Peritubular capillary rarefaction is hypothesized to contribute to the increased risk of future CKD after AKI. Here, we directly tested the role of Gli1+ kidney pericytes in the maintenance of peritubular capillary health, and the consequences of pericyte loss during injury. Using bigenic Gli1-CreERt2; R26tdTomato reporter mice, we observed increased distance between Gli1+ pericytes and endothelial cells after AKI (mean±SEM: 3.3±0.1 µm before injury versus 12.5±0.2 µm after injury; P<0.001). Using a genetic ablation model, we asked whether pericyte loss alone is sufficient for capillary destabilization. Ten days after pericyte ablation, we observed endothelial cell damage by electron microscopy. Furthermore, pericyte loss led to significantly reduced capillary number at later time points (mean±SEM capillaries/high-power field: 67.6±4.7 in control versus 44.1±4.8 at 56 days; P<0.05) and increased cross-sectional area (mean±SEM: 21.9±0.4 µm2 in control versus 24.1±0.6 µm2 at 10 days; P<0.01 and 24.6±0.6 µm2 at 56 days; P<0.001). Pericyte ablation also led to hypoxic focal and subclinical tubular injury, reflected by transient expression of Kim1 and vimentin in scattered proximal tubule segments. This analysis provides direct evidence that AKI causes pericyte detachment from capillaries, and that pericyte loss is sufficient to trigger transient tubular injury and permanent peritubular capillary rarefaction.

A survey of opinions regarding wishes toward the end-of-life among Thai elderly.

BACKGROUND: Knowledge of wishes toward the end-of-life is crucial for carrying out high quality palliative care. However, advance directive is not commonly available among Thais, particularly for non-cancerous older patients. OBJECTIVE: The present study aimed to explore Thai older person's wishes toward cares needed at the end-of-life. MATERIAL AND METHOD: A convenience sample of 100 older patients, who attended geriatric clinic at a university hospital in Thailand, was recruited. A 3-page questionnaire developed to suit Thai culture was utilized to elicit opinions concerning circumstances around end-of-life period. RESULTS: All participants were Buddhists with mean age of 75.9 (8.2). Toward the end-of-life, the majority wanted to know the truth about their illnesses and to be free from uncomfortable symptoms. Seventy-five percent did not want "prolong-life" treatments when chance of surviving is slim. Age less than 70 and having education of no more than 6 years were factors associated with being unwilling to prolong suffering with OR of 9.88 (1.20-81.57, p = 0.03) and 3.15 (1.11-8.95, p = 0.03), respectively. Interestingly, fifty-six percent of elderly did not want to die at home. Age less than 70 was the only factor significantly associated with being unwilling to die at home with OR of 2.80 (95% CI = 1.05-7.47, p = 0.04). CONCLUSION: The present study illustrated older persons' opinions in relation to cares at the end-of-life from a Thai perspective, which showed some similarities and differences when compared to western countries. These opinions should be crucial for carrying out optimal and qualitative end-of-life care for older people when advanced care planning is not in place for the individual.

Travel arrangements in chronic hemodialysis patients: A qualitative study.

INTRODUCTION: For patients on renal replacement therapy (RRT), "travel" and "independence" are rated as 2 of the top 5 factors that inform their choice of treatment modality. While home dialysis modalities offer patients a high degree of independence, the most common RRT in the United States is in-center hemodialysis (IHD). The limits imposed by IHD treatment can present a variety of challenges for patients who wish to travel. This study explored how IHD patients managed their travel and the role of dialysis social workers in executing travel arrangements for patients. METHODS: We performed a qualitative descriptive investigation using semi-structured interviews with adults receiving IHD (n = 16) and renal social workers (n = 8) from Iowa, Minnesota, North Dakota, South Dakota, and Wisconsin. Data were analyzed using a constant comparative method. FINDINGS: Three themes emerged from the interviews: travel process, travel-related barriers, and travel-related facilitators. The travel process entailed transient dialysis unit challenges and the need for multiple preparations and precautions. Barriers included comorbidities and not having a relationship with transient dialysis unit staff. Facilitators focused on the importance of travel and staff professionalism at transient dialysis units. Overall, there was lack of uniform protocols to guide the travel process at the patient and the dialysis unit levels. DISCUSSION: This study identified multiple perspectives regarding travel arrangements in chronic IHD patients. There is limited research on travel issues for IHD patients and this investigation is among the first to articulate barriers and facilitators associated with travel from the perspective of patients and social workers. Supporting travel for IHD patients can increase their sense of autonomy and provide opportunities to improve their quality of life.

Acetazolamide Therapy in Patients with Heart Failure: A Meta-Analysis.

BACKGROUND AND OBJECTIVES: Fluid overload and central sleep apnea are highly prevalent in patients with heart failure (HF). We performed this meta-analysis to assess the effects of acetazolamide therapy on acid/base balance and apnea indexes. METHODS: A literature search was conducted using EMBASE, MEDLINE, and Cochrane Database from inception through 18 November 2017 to identify studies evaluating the use of acetazolamide in HF. Study results were analyzed using a random effects model. The protocol for this systematic review is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42017065401). RESULTS: Nine studies (three randomized controlled trials and six cohort studies) with a total of 229 HF patients were enrolled. After acetazolamide treatment, there were significant decreases in serum pH (mean difference (MD) of -0.04 (95% CI, -0.06 to -0.02)), pCO2 (MD of -2.06 mmHg (95% CI, -3.60 to -0.53 mmHg)), and serum bicarbonate levels (MD of -6.42 mmol/L (95% CI, -10.05 to -2.79 mmol/L)). When compared to a placebo, acetazolamide significantly increased natriuresis (standardized mean difference (SMD) of 0.67 (95% CI, 0.08 to 1.27)), and decreased the apnea-hypopnea index (AHI) (SMD of -1.06 (95% CI, -1.75 to -0.36)) and central apnea index (CAI) (SMD of -1.10 (95% CI, -1.80 to -0.40)). Egger's regression asymmetry tests revealed no publication bias with p = 0.20, 0.75 and 0.59 for analysis of the changes in pH, pCO2, and serum bicarbonate levels with use of acetazolamide in HF patients. CONCLUSION: Our study demonstrates significant reduction in serum pH, increase in natriuresis, and improvements in apnea indexes with use of acetazolamide among HF patients.

Gli1+ Mesenchymal Stromal Cells Are a Key Driver of Bone Marrow Fibrosis and an Important Cellular Therapeutic Target.

Bone marrow fibrosis (BMF) develops in various hematological and non-hematological conditions and is a central pathological feature of myelofibrosis. Effective cell-targeted therapeutics are needed, but the cellular origin of BMF remains elusive. Here, we show using genetic fate tracing in two murine models of BMF that Gli1+ mesenchymal stromal cells (MSCs) are recruited from the endosteal and perivascular niche to become fibrosis-driving myofibroblasts in the bone marrow. Genetic ablation of Gli1+ cells abolished BMF and rescued bone marrow failure. Pharmacological targeting of Gli proteins with GANT61 inhibited Gli1+ cell expansion and myofibroblast differentiation and attenuated fibrosis severity. The same pathway is also active in human BMF, and Gli1 expression in BMF significantly correlates with the severity of the disease. In addition, GANT61 treatment reduced the myofibroblastic phenotype of human MSCs isolated from patients with BMF, suggesting that targeting of Gli proteins could be a relevant therapeutic strategy.

Adventitial MSC-like Cells Are Progenitors of Vascular Smooth Muscle Cells and Drive Vascular Calcification in Chronic Kidney Disease.

Mesenchymal stem cell (MSC)-like cells reside in the vascular wall, but their role in vascular regeneration and disease is poorly understood. Here, we show that Gli1+ cells located in the arterial adventitia are progenitors of vascular smooth muscle cells and contribute to neointima formation and repair after acute injury to the femoral artery. Genetic fate tracing indicates that adventitial Gli1+ MSC-like cells migrate into the media and neointima during athero- and arteriosclerosis in ApoE-/- mice with chronic kidney disease. Our data indicate that Gli1+ cells are a major source of osteoblast-like cells during calcification in the media and intima. Genetic ablation of Gli1+ cells before induction of kidney injury dramatically reduced the severity of vascular calcification. These findings implicate Gli1+ cells as critical adventitial progenitors in vascular remodeling after acute and during chronic injury and suggest that they may be relevant therapeutic targets for mitigation of vascular calcification.

Pharmacological GLI2 inhibition prevents myofibroblast cell-cycle progression and reduces kidney fibrosis.

Chronic kidney disease is characterized by interstitial fibrosis and proliferation of scar-secreting myofibroblasts, ultimately leading to end-stage renal disease. The hedgehog (Hh) pathway transcriptional effectors GLI1 and GLI2 are expressed in myofibroblast progenitors; however, the role of these effectors during fibrogenesis is poorly understood. Here, we demonstrated that GLI2, but not GLI1, drives myofibroblast cell-cycle progression in cultured mesenchymal stem cell-like progenitors. In animals exposed to unilateral ureteral obstruction, Hh pathway suppression by expression of the GLI3 repressor in GLI1+ myofibroblast progenitors limited kidney fibrosis. Myofibroblast-specific deletion of Gli2, but not Gli1, also limited kidney fibrosis, and induction of myofibroblast-specific cell-cycle arrest mediated this inhibition. Pharmacologic targeting of this pathway with darinaparsin, an arsenical in clinical trials, reduced fibrosis through reduction of GLI2 protein levels and subsequent cell-cycle arrest in myofibroblasts. GLI2 overexpression rescued the cell-cycle effect of darinaparsin in vitro. While darinaparsin ameliorated fibrosis in WT and Gli1-KO mice, it was not effective in conditional Gli2-KO mice, supporting GLI2 as a direct darinaparsin target. The GLI inhibitor GANT61 also reduced fibrosis in mice. Finally, GLI1 and GLI2 were upregulated in the kidneys of patients with high-grade fibrosis. Together, these data indicate that GLI inhibition has potential as a therapeutic strategy to limit myofibroblast proliferation in kidney fibrosis.