Impact of body mass index on disease progression and outcomes in patients with nonalcoholic fatty liver disease.

BACKGROUND: The relationship between body mass index (BMI) and outcomes in patients with nonalcoholic fatty liver disease (NAFLD) is not well defined. This study aimed to assess the presentations, outcomes, and development of liver-related events (LREs) and non-LREs in patients with NAFLD stratified by BMI. METHODS: Records of NAFLD patients from 2000-2022 were reviewed. Patients were categorized as lean (18.5-22.9 kg/m2), overweight (23-24.9 kg/m2), and obese (>25 kg/m2) based on BMI. Stage of steatosis, fibrosis, and NAFLD activity score were noted in the patients undergoing liver biopsy in each group. RESULTS: Out of 1051 NAFLD patients, 127 (12.1%) had normal BMI, 177 (16.8%) and 747 (71.1%) were overweight and obese, respectively. Median [interquartile range] BMI was 21.9 [20.6-22.5], 24.2 [23.7-24.6], and 28.3 [26.6-30.6] kg/m2 in each group, respectively. Prevalence of metabolic syndrome and dyslipidemia were significantly higher in the obese. Obese patients had significantly higher median [interquartile range] liver stiffness (6.4 [4.9-9.4] kPa) than overweight and lean subjects. A higher proportion of obese patients had significant and advanced liver fibrosis. At follow-up, there were no significant differences in the progression of liver disease, new LREs, coronary artery disease, or hypertension across the BMI groups. Overweight and obese patients were more likely to develop new-onset diabetes by follow-up. The mortality rates in the three groups were comparable (0.47, 0.68, and 0.49 per 100 person-years, respectively), with similar causes of death (liver-related vs non-liver-related). CONCLUSIONS: Patients with lean NAFLD have similar disease severity and rates of progression as the obese. BMI is not a reliable determinant of outcomes in NAFLD patients.

Cytokines and Immune Cell Phenotype in Acute Kidney Injury Associated With Immune Checkpoint Inhibitors.

Introduction: Immune checkpoint inhibitors (ICIs) induce impressive antitumor responses but may lead to acute kidney injury (AKI) associated with ICI therapy (AKI-ICI). Biomarkers distinguishing AKI-ICI from AKI because of other causes (AKI-other) are currently lacking. Because ICIs block immunoregulatory pathways, we hypothesized that biomarkers related to immune cell dysregulation, including tumor necrosis factor alpha (TNF-α) and other markers of B and T cell activation in the systemic circulation and kidney tissue, may aid with the diagnosis of AKI-ICI. Methods: This is a prospective study consisting of 24 participants who presented with AKI during ICI therapy, adjudicated to either have AKI-ICI (n = 14) or AKI-other (n = 10). We compared markers of kidney inflammation and injury (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1) as well as plasma and urine levels of T cell-associated cytokines (TNF-α, interferon-γ, interleukin (IL)-2, IL-4, IL-6, IL-8, IL-9, and IL-10) between groups. We also compared T-cell responses in the systemic circulation and in kidney tissue across groups, using mass cytometry systems. Results: We observed increase in several specific immune cells, including CD4 memory, T helper cells, and dendritic cells in the kidney tissue, as well as in the urine cytokines IL-2, IL-10, and TNF-α, in patients who developed AKI-ICI compared to patients with AKI-other (P < 0.05 for all). The discriminatory ability of TNF-α on AKI cause was strong (area under the curve = 0.814, 95% confidence interval: 0.623-1.00. The CD4+ T cells with memory phenotype formed the dominant subset. Conclusion: These results suggest that specific T-cell responses and their respective cytokines may be indicative of AKI associated with ICI therapy and may help to differentiate AKI-ICI from AKI-other. Urine TNF-α is a promising biomarker for AKI-ICI, which is most often caused by acute interstitial nephritis (AIN), and TNF-α pathway may serve as a potential target for therapeutic intervention.

Association of vitamin D status with disease severity and outcome in Indian patients with IgA nephropathy.

BACKGROUND: Vitamin D deficiency has been examined as a risk factor for severity and progression of kidney disease due to its immunomodulatory effects. There is paucity of data about its impact in IgA nephropathy (IgAN). METHODS: In a retrospective cohort study, 25 (OH) vitamin D assay was performed in bio-banked baseline serum samples collected during kidney biopsy of 105 adult patients with primary IgAN diagnosed between 2015 and 2019. A level of < 10 ng/mL was defined as Vitamin D deficiency. RESULTS: Mean age of patients was 34 ± 10.6 years, 69.5% were males. Mean baseline 25(OH) Vitamin D levels was 15.9 ± 11.9 ng/mL and 41(39%) patients had vitamin D deficiency. Serum albumin level was lower in vitamin D deficient patients compared to those who had higher vitamin D levels (3.7 ± 0.9 vs 4.1 ± 0.7 g/dl, p = 0.018)but there was no significant difference in baseline proteinuria and eGFR. Crescentic lesions were more frequent in vitamin D deficient group (19.5% vs 6.3%, p = 0.022). At median follow up of 21.5 months (6 - 56 months), there was no difference in remission (68.3% vs 65.6%, p = 0.777) and disease progression (12.5% vs 9.4%, p = 0.614) in those with and without Vitamin D deficiency respectively. On multivariate cox proportional hazard analysis, vitamin D deficiency was not a significant risk factor for renal survival (HR-1.79, 95% confidence interval:0.50-6.34, p = 0.368). CONCLUSION: There was no association between vitamin D deficiency and disease profile as well as renal outcome in Indian patients with IgAN.

Effect of Hypoxia Preconditioning on the Regenerative Capacity of Adipose Tissue Derived Mesenchymal Stem Cells in a Model of Renal Artery Stenosis.

Atherosclerotic renal artery stenosis (ARAS) is associated with irreversible parenchymal renal disease and regenerative stem cell therapies may improve renal outcomes. Hypoxia preconditioning (HPC) may improve the regenerative functions of adipose tissue-derived mesenchymal stem cells (AMSC) by affecting DNA 5-hydroxymethylcytosine (5hmC) marks in angiogenic genes. Here, we investigated using a porcine ARAS model, whether growth of ARAS AMSCs in hypoxia (Hx) versus normoxia (Nx) would enhance renal tissue repair, and comprehensively analyze how HPC modifies DNA hydroxymethylation compared to untreated ARAS and healthy/normal pigs (n=5 each). ARAS pigs exhibited elevated serum cholesterol, serum creatinine and renal artery stenosis, with a concomitant decrease in renal blood flow (RBF) and increased blood pressure (BP) compared to healthy pigs. Renal artery injection of either autologous Nx or Hx AMSCs improved diastolic BP, reduced kidney tissue fibrosis, and inflammation (CD3+ T-cells) in ARAS pigs. In addition, renal medullary hypoxia significantly lowered with Nx but not Hx AMSC treatment. Mechanistically, levels of epigenetic 5hmC marks (which reflect gene activation) estimated using DNA immunoprecipitation technique were elevated in profibrotic and inflammatory genes in ARAS compared with normal AMSCs. HPC significantly reduced 5hmC levels in cholesterol biosynthesis and oxidative stress response pathways in ARAS AMSCs. Thus, autologous AMSCs improve key renovascular parameters and inflammation in ARAS pigs, with HPC mitigating pathological molecular effects on inflammatory and profibrotic genes which may play a role in augmenting regenerative capacity of AMSCs.

Incidence and Risk Factors for Acute Kidney Injury After Chimeric Antigen Receptor T-Cell Therapy.

OBJECTIVE: To evaluate the association of baseline and postinfusion patient characteristics with acute kidney injury (AKI) in the month after chimeric antigen receptor T-cell (CAR-T) therapy. METHODS: We retrospectively reviewed records of 83 patients with non-Hodgkin lymphoma undergoing CAR-T therapy (axicabtagene ciloleucel) between June 2016 and November 2020. Patients were followed up to 1 month after treatment. Post-CAR-T AKI was defined as a more than 1.5-fold increase in serum creatinine concentration from baseline (on the day of CAR-T infusion) at any time up to 1 month after CAR-T therapy. RESULTS: Of 83 patients, 14 (17%) developed AKI during follow-up. At 1 month after CAR-T infusion, 10 of 14 (71%) AKI events had resolved. Lower baseline estimated glomerular filtration rate, use of intravenous contrast material, tumor lysis prophylaxis, higher peak uric acid and creatine kinase levels during follow-up, and change in lactate dehydrogenase from baseline to peak level within 1 month after initiation of CAR-T therapy were significantly associated with AKI incidence during follow-up. Incidence of AKI was also higher in patients who received higher doses of corticosteroids and tocilizumab. CONCLUSION: Acute kidney injury occurred in approximately 1 in 6 patients who received axicabtagene ciloleucel for non-Hodgkin lymphoma. Patients with high tumor burden receiving higher total doses of corticosteroids or tocilizumab should be closely monitored for development of AKI. Lower baseline kidney function at CAR-T initiation, exposure to contrast material, and progressive increase in levels of tumor lysis markers (uric acid, lactate dehydrogenase, creatine kinase) after CAR-T infusion may predict risk of AKI during the 1 month after infusion.

A Current Understanding of Bile Acids in Chronic Liver Disease.

Chronic liver disease (CLD) is one of the leading causes of disability-adjusted life years in many countries. A recent understanding of nuclear bile acid receptor pathways has increased focus on the impact of crosstalk between the gut, bile acids, and liver on liver pathology. While conventionally used in cholestatic disorders and to dissolve gallstones, the discovery of bile acids' influence on the gut microbiome and human metabolism offers a unique potential for their utility in early and advanced liver diseases because of diverse etiologies. Based on these findings, preclinical studies using bile acid-based molecules have shown encouraging results at addressing liver inflammation and fibrosis. Emerging data also suggest that bile acid profiles change distinctively across various causes of liver disease. We summarize the current knowledge and evidence related to bile acids in health and disease and discuss culminated and ongoing therapeutic trials of bile acid derivatives in CLD. In the near future, further evidence in this area might help clinicians better detect and manage liver diseases.

Prevalence of celiac disease in patients with short stature: A systematic review and meta-analysis.

BACKGROUND AND AIM: Short stature is a common extraintestinal manifestation of celiac disease (CeD). We conducted a systematic review and meta-analysis to assess the global prevalence of CeD in patients presenting with short stature. METHODS: We searched Medline and EMBASE databases for the keywords "celiac disease, coeliac disease, anti-gliadin, tissue transglutaminase antibody, anti-endomysial antibody, short stature and growth retardation." All the studies published from January 1991 to May 2020 were included. Patients without any prior evaluation for short stature were classified as all-cause short stature, while prior evaluated patients, where no cause was found for short stature, were classified as idiopathic short stature. The diagnosis of CeD was based on the European Society for Paediatric Gastroenterology, Hepatology and Nutrition guidelines. A random-effects model was used to pool the data. RESULTS: Seventeen studies screening 3759 patients (1582 with all-cause short stature and 2177 with idiopathic short stature) were included. The pooled seroprevalence of CeD based on positive anti-tissue transglutaminase antibody and anti-endomysial antibody was 11.2% (95% CI 4.0-21.2%; I2  = 86%) and 9.7% (95% CI 2.7-20.2%; I2  = 95%) for all-cause and idiopathic short stature, respectively. Similarly, pooled prevalence of biopsy-confirmed CeD was 7.4% (95% CI 4.7-10.6%; I2  = 76%) and 11.6% (95% CI 4.1-22.2%; I2  = 97%), for all-cause and idiopathic short stature, respectively. There was an overall severe risk of selection bias and significant heterogeneity in the pooled results. CONCLUSIONS: Approximately one in 14 patients with all-cause short stature and one in nine patients with idiopathic short stature had biopsy-confirmed CeD. Therefore, evaluation for CeD may be prudent in all patients with short stature.