The use of lung ultrasound in evaluation of extravascular lung water in hemodialysis patients: Systematic review and meta-analysis.

RATIONALE AND OBJECTIVES: Determining dry weight is crucial for optimizing hemodialysis, influencing efficacy, cardiovascular outcomes, and overall survival. Traditional clinical assessment methods for dry weight, relying on factors such as blood pressure and edema, frequently lack reliability. Lung ultrasound stands out as a promising tool for assessing volume status, given its non-invasiveness and reproducibility. This study aims to explore the role of Lung ultrasound in evaluating the impact of hemodialysis and ultrafiltration on extravascular lung water, with a specific focus on changes in B-lines post-hemodialysis compared to pre-hemodialysis. MATERIALS AND METHODS: The research encompassed searches across PubMed, WOS, and Scopus databases for studies related to lung ultrasound and hemodialysis. A meta-analysis was then performed to determine the mean differences in various parameters before compared to after, hemodialysis, including the number of B-lines, indexed end-inspiratory and end-expiratory inferior vena cava diameters, inferior vena cava collapsibility index, weight, blood pressure, and serum levels of NT-pro-BNP. RESULTS: Our meta-analysis, included 33 studies with 2301 hemodialysis patients, revealed a significant decrease in the number of B-lines post-hemodialysis (mean difference = 8.30, 95% CI [3.55 to 13.05]). Furthermore, there was a noteworthy reduction in inspiratory and expiratory inferior vena cava diameters post-hemodialysis (mean difference = 2.32, 95% CI [0.31 to 4.33]; mean difference = 4.05, 95% CI [2.44 to 5.65], respectively). Additionally, a significant positive correlation was observed between B-lines and the maximum inferior vena cava diameter both pre- and post-hemodialysis (correlation coefficient = 0.39; correlation coefficient = 0.32, respectively). CONCLUSION: These findings indicate the effectiveness of lung ultrasound in detection of volume overload and assessment of response to ultrafiltration in hemodialysis patients.

Cause-specific mortality among patients with renal cell carcinoma in the United States from 2000 to 2018.

OBJECTIVES: There has been little focus on the non-cancer causes of death in patients with renal cell carcinoma (RCC). Therefore, we aimed to assess the frequency and risk of different causes of death, stratified by tumor stage, and demographics, after a diagnosis of RCC in the United States. MATERIALS AND METHODS: Data on eligible patients with RCC from January 1, 2000, to December 31, 2018, in the United States were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Standardized mortality ratios for causes of death were calculated using the SEER*Stat software 8.3.9.2 for the overall population and stratified subgroups. RESULTS: A total of 165,969 patients with RCC were included and 60,290 (36.3%) died during follow-up. The majority of deaths were due to kidney cancer (51.3%) but a significant proportion was non-cancer causes (37.6%). The proportion of deaths attributed to RCC decreased with increasing follow-up with non-cancer causes becoming dominant after the fifth year following RCC diagnosis. Overall, cardiovascular diseases and cerebrovascular diseases were the most common non-RCC-related causes of death. AJCC stage I and localized RCC had the most deaths attributed to non-cancerous causes (66.2% and 61.2%, respectively) while AJCC stage IV and distant RCC had the most deaths due to RCC (86.2% and 86.5%, respectively). CONCLUSION: A large proportion of RCC patients die of non-cancerous causes especially early-stage patients and advanced-stage patients who survive >5 years. Coordination of multidisciplinary care with relevant specialists depending on the stage of the disease is needed to better prevent death overtime from non-cancer causes.

Serum Zinc Levels in Chronic Kidney Disease Patients, Hemodialysis Patients, and Healthy Controls: Systematic Review and Meta-Analysis.

OBJECTIVES: Patients with chronic kidney disease (CKD) are susceptible to changes in zinc homeostasis through anorexia and dietary restrictions, as well as hemodialysis (HD). Changes in zinc homeostasis might predispose CKD and HD patients to specific adverse effects, including erythropoietin-resistant anemia, oxidative stress, atherosclerosis, and cardiovascular disease. Because serum zinc levels are rarely measured in CKD and HD patients, zinc supplementations do not represent a routine therapy for CKD and dialysis patients. Therefore, in this meta-analysis, we aimed to assess serum zinc levels in CKD and HD patients compared with healthy controls (HC). In addition, we investigated whether HD affects serum zinc levels by comparing serum zinc levels in HD versus CKD patients and comparing serum zinc pre- versus post-HD. DESIGN AND METHODS: A comprehensive search of databases was conducted to identify either observational studies or randomized trials that assessed serum zinc levels in either CKD and/or HD patients in comparison to HC. We conducted a random-effects meta-analysis. RESULTS: Our meta-analysis included 42 studies with a total of 4,161 participants, of whom 460 were CKD patients, 2,047 were HD patients, and 1,654 were HCs. Both CKD and HD patients showed lower serum zinc levels compared with HC (mean difference = -22.86 µg/dL, 95% CI -33.25 to -12.46; mean difference = -13.64 µg/dL, 95% CI -21.47 to -53.80, respectively). CKD and HD patients showed no significant difference in serum zinc levels (mean difference = 15.39, 95% CI -8.91 to 39.68). Pre-HD serum zinc levels were significantly lower than those post-HD (mean difference = -7.51 µg/dL, 95% CI -14.24 to -0.78). CONCLUSION: In the current study, the serum zinc levels were lower in CKD and HD patients compared to HCs and appears to be more common than reported in daily clinical practice. It may be beneficial to assess serum zinc levels in CKD and HD patients. More research on zinc in kidney disease is encouraged.

Revisiting maintenance immunosuppression in patients with renal transplant failure: early weaning of immunosuppression versus prolonged maintenance-systematic review and meta-analysis.

INTRODUCTION: Prolonged immunosuppression after dialysis start has been assumed to reduce sensitization, need for graft nephrectomy, and to favor re-transplantation. In contrast, immunosuppression is considered to increase the risk of mortality, infection, and malignancy. We aimed to assess the evidence regarding superiority of early or late withdrawal of maintenance immunosuppression post renal transplant failure. METHODS: A literature search of the PubMed, WOS, Ovid, and Scopus databases was conducted. Combined relative risks, (RRs), mean differences, and 95% confidence intervals (CIs) were calculated by using a random-effect model. RESULTS: Ten studies involving 1187 patients with kidney transplant failure were included. No difference could be detected between patients with early withdrawal of  immunosuppressive drugs (≤ 3 months) or prolonged immunosuppressive treatment (> 3 months) regarding mortality (95% CI 0.91-2.28), panel reactive antibodies (PRAs) (95% CI - 0.75-30.10), re-transplantation rate (95% CI 0.55-1.35), infectious episodes (95% CI 0.67, 1.17), cancer (95% CI 0.26-1.54), and graft nephrectomy (95% CI 0.82-1.63). Similarly, no difference was found between immunosuppressive drug withdrawal over < 6 or ≥ 6 months regarding mortality (95% CI 0.16, 2.89), re-transplantation rate (95% CI 0.85-1.55), cancer (95% CI 0.37-1.63), and allograft nephrectomy (95% CI 0.87-4.33). CONCLUSION: Prolonged maintenance immunosuppression post kidney transplant failure is not associated with increased risk of mortality, infection, or malignancy, or reduced risk of sensitization or allograft nephrectomy compared with early withdrawal.

Relation of Liver Siderosis to Liver Fibrosis in Hemodialysis Patients With Severe Hyperferritinemia Secondary to High Doses of Intravenous Iron Supplementation.

OBJECTIVE: Aggressive iron substitution in hemodialysis (HD) patients leads to iron overload. The association between liver siderosis and fibrosis is still debatable. We studied the association of liver siderosis with liver fibrosis in HD patients. Furthermore, we studied the performance of liver stiffness measurements (LSMs) in identifying advanced liver fibrosis. We investigated the performance of biochemical indicators of iron status in identifying advanced liver fibrosis. METHODS: Fifty-five HD patients (average HD duration 6 ± 2 years) with hyperferritinemia secondary to intravenous iron supplementation (weakly iron dose 252.7 ± 63 mg; median blood transfusions 3 [2-5]) were recruited. The liver fibrosis grade was determined with Fibroscan, aminotransferase-to-platelet ratio index (APRI), and Fib-4 index. Liver iron concentration (LIC) was estimated with magnetic resonance imaging (MRI). Iron parameters and liver function biochemical indicators were also assessed. RESULTS: The median serum ferritin and transferrin saturation (TSAT) were 3531 µg/L and 77%, respectively. 34.5%, 20%, and 45.5% of the patients showed mild, moderate, or severe liver siderosis, respectively. All patients with severe liver siderosis showed advanced liver fibrosis. Patients with severe liver siderosis and advanced liver stiffness showed higher serum iron, TSAT, aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum bilirubin, APRI, and Fib-4 index scores than those with mild liver siderosis. Serum iron and TSAT showed good utility in identifying advanced liver fibrosis determined with Fibroscan, APRI, and Fib-4 index. Liver stiffness exhibited good utility in identifying advanced liver fibrosis diagnosed with APRI and Fib-4 index. CONCLUSIONS: High weekly intravenous iron dose associated with severe hyperferritinemia, high serum iron, and TSAT might lead to severe liver siderosis and concomitant liver fibrosis in HD patients. Serum iron, TSAT, Fibroscan, Fib-4, and APRI scores might offer noninvasive tools for identifying advanced liver fibrosis in those patients.

CD4+CD25+CD127-Foxp3+ and CD8+CD28- Tregs in Renal Transplant Recipients: Phenotypic Patterns, Association With Immunosuppressive Drugs, and Interaction With Effector CD8+ T Cells and CD19+IL-10+ Bregs.

Introduction: Gaps still exist regarding knowledge on regulatory cells in transplant recipients. We studied the phenotypic patterns of CD4+, CD8+CD28- Tregs, and CD19+IL-10+ Bregs in the blood of healthy controls (HC), end-stage kidney disease patients (ESKD), early and late stable renal transplant recipients (Tx), and transplant recipients with steroid-treated acute cellular rejection 1 week-3 months after successful treatment. We also investigated the relationship between immunosuppressive drugs and the aforementioned regulatory cells in transplant recipients. Methods: We recruited 32 HC, 83 ESKD, 51 early Tx, 95 late Tx, and 9 transplant patients with a recent steroid-treated acute cellular rejection. Besides CD19+IL-10+ Bregs, we analyzed absolute and relative frequencies of CD4+CD25+CD127-Foxp3+ Tregs and CD8+CD28- Tregs and their expression of IL-10, TGF-ß, IFN-g, and Helios. Results: We found a negative correlation between absolute CD4+CD25+CD127-Foxp3+ Treg and relative CD19+IL-10+ Breg frequencies in early Tx recipients (r=-0.433, p=0.015, n=31). In that group, absolute CD4+CD25+CD127-Foxp3+ Tregs were negatively associated with steroid dose and tacrolimus trough levels (r=-0.377, p = 0.021, n=37; r=-0.43, p=0.033, n=25, respectively), opposite to IL-10+ Bregs, whose frequency apparently was not negatively affected by potent immunosuppression early posttransplant. We found also lower CD4+CD25+CD127-Foxp3+ Tregs in patients treated with basiliximab or rATG as compared with ESKD patients (p=0.001 and p <0.001, respectively). No difference in absolute IL-10+ Bregs could be detected among these 3 patient groups. Early Tx recipients showed lower CD4+CD25+CD127-Foxp3+ Tregs within 3 months of antibody induction than after 3 months (p = 0.034), whereas IL-10+ Bregs showed higher relative counts during the first 3 months post antibody induction than after 3 months (p = 0.022). Our findings suggest that IL-10+ Bregs decrease with time posttransplantation independent of the effect of antibody induction and dose of other immunosuppressive drugs. Conclusion: These findings suggest that CD19+IL-10+ Bregs and CD4+CD25+CD127-Foxp3+ Tregs behave in opposite ways during the early posttransplant period, possibly due to a predominant negative impact of high doses of immunosuppressants on Tregs. CD19+IL-10+Bregs do not seem to be suppressed by antibody induction and early potent immunosuppression with chemical drugs.

Higher CD19+CD25+ Bregs are independently associated with better graft function in renal transplant recipients.

BACKGROUND: The Identification of B cell subsets with regulatory functions might open the way to new therapeutic strategies in the field of transplantation, which aim to reduce the dose of immunosuppressive drugs and prolong the graft survival. CD25 was proposed as a marker of a B-cell subset with an immunosuppressive action termed Bregs. The effect of CD19 + CD25 + Bregs on graft function in renal transplant recipients has not yet been elucidated. We investigated a potential impact of CD19 + CD25 + Bregs on renal graft function as well as a possible interaction of CD19 + CD25 + Bregs with peripheral Tregs in healthy controls, end-stage kidney disease patients (ESKD), and renal transplant recipients. Moreover, we aimed to investigate the association of CD19 + CD25 + Bregs with serum IL-10, TGF-ß1, and IFN-γ in the same study groups. METHOD: Thirty-one healthy controls, ninety renal transplant recipients, and eighteen ESKD patients were enrolled. We evaluated the CD19 + CD25 + Bregs and Treg absolute counts. Next, we investigated CD19 + CD25 + Bregs as predictors of good graft function in multiple regression and ROC analyses. Finally, we evaluated the association between CD19 + CD25+ Bregs and serum IL-10, TGF-ß, and IFN-γ. RESULTS: ESKD patients and renal transplant recipients showed lower counts of CD19 + CD25+ Bregs compared to healthy controls (p < 0.001). Higher CD19 + CD25+ Breg counts were independently associated with a better GFR in renal transplant recipients (unstandardized B coefficient = 9, p = 0.02). In these patients, higher CD19 + CD25+ Bregs were independently associated with higher Treg counts (unstandardized B = 2.8, p = 0.004). In ROC analysis, cut-offs for CD19 + CD25 + Breg counts and serum TGF-ß1 of 0.12 cell/µl and 19,635.4 pg/ml, respectively, were shown to provide a good sensitivity and specificity in identifying GFR ≥ 30 ml/min (AUC = 0.67, sensitivity 77%, specificity 43%; AUC = 0.65, sensitivity 81%, specificity 50%, respectively). Finally, a significant positive association between CD19 + CD25+ Bregs and TGF-ß1 was shown in renal transplant recipients (r = 0.255, p = 0.015). CONCLUSIONS: Our findings indicate that higher counts of CD19 + CD25+ Bregs are independently associated with better renal function and higher absolute Treg counts in renal transplant recipients.

Low utility of serum 25-hydroxyvitamin D3 and 1, 25-dihydroxyvitamin D3 in predicting peripheral Treg and Th17 cell counts in ESRD and renal transplant patients.

BACKGROUND: Vitamin D has shown an immune-modulatory effect in different studies. Vitamin D stimulates Tregs and inhibits Th17 cells. The immune-modulatory role of vitamin D in chronic kidney disease (CKD) and renal transplant patients is unclear. We measured whether different serum levels of vitamin D were associated with an increased or decreased presence of lymphocyte subsets including Treg and Th17 cells in end-stage renal disease (ESRD) and renal transplant recipients. METHODS: Eighty-seven renal transplant recipients and 53 end-stage renal disease (ESRD) patients were enrolled in this study. The absolute counts of CD4+ and CD8+ T, CD16+ CD56+ NK, CD19+ B, CD4+ CD25+ CD127- Foxp3+ (Tregs), Helios+ Tregs, CD38+ Tregs, and CD4+ CD17+ (Th17) cells were analyzed in peripheral blood in both patient groups. In addition, serum 25 (OH) D3, 1, 25 (OH)2 D3, IL-6, IL-17, IL-23, and TGF-ß1 were measured. The association between lymphocyte subset counts and 1, 25 (OH)2 D3 or 25 (OH) D3 was studied, as was the association between serum IL-6, IL-17, IL-23, or TGF-ß1 and 1,25 (OH)2 D3 or 25 (OH) D3. RESULTS: Serum 25 (OH) D3 and 1,25 (OH)2 D3 levels were not independently associated with peripheral CD4+ T, CD19+ B, CD16+ CD56+ NK, Treg, or Th17 cell counts. In contrast to serum 25 (OH) D3, serum1, 25 (OH)2 D3 was positively associated with CD8+ T cells counts in renal transplant recipients. CONCLUSION: Our findings indicate low utility of serum 25 (OH) D3 and 1, 25 (OH)2 D3 levels in predicting a change in lymphocyte subset counts in ESRD and renal transplant patients.

Low-dose oral cholecalciferol is associated with higher numbers of Helios(+) and total Tregs than oral calcitriol in renal allograft recipients: an observational study.

BACKGROUND: Regulatory T cells (Tregs) are a cornerstone of graft acceptance. High numbers of Tregs are associated with better long-term graft survival. Recently, Vitamin D was suggested as an immunomodulator, in addition to its classical role in calcium metabolism. Vitamin D modulates Tregs and might, thereby, promote graft acceptance and long-term graft survival. METHODS: One hundred twenty-three renal allograft recipients attending either Heidelberg nephrology or Giessen internal medicine clinic were enrolled in this cross- sectional study. Sixteen healthy controls were studied in addition. Sixty-nine patients were receiving no vitamin D, 38 calcitriol, and 16 cholecalciferol supplementations. We evaluated whether there was a difference in the absolute numbers of Helios(+), Helios(-), CTLA-4(+), IFNg(+), and total Tregs among the patient groups. RESULTS: Cholecalciferol supplementation was associated with higher absolute numbers of Helios(+), CTLA-4(+), and total Tregs than calcitriol (p < 0.001, p = 0.004, p = 0.001 respectively). Helios(+) Tregs were also higher in cholecalciferol than no vitamin D supplementation patients (p = 0.001), whereas CTLA-4(+) and total Tregs were similar in both groups (p = NS). Helios(+), Helios(-), CTLA-4(+), IFNg(+), and total Tregs were similar in the cholecalciferol and healthy control groups (p = NS). CONCLUSION: Our findings indicate that cholecalciferol, even when administered at low dosages, has a stabilizing effect on Tregs (particularly the Helios + subset), in contrast to calcitriol which showed neither a stabilizing nor a proliferation-inducing effect on the same cell population.