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Table 2 Clinical studies of microparticles in renal transplantation

From: Microparticles in kidney diseases: focus on kidney transplantation

Author/year Design of study Patients Main outcomes Conclusion
Dimuccio V et al. 2014 [75] prospective, randomized and monocentric trial 25 transplanted patients
20 age-matched control
5 ESRD patients with residual diuresis
Urinary CD133 EVs significantly increased 1. CD133 EVs may reflect activity of CD133 progenitor cells in renal homeostasis and may provide information on their regenerative potential after kidney injury
Al-Massarani et al. 2009 [76] Open, prospective, randomized and mono- 52 patients
50 healthy control
At 12 months after Tx,↓ in MP and MP procoagulant was more pronounced in patients without CVD history ↓ MP and MP procoagulant activity in renal graft even in patients without CVD history
Quamri et al. 2014 [77] Prospective, randomized and monocentric trial 213 patients with KTx, 14 KTx and 60 healthy donors No difference in the quantity of circulating EMP in the pre-KTx or after KTx recipient sera and healthy donor sera ↓ in circulating EMP and Scr after kidney transplantation
Al-Massarani et al. 2008 [66] Open, prospective, randomized and mono 52 patients
50 healthy control
Positive correlation between circulating endothelial cells (CEC) and history of CVD and between EMP and CMV infection at M12 (month of 12) CEC usage in indexing vascular injury therapeutic options
Wu et al. 2014 [78] Randomized, double blind, placebo-controlled crossover trial 84 patients with moderate risk of CVD (GG n = 40; GT/TT n = 44) No significant effect of fish oil supplementation on BP plasma lipids or plasma glucose GT/TT subjects tended to higher concentrations total cholesterol and LDL but vascular function not affected by Tx or eNOS genotype
Schuerholz et al. 2007 [79] Clinical controlled trial 20 patients
Group 1 with 10.4+/−6.1 h
Group 2 with 23.7+/−3.8 h
Platelet-derived ex vivo microvesicle formation was higher in group 1
Platelet count was higher in short term ischemia
Lower platelet microvesicle formation after ex vivo stimulation with TRAP was associated with Cr that was lower in both groups longer graft ischemia
Renner et al. 2013 [80] Animal and human experimental study Animal Cyclosporine injection (subcutaneously) for 8–12 weeks to old-man C57BL/6 mice
Human EDTA-plasma from five patients before renal Tx and 14 days after initiation of treatment with tacrolimus
Cyclosporine-induced microparticles caused injury to bystander endothelial cells and complement mediated injury of the kidneys and vasculature in cyclosporine-treated mice
Number of endothelial MPs in plasma of renal transplant patients increases 2 weeks after initiation of tacrolimus and it was associated with increased C3 deposition on endothelial MPs in some of patients
Injury-associated release of endothelial MPs is a mechanism for systemic insults trigger intravascular complement activation and complement-dependent renal diseases
Kas-Deelen et al. 2000 [81] Prospective clinical trial 54 patients before HCMV infection at ~15 days after Tx weekly (40, 50, 60 days) in first antigenemia test until negative antigenemia
32 patients high antigenemia
12 patients mild antigenemia (<5 pp 65-positive granulocytes/50000 cells)
10 patients without HCMV infection
1. Cytomegalic endothelial cells in moderate or high HCMV antigenemia
2. Uninfected endothelial cells in patients with or without HCMV antigenemia
3. Incidence of either CEC, EC or combination of both cells was with HCMV-related symptoms (p < 0.01)
Occurrence of rejection episodes before HCMV infection was an important risk for the occurrence of ECs in blood (ECs, CECs, or both) during HCMV infection (p < 0. 001)
Werner et al. 2006 [48] Prospective clinical trial 50 patients with coronary artery disease underwent coronary angiography Circulating CD31+/annexin V+ apoptotic microparticles in peripheral blood was quantified by flow cytometry Increased apoptotic microparticles counts positively correlated with impairment of coronary endothelial function In patients with CAD endothelial-dependent vasodilatation closely relies on the degree of endothelial cell apoptosis. In patients with CAD, endothelial-dependent vasodilatation closely relies on the degree of endothelial cell apoptosis increased apoptotic MPs counts predict sever endothelial dysfunction independent of classical risk factors such as HTN, hypercholesterolemia, smoking, diabetes, age or sex
Shahbazian et al. 2002 [55] Prospective clinical trial 173 renal transplant recipients were examined for VEGF promoter Polymorphism using sequence-specific primer-PCR Acute rejection occurred in 38.7%; -1154*G and -2578*C alleles were associated with higher VEGF production
VEGF-1154 GG and GA genotypes were significantly associated with acute rejection risk at 3 months
VEGF-2578 CC and CA genotypes were associated with increased rejection risk
-1154*G and -2578*C containing genotypes, encoding higher VEGF production as strongly associated with acute rejection and may be a useful marker for acute rejection
Lorenzen et al. 2011 [53] Prospective cohort study 62 patients with acute rejection
19 control transplant patients without rejection
13 stable transplant patients with UTI by quantitative RT-PCR
The miR-10b and miR-210 were downregulated and miR-10a upregulated in patients with acute rejection compared to controls. Only miR-210 differed between patients with acute rejection when compared with UTI or transplant patients before/after rejection Low miR-210 levels were associated with higher decline in GFR 1 year after transplantation. Selected miRNA are strongly altered in urine of the patients with acute renal graft rejection. The miR-210 levels identify patients with acute rejection and predict long-term kidney function. Urinary miR-210 may thus serve as a novel biomarker of acute rejection
Scian et al. 2011 [54] Prospective study 65 miRNA in samples with CAD with IF/TA vs. normal allografts by microarray
Five miRNAs were selected and differential expression By RT-qPCR
Differential expression were detected for miR-142-3p, miR-204, miR-107, and miR-211 Differential expression of miR-142-3p, miR-204, and miR-211 were observed between patient groups in urine samples. A characteristic miRNA signature for IF/TA that correlates with paired urine samples was identified. This study support the potential use of miRNAs as noninvasive markers of IF/TA and for monitoring graft function.
Simmons et al. 2005 [60] Prospective cohort study 19 patients of living-donor kidney Txs were enrolled.
CRP, IL-1, IL-6, IL-10, TNF-a, protein-associated carbonyl content, and F-2 isoprostanes at 1 week pretransplant and 1 week and 2 months posttransplant
↑pretransplant levels of the pro-inflammatory proteins IL-6, TNF-a, CRP, oxidative markers (plasma protein carbonyls and F2-isoprostanes in ESRD patients vs. healthy control subjects
↓ posttransplant levels of pro-inflammatory proteins and oxidative markers on 2 months
Kidney Tx improves the chronic inflammation and ↑ oxidative stress due to uremia and may contribute to survival
Jarmo et al. 1997 [59] Prospective study 20 pediatric renal allograft recipients
12 patients with chronic rejection and 8 with normal histology
9 pediatric liver allograft recipients
7 children with minimal change nephrotic syndrome
Apoptotic cell death by apoptosis-induced oligonucleosomal DNA fragmentation in the biopsy using 3′ end labeling with terminal transferase gel fractionation and southern blotting specific cell types with ↑ DNA fragmentation using 3′ end labeling were determined
Specific DNA fragmentation in chronic rejection
↑apoptosis of both the proximal and distal tubular epithelial cells
Mean number of apoptotic tubular cells was higher in the renal allografts than liver allograft recipients and patients with minimal change nephrotic syndrome
Increased apoptotic cell death of renal tubular epithelial cells in patients undergoing chronic renal allograft rejection
  1. AR acute rejection, BP blood pressure, CAD coronary artery disease, CECs circulating endothelial cells, CD cluster of differentiation, CRP C-reactive protein, CSA cyclosporine A, CVD cardiovascular disease, ECs endothelial cells, EDTA ethylene diamine tetra-acetate, eNOS endothelial nitric oxide synthase, ESRD end-stage renal disease, EVs extracellular vesicles, GFR glomerular filtration rate, HCMV human cytomegalovirus, HRECs human renal epithelial cells, HTN hypertension, IF/TA interstitial fibrosis/tubular atrophy, KTx kidney transplantation, LDL low density lipoprotein, MPs microparticles, mRNAs messenger RNAs, miRNAs microRNAs, PBMCs peripheral blood mononuclear cells, RT-qPCR real-time quantitative-polymerase chain reaction, Scr serum creatinine, TRAP tartrate-resistant acid phosphatase, VEGF vascular endothelial growth factor