Safety and Tolerability of Sodium Thiosulfate in Patients with an Acute Coronary Syndrome Undergoing Coronary Angiography:A Dose-Escalation Safety Pilot Study (SAFE-ACS)

Background. In animal studies, hydrogen sulfide (H2S) has been shown to protect the heart from ischemia-reperfusion injury. This study evaluates the safety and tolerability of the H2S donor sodium thiosulfate (STS) in patients with acute coronary syndrome (ACS). Methods. Eighteen patients, undergoing coronary angiography for ACS, received STS intravenously immediately after arrival at the catheterization laboratory according to a “3 + 3 dose-escalation design” with fixed dosing endpoint (0, 2.5, 5, 10, 12.5, and 15 grams). This first dose STS was combined with verapamil and nitroglycerin required for transradial procedures. A second dose STS was administered 6 hours later. Primary endpoint was dose-limiting toxicity, defined as significant hemodynamic instability or death up to 24 hours or before discharge from the coronary care unit. Secondary outcomes included the occurrence of anaphylaxis, nausea, vomiting, and systolic blood pressure (SBP) course. Results. Sixteen patients received two dosages of STS and two patients one dosage. None of the patients reached the primary endpoint, nor experienced a serious adverse event. We observed a clinically well-tolerated decline in SBP 1 hour after administration of the first STS dose and concomitant verapamil/nitroglycerin. SBP for all patients together reduced 16.8 (8.1–25.5) mmHg (P=0.0008). No significant decline in SBP occurred after the second dose. Mild nausea was observed in one patient. Conclusion. This is the first report on sodium thiosulfate administration in patients with acute coronary syndromes. Our data suggest that sodium thiosulfate was well tolerated in this setting. The potential benefit of this intervention has to be examined in larger studies

Molecular profiling of single circulating tumor cells with diagnostic intention

Several hundred clinical trials currently explore the role of circulating tumor cell (CTC) analysis for therapy decisions, but assays are lacking for comprehensive molecular characterization of CTCs with diagnostic precision. We therefore combined a workflow for enrichment and isolation of pure CTCs with a non-random whole genome amplification method for single cells and applied it to 510 single CTCs and 189 leukocytes of 66 CTC-positive breast cancer patients. We defined a genome integrity index (GII) to identify single cells suited for molecular characterization by different molecular assays, such as diagnostic profiling of point mutations, gene amplifications and whole genomes of single cells. The reliability of >90% for successful molecular analysis of high-quality clinical samples selected by the GII enabled assessing the molecular heterogeneity of single CTCs of metastatic breast cancer patients. We readily identified genomic disparity of potentially high relevance between primary tumors and CTCs. Microheterogeneity analysis among individual CTCs uncovered pre-existing cells resistant to ERBB2-targeted therapies suggesting ongoing microevolution at late-stage disease whose exploration may provide essential information for personalized treatment decisions and shed light into mechanisms of acquired drug resistance

Living kidney donation does not adversely affect serum calcification propensity and markers of vascular stiffness

Living kidney donors (LKDs) experience a decline in glomerular filtration rate (GFR) after donation. Calcification propensity (T50 ) can be determined by a blood test predicting all-cause mortality in patients with chronic kidney disease. We studied the impact of kidney donation on T50 and markers of arterial stiffness. We analyzed T50 prospectively before and 1 year after kidney donation in 21 LKDs along with fetuin-A, mineral metabolism markers, kidney length, pulse wave velocity (PWV), augmentation index (AI), and renal resistive index (RRI) as markers of arterial stiffness. We studied the impact of kidney donation on these parameters. LKDs were 54 ± 10 years old and had a GFR of 101 ± 18 ml/min/1.73 m(2) before donation, decreasing to 67 ± 8 ml/min/1.73 m(2) after donation (P < 0.001). Despite this, T50 improved after donation (290 ± 53 to 312 ± 38 min, P = 0.049). This change was inversely related to plasma phosphate (P = 0.03), which declined after donation (P = 0.002). Fetuin-A levels increased after donation (P = 0.01). Upon donation, the length of the remaining kidney increased (P < 0.001) while PWV, AI, and RRI remained unchanged. Calcification propensity was not adversely affected by kidney donation. This indicates that T50 is independent from GFR in LKDs and that kidney donation does neither worsen calcification propensity nor markers of vascular stiffness at 1 year

Calcification Propensity (T50) Predicts a Rapid Decline of Renal Function in Kidney Transplant Recipients

Background: Serum creatinine level, proteinuria, and interstitial fibrosis are predictive of renal prognosis. Fractional excretion of phosphate (FEP)/FGF23 ratio, tubular reabsorption of phosphate (TRP), serum calcification propensity (T50), and Klotho’s serum level are emerging as determinants of poor kidney outcomes in CKD patients. We aimed at analysing the use of FGF23, FEP/FGF23, TRP, T50, and Klotho in predicting the rapid decline of renal function in kidney allograft recipients. Methods: We included 103 kidney allograft recipients in a retrospective study with a prospective follow-up of 4 years. We analysed the predictive values of FGF23, FEP/FGF23, TRP, T50, and Klotho for a rapid decline of renal function defined as a drop of eGFR > 30%. Results: During a follow-up of 4 years, 23 patients displayed a rapid decline of renal function. Tertile of FGF23 (p value = 0.17), FEP/FGF23 (p value = 0.78), TRP (p value = 0.62) and Klotho (p value = 0.31) were not associated with an increased risk of rapid decline of renal function in kidney transplant recipients. The lower tertile of T50 was significantly associated with eGFR decline >30% with a hazard ratio of 3.86 (p = 0.048) and remained significant in multivariable analysis. Conclusion: T50 showed a strong association with a rapid decline of renal function in kidney allograft patients. This study underlines its role as an independent biomarker of loss of kidney function. We found no association between other phosphocalcic markers, such as FGF23, FEP/FGF23, TRP and Klotho, with a rapid decline of renal function in kidney allograft recipients

Phosphocalcic Markers and Calcification Propensity for Assessment of Interstitial Fibrosis and Vascular Lesions in Kidney Allograft Recipients

Renal interstitial fibrosis and arterial lesions predict loss of function in chronic kidney disease. Noninvasive estimation of interstitial fibrosis and vascular lesions is currently not available. The aim of the study was to determine whether phosphocalcic markers are associated with, and can predict, renal chronic histological changes. We included 129 kidney allograft recipients with an available transplant biopsy in a retrospective study. We analyzed the associations and predictive values of phosphocalcic markers and serum calcification propensity (T50) for chronic histological changes (interstitial fibrosis and vascular lesions). PTH, T50 and vitamin D levels were independently associated to interstitial fibrosis. PTH elevation was associated with increasing interstitial fibrosis severity (r = 0.29, p = 0.001), while T50 and vitamin D were protective (r = -0.20, p = 0.025 and r = -0.23, p = 0.009 respectively). On the contrary, fibroblast growth factor 23 (FGF23) and Klotho correlated only modestly with interstitial fibrosis (p = 0.045) whereas calcium and phosphate did not. PTH, vitamin D and T50 were predictors of extensive fibrosis (AUC: 0.73, 0.72 and 0.68 respectively), but did not add to renal function prediction. PTH, FGF23 and T50 were modestly predictive of low fibrosis (AUC: 0.63, 0.63 and 0.61) but did not add to renal function prediction. T50 decreased with increasing arterial lesions (r = -0.21, p = 0.038). The discriminative performance of T50 in predicting significant vascular lesions was modest (AUC 0.61). In summary, we demonstrated that PTH, vitamin D and T50 are associated to interstitial fibrosis and vascular lesions in kidney allograft recipients independently of renal function. Despite these associations, mineral metabolism indices do not show superiority or additive value to fibrosis prediction by eGFR and proteinuria in kidney allograft recipients, except for vascular lesions where T50 could be of relevance

Associations of serum biomarkers with interstitial fibrosis in kidney allograft recipients (n = 129).

<p>Univariate and multivariate linear regression analysis.</p

Associations of T₅₀ with vascular lesions in kidney allograft recipients (n = 129), univariate and multivariate linear regression analysis.

<p>Associations of T₅₀ with vascular lesions in kidney allograft recipients (n = 129), univariate and multivariate linear regression analysis.</p

ROC curves of ln FGF23, ln PTH, T₅₀, proteinuria and eGFR in predicting fibrosis ≤20%.

<p>ROC curve analysis of ln FGF23 (Fig 2A), ln PTH (Fig 2B), T₅₀ (Fig 2C), proteinuria (Fig 2D), eGFR (Fig 2E) for the prediction of fibrosis ≤20%. (2F): ROC cuvre analysis of ln FGF23, ln PTH and T₅₀ combined for the prediction of fibrosis ≤20%. As T₅₀ and eGFR are markers that are negatively associated with fibrosis, we used the opposite values of those markers. AUC: Area Under the Curve; eGFR: estimated Glomerular Filtration Rate; FGF23: Fibroblast growth factor 23; Ln: log-transformed; PTH: parathyroid hormone; ROC: Receiver Operating Characteristic; T₅₀: Calcification propensity.</p