Isidor Minovic

Iron Deficiency, Anemia and Mortality in Renal Transplant Recipients

Anemia, iron deficiency anemia (IDA), and iron deficiency (ID) are highly prevalent in renal transplant recipients (RTR). Anemia is associated with poor outcome, but the role of ID is unknown. Therefore, we aimed to investigate the association of ID, irrespective of anemia, with all-cause mortality in RTR. Cox regression analyses were used to investigate prospective associations. In 700 RTR, prevalences of anemia, IDA, and ID were 34%, 13%, and 30%, respectively. During follow-up for 3.1 (2.7-3.9) years, 81 (12%) RTR died. In univariable analysis, anemia [HR, 1.72 (95%CI: 1.11-2.66), P = 0.02], IDA [2.44 (1.48-4.01), P < 0.001], and ID [2.04 (1.31-3.16), P = 0.001] were all associated with all-cause mortality. In multivariable analysis, the association of anemia with mortality became weaker after adjustment for ID [1.52 (0.97-2.39), P = 0.07] and disappeared after adjustment for proteinuria and eGFR [1.09 (0.67-1.78), P = 0.73]. The association of IDA with mortality attenuated after adjustment for potential confounders. In contrast, the association of ID with mortality remained independent of potential confounders, including anemia [1.77 (1.13-2.78), P = 0.01]. In conclusion, ID is highly prevalent among RTR and is associated with an increased risk of mortality, independent of anemia. As ID is a modifiable factor, correction of ID could be a target to improve survival.

The fate of sulfate in chronic heart failure

New leads to advance our understanding of heart failure (HF) pathophysiology are urgently needed. Previous studies have linked urinary sulfate excretion to a favorable cardiovascular risk profile. Sulfate is not only the end product of hydrogen sulfide metabolism but is also directly involved in various (patho)physiological processes, provoking scientific interest in its renal handling. This study investigates sulfate clearance in chronic HF (CHF) patients and healthy individuals and considers its relationship with disease outcome. Parameters related to renal sulfate handling were determined in and compared between 96 previously characterized CHF patients and sex-matched healthy individuals. Among patients, sulfate clearance was analyzed for associations with clinical and outcome parameters. In CHF patients, plasma sulfate concentrations are significantly higher, whereas 24-h urinary excretion, fractional excretion, and clearance of sulfate are significantly lower, compared with healthy individuals. Among patients, sulfate clearance is independently associated with diuretics use, creatinine clearance and 24-h urinary sodium excretion. Sulfate clearance is associated with favorable disease outcome [hazard ratio per SD increase 0.38 (95% confidence interval 0.23-0.63), P < 0.001]. Although significance was lost after adjustment for creatinine clearance, the decrease of sulfate clearance in patients is independent of this parameter, indicating that sulfate clearance is not merely a reflection of renal function. This exploratory study reveals aberrant sulfate clearance as a potential contributor to CHF pathophysiology, with reduced levels in patients and a positive association with favorable disease outcome. Further research is needed to unravel the nature of its involvement and to determine its potential as a biomarker and target for therapy.NEW & NOTEWORTHY Sulfate clearance is decreased in chronic heart failure patients compared with healthy individuals. Among patients, sulfate clearance is positively associated with favorable disease outcome, i.e., a decreased rehospitalization rate and increased patient survival. Hence, decreased sulfate clearance may be involved in the pathophysiology of heart failure.

Circulating Haptoglobin and Metabolic Syndrome in Renal Transplant Recipients

Haptoglobin (Hp) is an acute phase protein that has recently been linked to components of the metabolic syndrome (MetS). We aimed to evaluate Hp as marker of MetS, and to assess its association with long-term outcome in renal transplant recipients (RTR). We measured plasma Hp in a prospective cohort of 699 stable RTR and 149 healthy controls. Median plasma Hp concentration in RTR was 1.4 [interquartile range (IQR), 1.0–1.8] g/L, which was higher compared to 1.1 [0.9–1.4] g/L in controls (P < 0.001). Hp was independently associated with the MetS (β = 0.10) (P = 0.005). During follow-up of 5.4 [4.8–6.1] years, 150 (21%) recipients died, of whom 60 (9%) due to cardiovascular causes, and 83 (12%) RTR developed graft failure. High (≥2.0 g/L) and low (≤0.9 g/L) plasma Hp were associated with increased risk of mortality (HR’s 2.3 [1.3–4.1] and 1.9 [1.0–3.5], resp.), predominantly cardiovascular. The association of high Hp lost significance upon adjustment for inflammation markers (HR 1.5 [0.8–2.7]), while low Hp was independently associated with mortality (HR 2.2 [1.2–4.0]). Hp was not associated with graft failure (P = 0.49). In conclusion, plasma Hp is independently associated with MetS in RTR. Importantly, high and low Hp are associated with increased mortality risk, independent of MetS.

Author Correction : Circulating Haptoglobin and Metabolic Syndrome in Renal Transplant Recipients

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.Citation for published version (APA): Minovic, I., Eisenga, M. F., Riphagen, I. J., van den Berg, E., Kootstra-Ros, J., Frenay, A-R. S., ... Bakker, S. J. L. (2018). Circulating Haptoglobin and Metabolic Syndrome in Renal Transplant Recipients (vol 7, 14264, 2017): Circulating Haptoglobin and Metabolic Syndrome in Renal Transplant Recipients. Scientific Reports, 8(1), 6501. [6501]. https://doi.org/10.1038/s41598-018-24791-4, https://doi.org/10.1038/s41598018-24791-4

Renal sulfate reabsorption in healthy individuals and renal transplant recipients

Inorganic sulfate is essential for normal cellular function and its homeostasis is primarily regulated in the kidneys. However, little is known about renal sulfate handling in humans and particularly in populations with impaired kidney function such as renal transplant recipients (RTR). Hence, we aimed to assess sulfate reabsorption in kidney donors and RTR. Plasma and urinary sulfate were determined in 671 RTR and in 251 kidney donors. Tubular sulfate reabsorption (TSR) was defined as filtered load minus sulfate excretion and fractional sulfate reabsorption (FSR) was defined as 1‐fractional excretion. Linear regression analyses were employed to explore associations of FSR with baseline parameters and to identify the determinants of FSR in RTR. Compared to kidney donors, RTR had significantly lower TSR (15.2 [11.2–19.5] vs. 20.3 [16.7–26.3] μmol/min), and lower FSR (0.56 [0.48–0.64] vs. 0.64 [0.57–0.69]) (all P < 0.001). Kidney donation reduced both TSR and FSR by circa 50% and 25% respectively (both P < 0.001). In RTR and donors, both TSR and FSR associated positively with renal function. In RTR, FSR was independently associated with urinary thiosulfate (β = −0.18; P = 0.002), growth hormone (β = 0.12; P = 0.007), the intakes of alcohol (β = −0.14; P = 0.002), methionine (β = −0.34; P < 0.001), cysteine (β = −0.41; P < 0.001), and vitamin D (β = −0.14; P = 0.009). In conclusion, TSR and FSR are lower in RTR compared to kidney donors and both associated with renal function. Additionally, FSR is determined by various dietary and metabolic factors. Future research should determine the mechanisms behind sulfate handling in humans and the prognostic value of renal sulfate reabsorption in RTR.

Lower Renal Function Is Associated With Derangement of 11- Hydroxysteroid Dehydrogenase in Type 2 Diabetes

Abstract Context Derangement of 11-β hydroxysteroid dehydrogenase type 1 and type 2 (11β-HSD1 and 11β-HSD2), which regulate intracellular cortisol production, has been suggested in both type 2 diabetes (T2D) and chronic kidney disease (CKD). However, activity of 11β-HSD enzymes in patients with T2D and CKD has never been assessed. Objectives To compare 11β-HSD activities between patients with T2D and healthy controls, and assess whether in T2D, renal function is associated with 11β-HSD activities. Design Cross-sectional analysis in the Diabetes and Lifestyle Cohort Twente (DIALECT-1). Setting Referral center for T2D. Patients Patient with T2D [n = 373, age 64 ± 9 years, 58% men, 26% of patients estimated glomerular filtration rate (eGFR) <60 mL/min·1.73 m2] and healthy controls (n = 275, age 53 ± 11 years, 48% men). Mean Outcome Measure We measured cortisol, cortisone, and metabolites [tetrahydrocortisol (THF), allo-THF (aTHF), and tetrahydrocortisone (THE)] in 24-hour urine samples. Whole body 11β-HSD and 11β-HSD2 activities were calculated as the urinary (THF + aTHF)/THE and cortisol/cortisone ratios, respectively. Results Patients with T2D had a higher (THF + aTHF)/THE ratio [1.02 (0.84 to 1.27) vs 0.94 (0.79 to 1.0), P < 0.001] and cortisol/cortisone ratio [0.70 (0.58 to 0.83) vs 0.63 (0.54 to 0.74), P < 0.001] than healthy controls. In T2D, lower eGFR was associated with a higher (THF + aTHF)/THE ratio (β = −0.35, P < 0.001), and a higher cortisol/cortisone ratio (β = −0.16, P = 0.001). Conclusions In this real-life secondary care setting of patients with T2D, 11β-HSD enzymes activities were shifted to higher intracellular cortisol production in T2D, which was further aggravated in patients with CKD. Prospective analyses are warranted to investigate causality of these associations.

Is excretion of sulfur metabolites related to risk of cardiovascular events or mortality in the general population

Aims: Thiosulfate and sulfate are metabolites of hydrogen sulfide (H2S), a gaseous signaling molecule with cardiovascular (CV) protective properties. Urinary thiosulfate excretion and sulfate excretion are associated with favorable disease outcome in high-risk patient groups. We investigated the relationship between urinary excretion of sulfur metabolites, and risk of CV events and all-cause mortality in the general population. Results: Subjects (n = 6839) of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study were followed prospectively. At baseline, 24-h urinary excretion of thiosulfate and sulfate was determined. Median urinary thiosulfate and sulfate excretion values were 1.27 (interquartile range [IQR] 0.89-2.37) μmol/24 h and 15.7 (IQR 12.0-20.3) mmol/24 h, respectively. Neither thiosulfate nor sulfate excretion showed an independent association with risk of CV events. Sulfate, but not thiosulfate, was inversely associated with risk of all-cause mortality, independent of potential confounders (hazard ratio 0.73 [95% confidence interval 0.63-0.84], p < 0.001). This association appeared most pronounced for normolipidemic subjects (pinteraction = 0.019). Innovation: The strong association between sulfate excretion and mortality in the general population emphasizes the (patho)physiological importance of sulfate or its precursor H2S. Conclusion: We hypothesize that urinary sulfate excretion, which is inversely associated with all-cause mortality in the general population, holds clinical relevance as a beneficial modulator in health and disease. Antioxid. Redox Signal. 30, 1999-2010.

Urinary Excretion of Sulfur Metabolites and Risk of Cardiovascular Events and All-Cause Mortality in the General Population

Aims: Thiosulfate and sulfate are metabolites of hydrogen sulfide (H2S), a gaseous signaling molecule with cardiovascular (CV) protective properties. Urinary thiosulfate excretion and sulfate excretion are associated with favorable disease outcome in high-risk patient groups. We investigated the relationship between urinary excretion of sulfur metabolites, and risk of CV events and all-cause mortality in the general population. Results: Subjects (n = 6839) of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study were followed prospectively. At baseline, 24-h urinary excretion of thiosulfate and sulfate was determined. Median urinary thiosulfate and sulfate excretion values were 1.27 (interquartile range [IQR] 0.89-2.37) μmol/24 h and 15.7 (IQR 12.0-20.3) mmol/24 h, respectively. Neither thiosulfate nor sulfate excretion showed an independent association with risk of CV events. Sulfate, but not thiosulfate, was inversely associated with risk of all-cause mortality, independent of potential confounders (hazard ratio 0.73 [95% confidence interval 0.63-0.84], p < 0.001). This association appeared most pronounced for normolipidemic subjects (pinteraction = 0.019). Innovation: The strong association between sulfate excretion and mortality in the general population emphasizes the (patho)physiological importance of sulfate or its precursor H2S. Conclusion: We hypothesize that urinary sulfate excretion, which is inversely associated with all-cause mortality in the general population, holds clinical relevance as a beneficial modulator in health and disease. Antioxid. Redox Signal. 30, 1999-2010.

Vitamin and mineral status in chronic fatigue syndrome and fibromyalgia syndrome: A systematic review and meta-analysis

Background Many chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS) patients (35–68%) use nutritional supplements, while it is unclear whether deficiencies in vitamins and minerals contribute to symptoms in these patients. Objectives were (1) to determine vitamin and mineral status in CFS and FMS patients as compared to healthy controls; (2) to investigate the association between vitamin and mineral status and clinical parameters, including symptom severity and quality of life; and (3) to determine the effect of supplementation on clinical parameters. Methods The databases PubMed, EMBASE, Web of Knowledge, and PsycINFO were searched for eligible studies. Articles published from January 1st 1994 for CFS patients and 1990 for FMS patients till March 1st 2017 were included. Articles were included if the status of one or more vitamins or minerals were reported, or an intervention concerning vitamins or minerals was performed. Two reviewers independently extracted data and assessed the risk of bias. Results A total of 5 RCTs and 40 observational studies were included in the qualitative synthesis, of which 27 studies were included in the meta-analyses. Circulating concentrations of vitamin E were lower in patients compared to controls (pooled standardized mean difference (SMD): -1.57, 95%CI: -3.09, -0.05; p = .042). However, this difference was not present when restricting the analyses to the subgroup of studies with high quality scores. Poor study quality and a substantial heterogeneity in most studies was found. No vitamins or minerals have been repeatedly or consistently linked to clinical parameters. In addition, RCTs testing supplements containing these vitamins and/or minerals did not result in clinical improvements. Discussion Little evidence was found to support the hypothesis that vitamin and mineral deficiencies play a role in the pathophysiology of CFS and FMS, and that the use of supplements is effective in these patients. Registration Study methods were documented in an international prospective register of systematic reviews (PROSPERO) protocol, registration number: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015032528.

Ready-to-use parenteral amiodarone: a feasibility study towards a long-term stable product formulation

Objectives To determine the feasibility of preparing a long-term stable ready-to-use parenteral amiodarone formulation using cyclodextrins as dissolution enhancer. Methods A preformulation study was performed with different molar ratios of hydroxypropyl-beta-cyclodextrin (HP-BCD) or sulfobutylether-beta-cyclodextrin (SBE-BCD) to amiodarone in order to investigate enhancement of amiodarones water solubility. Further, effects of pH and temperature on the dissolution rate during production were investigated. Shelf-life was determined for a ready-to-use iso-osmotic preparation of 1.8 mg/mL amiodarone with SBE-BCD in a molar ratio of 1:3. Amiodarone content was assessed using a validated high-pressure liquid chromatography ultraviolet method. Results Amiodarone–SBE-BCD in a molar ratio of 1:3 at pH 4.0–5.0 yielded the best results in terms of increased solubility and dissolution time (90 min). With SBE-BCD, a smaller molar ratio to amiodarone was needed than with HP-BCD. The amiodarone content of the final formulation stored 12 months at 21°C in daylight remained unchanged. Conclusions A ready-to-use or ready-to-administer amiodarone product, prepared in a hospital pharmacy, for intravenous application in an acute clinical setting is a feasible option from a chemical, physical and microbiological point of view. The availability of such a product will have a significant impact on medication safety, and production should therefore be considered.