Cost-effectiveness of home-based screening of the general population for albuminuria to prevent progression of cardiovascular and kidney disease.

Background: Chronic kidney disease (CKD) is often detected late, leading to substantial health loss and high treatment costs. Screening the general population for albuminuria identifies individuals at high risk of kidney events and cardiovascular disease (CVD) who may benefit from early start of preventive interventions. Previous studies on the cost-effectiveness of albuminuria population screening were inconclusive, but were based on survey or cohort data rather than an implementation study, modelled screening as performed by general practitioners rather than home-based screening, and often included only benefits with respect to kidney events. We evaluated the cost-effectiveness of home-based general population screening for increased albuminuria based on real-world data obtained from a prospective implementation study taking into account prevention of CKD as well as CVD events. Methods: We developed an individual-level simulation model to compare home-based screening using a urine collection device with usual care (no home-based screening) in individuals of the general population aged 45-80, based on the THOMAS study (Towards HOMe-based Albuminuria Screening). Cost-effectiveness was assessed from the Dutch healthcare perspective with a lifetime horizon. The costs of the screening process and benefits of preventing CKD progression (dialysis and kidney transplantation) and CVD events (non-fatal myocardial infarction, non-fatal stroke, fatal CVD event) were reflected. Albuminuria detection led to treatment of identified risk factors. The model subsequently simulated CKD progression, the occurrence of CVD events, and death. The risks of experiencing CVD events were calculated using the SCORE2 CKD risk prediction model and individual-level data from the THOMAS study. Relative treatment effectiveness, quality of life scores, resource use, and cost inputs were obtained from literature. Model outcomes were the number of CKD and CVD-related events, total costs, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) per QALY gained by screening versus usual care. All results were obtained through probabilistic analysis. Findings: The absolute difference between screening versus usual care in lifetime probability of dialysis, kidney transplantation, non-fatal myocardial infarction, non-fatal stroke, and fatal CVD events were 0.2%, 0.05%, 0.6%, 0.6%, and 0.2%, respectively. This led to relative decreases compared to usual care in lifetime incidence of these events of 10.7%, 11.1%, 5.1%, 4.1%, and 1.6%, respectively. The incremental costs and QALYs of screening were €1607 and 0.17 QALY, respectively, which led to a corresponding ICER of €9225/QALY. The probability of screening being cost-effective for the Dutch willingness-to-pay threshold for preventive population screening of €20,000/QALY was 95.0%. Implementing the screening in the subgroup of 45-64 years old reduced the ICER (€7946/QALY), whereas implementing screening in the subgroup of 65-80 years old increased the ICER (€10,310/QALY). A scenario analysis assuming treatment optimization in all individuals with newly diagnosed risk factors or known risk factors not within target range reduced the ICER to €7083/QALY, resulting from the incremental costs and QALY gain of €2145 and 0.30, respectively. Interpretation: Home-based screening for increased albuminuria to prevent CVD and CKD events is likely cost-effective. More health benefits can be obtained by screening younger individuals and better optimization of care in individuals identified with newly diagnosed or known risk factors outside target range. Funding: Dutch Kidney Foundation, Top Sector Life Sciences & Health of the Dutch Ministry of Economic Affairs.

Salivary cortisol in the diagnosis of adrenal insufficiency: cost efficient and patient friendly.

Saliva as a diagnostic tool is patient friendly and offers analytical advantages. Hormonal analysis of saliva is not influenced by changes in concentrations of binding globulins as the free concentration of the hormones is measured. Analysis of salivary cortisol is common practice in the diagnostic work-up of hypercortisolism. We investigated the potential role of measuring salivary cortisol when adrenal insufficiency (AI) is suspected, to reduce the numbers of ACTH stimulation tests. Over a period of 6 years, patients undergoing an ACTH stimulation test (tetracosactide, 250 µg) in our hospital were included. Plasma cortisol (Elecsys, Cobas, Roche Diagnostics) and salivary cortisol and cortisone (LC-MS/MS) were determined at t = 0, 30 and 60 min after stimulation. Based on peak plasma cortisol levels, AI was ruled out in 113 patients and was established in 16 patients. Patients without AI displayed maximal salivary cortisol concentrations of 12.6-123.4 nmol/L (95th percentile) after stimulation, as opposed to 0.5-15.2 nmol/L in AI patients. At t = 0 min, a minimal salivary cortisol concentration of 1.0 nmol/L was observed in patients without AI, whereas AI patients had a maximum concentration of 5.9 nmol/L. Using these cut-off values, 34% of the initial patient group could be diagnosed without an ACTH stimulation test (28% >5.9 nmol/L, 6% <1.0 nmol/L). A novel diagnostic algorithm, including early morning salivary cortisol analysis can reduce the numbers of ACTH stimulation tests in patients suspected of AI. This patient-friendly method can thereby reduce total health care costs.

Prevalence of pseudonatremia in a clinical laboratory - role of the water content.

BACKGROUND: Sodium concentration is a frequently used marker to discriminate between differential diagnoses or for clinical follow-up. Pseudonatremia, as a result of indirect ion-selective electrode (ISE) measurements in automated chemistry analyzers, can lead to incorrect diagnosis and treatment. We investigated whether the estimated water content, based on total protein and lipid concentrations, can be used to reduce diagnoses of pseudonatremia. METHODS: Indirect and direct ISE measurements of sodium were compared in blood samples from intensive care unit (ICU) (n = 98) and random non-ICU patients (n = 100). Differences between direct measurements using whole blood and lithium-heparin plasma were also determined. Water content, estimated by a linear combination of total protein and lipid concentrations, was used to correct indirectly measured sodium concentrations. The prevalence of pseudonatremia was evaluated in the ICU patient group. RESULTS: An absolute difference of 3 mmol/L was observed between direct measurements using lithium-heparin plasma and whole blood, with higher concentrations in plasma. Additionally, we observed that differences between indirect and direct measurements displayed a linear relationship with the estimated water content. The prevalence of pseudohypernatremia after indirect measurements (32%) was reduced when measurements were corrected for water content (19%). CONCLUSIONS: In critically ill patients, sodium concentrations should be preferably measured by direct measurements. Whole blood is the preferred material for these measurements. For routine sodium analyses in other patients, correction using the estimated water content appears promising in reducing the prevalence of pseudohypernatremia by indirect measurements.

Biocompatibility and intradiscal application of a thermoreversible celecoxib-loaded poly-N-isopropylacrylamide MgFe-layered double hydroxide hydrogel in a canine model.

INTRODUCTION: Chronic low back pain due to intervertebral disc (IVD) degeneration is associated with increased levels of inflammatory mediators. Current medical treatment consists of oral anti-inflammatory drugs to alleviate pain. In this study, the efficacy and safety of a novel thermoreversible poly-N-isopropylacrylamide MgFe-layered double hydroxide (pNIPAAM MgFe-LDH) hydrogel was evaluated for intradiscal controlled delivery of the selective cyclooxygenase (COX) 2 inhibitor and anti-inflammatory drug celecoxib (CXB). METHODS: Degradation, release behavior, and the ability of a CXB-loaded pNIPAAM MgFe-LDH hydrogel to suppress prostaglandin E2 (PGE2) levels in a controlled manner in the presence of a proinflammatory stimulus (TNF-α) were evaluated in vitro. Biocompatibility was evaluated histologically after subcutaneous injection in mice. Safety of intradiscal application of the loaded and unloaded hydrogels was studied in a canine model of spontaneous mild IVD degeneration by histological, biomolecular, and biochemical evaluation. After the hydrogel was shown to be biocompatible and safe, an in vivo dose-response study was performed in order to determine safety and efficacy of the pNIPAAM MgFe-LDH hydrogel for intradiscal controlled delivery of CXB. RESULTS: CXB release correlated to hydrogel degradation in vitro. Furthermore, controlled release from CXB-loaded hydrogels was demonstrated to suppress PGE2 levels in the presence of TNF-α. The hydrogel was shown to exhibit a good biocompatibility upon subcutaneous injection in mice. Upon intradiscal injection in a canine model, the hydrogel exhibited excellent biocompatibility based on histological evaluation of the treated IVDs. Gene expression and biochemical analyses supported the finding that no substantial negative effects of the hydrogel were observed. Safety of application was further confirmed by the absence of clinical symptoms, IVD herniation or progression of degeneration. Controlled release of CXB resulted in a nonsignificant maximal inhibition (approximately 35 %) of PGE2 levels in the mildly degenerated canine IVDs. CONCLUSIONS: In conclusion, this study showed biocompatibility and safe intradiscal application of an MgFe LDH-pNIPAAM hydrogel. Controlled release of CXB resulted in only limited inhibition of PGE2 in this model with mild IVD degeneration, and further studies should concentrate on application of controlled release from this type of hydrogel in animal models with more severe IVD degeneration.

Engineering skeletal muscle tissues from murine myoblast progenitor cells and application of electrical stimulation.

Engineered muscle tissues can be used for several different purposes, which include the production of tissues for use as a disease model in vitro, e.g. to study pressure ulcers, for regenerative medicine and as a meat alternative (1). The first reported 3D muscle constructs have been made many years ago and pioneers in the field are Vandenburgh and colleagues (2,3). Advances made in muscle tissue engineering are not only the result from the vast gain in knowledge of biochemical factors, stem cells and progenitor cells, but are in particular based on insights gained by researchers that physical factors play essential roles in the control of cell behavior and tissue development. State-of-the-art engineered muscle constructs currently consist of cell-populated hydrogel constructs. In our lab these generally consist of murine myoblast progenitor cells, isolated from murine hind limb muscles or a murine myoblast cell line C2C12, mixed with a mixture of collagen/Matrigel and plated between two anchoring points, mimicking the muscle ligaments. Other cells may be considered as well, e.g. alternative cell lines such as L6 rat myoblasts (4), neonatal muscle derived progenitor cells (5), cells derived from adult muscle tissues from other species such as human (6) or even induced pluripotent stem cells (iPS cells) (7). Cell contractility causes alignment of the cells along the long axis of the construct (8,9) and differentiation of the muscle progenitor cells after approximately one week of culture. Moreover, the application of electrical stimulation can enhance the process of differentiation to some extent (8). Because of its limited size (8 x 2 x 0.5 mm) the complete tissue can be analyzed using confocal microscopy to monitor e.g. viability, differentiation and cell alignment. Depending on the specific application the requirements for the engineered muscle tissue will vary; e.g. use for regenerative medicine requires the up scaling of tissue size and vascularization, while to serve as a meat alternative translation to other species is necessary.

Advanced maturation by electrical stimulation: Differences in response between C2C12 and primary muscle progenitor cells.

Skeletal muscle tissue engineering still does not result in the desired functional properties and texture as preferred for regenerative medicine and meat production applications. Electrical stimulation has been appropriately used as a tool to advance muscle cell maturation in vitro, thereby simulating nerve stimulation, as part of the muscle cell niche in vivo. We first investigated the effects of electrical stimulation protocols in two-dimensional (2D) monolayers of C2C12 and translated these protocols to a three-dimensional (3D) model system, based on a collagen type I/Matrigel(™) hydrogel. More importantly, we addressed the ongoing debate of the translation of results found in cell lines (C2C12) to a primary cell source [muscle progenitor cells (MPCs)] in our 3D system. Striking differences in maturation level were found between the different cell sources. Constructs with MPCs were much more mature than C2C12 constructs, based on developed cross-striations and expression levels of mature myosin heavy chain (MHC) isoforms. Overall, electrical stimulation, when optimally timed, accelerated sarcomere assembly in both 2D and 3D. In addition, MPC constructs were more susceptible to the electrical stimulus, resulting in a shift of MHC expression to slower isoforms.

Effects of a combined mechanical stimulation protocol: Value for skeletal muscle tissue engineering.

Skeletal muscle is an appealing topic for tissue engineering because of its variety in applications for regenerative medicine, in vitro physiological model systems, and in vitro meat production. Besides conventional biochemical cues to promote muscle tissue maturation in vitro, biophysical stimuli are necessary to reach the desired functionality and texture of the engineered tissue. Stretch, caused by active movements of the body, is an important factor present in the niche of muscle progenitor cells in vivo. We therefore investigated the effects of uniaxial ramp stretch (2%) followed by uniaxial intermittent dynamic stretch (4%) on C2C12 and murine muscle progenitor cells in a 2D and 3D environment and found that stretch negatively influenced maturation in all cases, demonstrated by decreased expression of MRFs and sarcomere proteins at the RNA level and a delay in the formation of cross striations. We therefore conclude that the current protocol is not recommended for skeletal muscle tissue engineering purposes.