A Lifetime of Allograft Function with Kidneys from Older Donors.

Strategies to increase expanded criteria donor (ECD) transplantation are needed. We quantified the extent to which ECD kidneys provide recipients with a lifetime of allograft function by determining the difference between patient survival and death-censored allograft survival (graft survival). Initial analyses compared 5-year outcomes in the Eurotransplant Senior Program (European) and the United States Renal Data System. Among European recipients ≥65 years, patient survival exceeded graft survival, and ECD recipients returned to dialysis for an average of 5.2 months after transplant failure. Among United States recipients ≥60 years, graft survival exceeded patient survival. Although patient survival in elderly recipients in the United States was low (49% at 5 years), the average difference in patient survival at 10 years in elderly recipients in the United States with an ECD versus non-ECD transplant was only 7 months. The probability of patient survival with a functioning allograft at 5 years was higher with ECD transplantation within 1 year after activation to the waiting list than with delayed non-ECD transplantation ≥3 years after activation to the waiting list. Subsequent analyses demonstrated that ECD transplants do not provide a lifetime of allograft function in recipients <50 years in the United States. These findings should encourage ECD transplantation in patients ≥60 years, demonstrate that rapid ECD transplantation is superior to delayed non-ECD transplantation, and challenge the policy in the United States of allowing patients <50 years to receive an ECD transplant.

Skin changes following organ transplantation: an interdisciplinary challenge.

BACKGROUND: The immunosuppressants used in transplantation medicine significantly elevate the incidence of neoplasia, particularly in the skin. The cumulative incidence of non-melanocytic skin cancer (NMSC) in renal transplant recipients was 20.5% in a study carried out in German centers. Data on more than 35 000 renal transplant recipients in the USA document a cumulative NMSC incidence of over 7% after 3 years of immunosuppression. METHOD: The authors selectively review publications obtained by a PubMed search to discuss the incidence of, and major risk factors for, skin tumors and infectious diseases of the skin in immunosuppressed patients. RESULTS: The main risk factors for skin tumors are age at the time of transplantation, light skin color, previous and present exposure to sunlight, and the type and duration of immunosuppressive treatment. Squamous-cell carcinoma (SCC) is the most common kind of skin tumor in immunosuppressed patients. Human herpesvirus 8 and Merkel-cell polyoma virus also cause neoplasia more often in immunosuppressed patients than in the general population. Surgical excision is the treatment of choice. Actinic keratosis markedly elevates the risk that SCC will arise in the same skin area (odds ratio 18.36, 95% confidence interval 3.03-111). Patients with multiple actinic keratoses can be treated with photodynamic therapy or with acitretin. To lower the skin cancer risk, organ transplant recipients should apply medical screening agents with a sun protection factor of at least 50 to exposed skin areas every day. 55% to 97% of organ transplant recipients have skin infections; these are treated according to their respective types. CONCLUSION: Squamous-cell carcinoma of the skin adds to the morbidity and mortality of transplant recipients and is therefore among the major oncological challenges in this patient group. Structured concepts for interdisciplinary care enable risk-adapted treatment.

Prevalence of occult hepatitis C infection in chronic hemodialysis and kidney transplant patients.

BACKGROUND & AIMS: Detection of hepatitis C virus (HCV) RNA in peripheral blood mononuclear cells (PBMC) and/or hepatocytes in absence of HCV RNA in serum, designated as 'occult HCV infection', has been a matter of controversy in recent years. We investigated for the first time the prevalence of occult HCV infection in large cohorts of chronic hemodialysis (CHD) and kidney transplant (KTx) patients. METHODS: We enrolled 417 CHD patients, 417 KTx recipients and 2 control groups - 25 anti-HCV (antibody against HCV)-positive and HCV RNA-positive patients with chronic hepatitis C, and 40 anti-HCV-, HCV RNA-, and HBsAg-negative healthy subjects. HCV RNA was tested in serum and PBMC using a sensitive commercial assay. RESULTS: In CHD patients, the prevalence of anti-HCV was 3.6% (15/417) and of positive serum HCV RNA 2.4% (10/417). HCV RNA was detected in PBMC in 1/407 (0.25%) HCV serum RNA-negative patients ("occult HCV infection"). In KTx recipients, prevalence of anti-HCV was 4.8% (20/417) and of positive serum HCV RNA 4.6% (19/417). Occult HCV infection was found in 2/398 (0.5%) serum HCV RNA-negative patients. On a mean longitudinal follow-up of 30months of the 3 patients with occult HCV infection, there was no clinical or virological evidence of HCV infection. CONCLUSIONS: The prevalence of occult HCV infection was very low in our CHD and KTx patients, and it did not appear to be clinically relevant. Further studies in geographic populations with high HCV endemicity are required to clarify the significance of occult HCV infection in these patient groups.

Potential lifetime cost-effectiveness of catheter-based renal sympathetic denervation in patients with resistant hypertension.

AIMS: Recent studies have demonstrated the safety and efficacy of catheter-based renal sympathetic denervation (RDN) for the treatment of resistant hypertension. We aimed to determine the cost-effectiveness of this approach separately for men and women of different ages. METHODS AND RESULTS: A Markov state-transition model accounting for costs, life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness was developed to compare RDN with best medical therapy (BMT) in patients with resistant hypertension. The model ran from age 30 to 100 years or death, with a cycle length of 1 year. The efficacy of RDN was modelled as a reduction in the risk of hypertension-related disease events and death. Analyses were conducted from a payer's perspective. Costs and QALYs were discounted at 3% annually. Both deterministic and probabilistic sensitivity analyses were performed. When compared with BMT, RDN gained 0.98 QALYs in men and 0.88 QALYs in women 60 years of age at an additional cost of €2589 and €2044, respectively. As the incremental cost-effectiveness ratios increased with patient age, RDN consistently yielded more QALYs at lower costs in lower age groups. Considering a willingness-to-pay threshold of €35 000/QALY, there was a 95% probability that RDN would remain cost-effective up to an age of 78 and 76 years in men and women, respectively. Cost-effectiveness was influenced mostly by the magnitude of effect of RDN on systolic blood pressure, the rate of RDN non-responders, and the procedure costs of RDN. CONCLUSION: Renal sympathetic denervation is a cost-effective intervention for patients with resistant hypertension. Earlier treatment produces better cost-effectiveness ratios.

Two novel equations to estimate kidney function in persons aged 70 years or older.

BACKGROUND: In older adults, current equations to estimate glomerular filtration rate (GFR) are not validated and may misclassify elderly persons in terms of their stage of chronic kidney disease. OBJECTIVE: To derive the Berlin Initiative Study (BIS) equation, a novel estimator of GFR in elderly participants. DESIGN: Cross-sectional. Data were split for analysis into 2 sets for equation development and internal validation. SETTING: Random community-based population of a large insurance company. PARTICIPANTS: 610 participants aged 70 years or older (mean age, 78.5 years). INTERVENTION: Iohexol plasma clearance measurement as gold standard. MEASUREMENTS: GFR, measured as the plasma clearance of the endogenous marker iohexol, to compare performance of existing equations of estimated GFR with measured GFR of the gold standard; estimation of measured GFR from standardized creatinine and cystatin C levels, sex, and age in the learning sample; and comparison of the BIS equations (BIS1: creatinine-based; BIS2: creatinine- and cystatin C-based) with other estimating equations and determination of bias, precision, and accuracy in the validation sample. RESULTS: The new BIS2 equation yielded the smallest bias followed by the creatinine-based BIS1 and Cockcroft-Gault equations. All other equations considerably overestimated GFR. The BIS equations confirmed a high prevalence of persons older than 70 years with a GFR less than 60 mL/min per 1.73 m2 (BIS1, 50.4%; BIS2, 47.4%; measured GFR, 47.9%). The total misclassification rate for this criterion was smallest for the BIS2 equation (11.6%), followed by the cystatin C equation 2 (15.1%) proposed by the Chronic Kidney Disease Epidemiology Collaboration. Among the creatinine-based equations, BIS1 had the smallest misclassification rate (17.2%), followed by the Chronic Kidney Disease Epidemiology Collaboration equation (20.4%). LIMITATION: There was no validation by an external data set. CONCLUSION: The BIS2 equation should be used to estimate GFR in persons aged 70 years or older with normal or mild to moderately reduced kidney function. If cystatin C is not available, the BIS1 equation is an acceptable alternative. PRIMARY FUNDING SOURCE: Kuratorium für Dialyse und Nierentransplatation (KfH) Foundation of Preventive Medicine.

Vitamin D status and mortality of German hemodialysis patients.

AIM: The goal was to analyze the link between blood levels of calcidiol and all-cause, cardiac and infectious diseases, and mortality due to cancer in hemodialysis patients. PATIENTS AND METHODS: This study retrospectively evaluated a representative sub-cohort (n=6,518) of German hemodialysis patients from the incidence cohorts 1997-2006. RESULTS: Most (58.8%) were found to be vitamin D deficient (25(OH)D<20 ng/ml), with 41.2% being severely deficient (25(OH)D<12.5 ng/ml). All-cause mortality risk more than doubled in patients with severe deficiency (adjusted odds ratio (aOR)=2.67; 95% confidence interval (CI)=2.30-3.10; p<0.0001). Comparable data were obtained for mortality from cardiac disease (aOR=1.57; 95% CI=1.30-1.88; p<0.0001), infectious disease (aOR=1.48; 95% CI=1.15-1.90; p=0.0026), and cancer (aOR=1.51; 95% CI=1.09-2.08; p=0.0121), respectively. CONCLUSION: These data highlight the need to ensure primarily adequate 25(OH)D levels in dialysis patients for an advantage of survival.

Overlapping pathways to transplant glomerulopathy: chronic humoral rejection, hepatitis C infection, and thrombotic microangiopathy.

Transplant glomerulopathy (TG) has received much attention in recent years as a symptom of chronic humoral rejection; however, many cases lack C4d deposition and/or circulating donor-specific antibodies (DSAs). To determine the contribution of other causes, we studied 209 consecutive renal allograft indication biopsies for chronic allograft dysfunction, of which 25 met the pathological criteria of TG. Three partially overlapping etiologies accounted for 21 (84%) cases: C4d-positive (48%), hepatitis C-positive (36%), and thrombotic microangiopathy (TMA)-positive (32%) TG. The majority of patients with confirmed TMA were also hepatitis C positive, and the majority of hepatitis C-positive patients had TMA. DSAs were significantly associated with C4d-positive but not with hepatitis C-positive TG. The prevalence of hepatitis C was significantly higher in the TG group than in 29 control patients. Within the TG cohort, those who were hepatitis C-positive developed allograft failure significantly earlier than hepatitis C-negative patients. Thus, TG is not a specific diagnosis but a pattern of pathological injury involving three major overlapping pathways. It is important to distinguish these mechanisms, as they may have different prognostic and therapeutic implications.

Specific removal of C-reactive protein by apheresis in a porcine cardiac infarction model.

BACKGROUND: C-reactive protein (CRP) is a possible causative factor of the destructive processes observed during the weeks after myocardial infarction. METHODS: We developed a clinically relevant animal model including the removal of CRP from blood plasma utilizing a specific CRP adsorber and the visualization of the infarct scar in the living animal by cardiovascular magnetic resonance imaging as a tool to investigate the impact of CRP after acute myocardial infarction. RESULTS: We describe the facets of this model system and kinetics of clinical blood parameters like CRP and troponin. In addition, we demonstrate the potency of CRP apheresis reducing CRP levels by ~70% in the established treatment system. CONCLUSION: We showed for the first time that it is possible to conduct apheresis at the following 2 days after acute myocardial infarction in a porcine infarction model and to analyze the infarct by cardiovascular magnetic resonance imaging at day 1 and 14.

Acute rejection in low-toxicity regimens: clinical impact and risk factors in the Symphony study.

The Symphony study assessed whether mycophenolate mofetil (MMF)-based regimens containing reduced doses of adjunct immunosuppressants could reduce toxicity while maintaining efficacy. Here, we examined the impact of acute rejection and associated risk factors. The incidence of biopsy-proven acute rejection in the low-dose tacrolimus group was approximately half that of the standard-dose cyclosporine and low-dose cyclosporine groups, and a third of that in the low-dose sirolimus group. The low-dose cyclosporine group had more severe rejection episodes (≥grade II) compared with other groups. Acute rejection was associated with a 10 mL/min glomerular filtration rate (GFR) reduction and a 5.3% absolute increase in graft loss at 12 months. Overall, the highest GFR was found in both rejecters and non-rejecters receiving low-dose tacrolimus, both in an intent-to-treat analysis and in patients successfully treated according to the protocol. In Cox regression models, human leukocyte antigen (HLA) mismatches and expanded criteria donors increased the acute rejection risk, while recipient age, living related donor, and MMF dose were associated with a reduced risk. Acute rejection was associated with worse outcome but did not entirely explain the differences among the treatment groups. The 2 g MMF plus low-dose tacrolimus combination appears to be the most efficient of all regimens examined regardless of acute rejection.

Low toxicity regimens in renal transplantation: a country subset analysis of the Symphony study.

Regional transplant practices may affect clinical outcomes within multinational studies. This study evaluated whether the overall results from the Symphony study can be generalized to the participating countries. De novo adult renal transplant recipients (n = 1645) were randomized to receive standard-dose cyclosporine, or daclizumab induction plus low-dose cyclosporine, low-dose tacrolimus,or low-dose sirolimus, all in addition to mycophenolate mofetil and steroids. Data for the highest patient-recruiting countries, Spain (n = 275),Germany (n = 316) and Turkey (n = 258), were compared. Patient transplant characteristics were different among the country subsets; only deceased donors in Spain, more expanded criteria donors in Germany, and mainly living donors in Turkey. Efficacy results for the three countries were consistent with that of the overall study - renal function and biopsy-proven acute rejection (BPAR)rates were superior with low-dose tacrolimus. Turkey had higher mean calculated glomerular filtration rate across all treatment groups (60.6-72.2 ml/min)compared with that of Spain (51.1-57.5 ml/min) and Germany (51.3-62.9 ml/min). Spain and Turkey had lower BPAR rates across the four treatment groups compared with the overall study; Germany had much higher rates(21.0-54.2%). These findings confirm the general applicability of the Symphony study results and highlight the importance of inclusion of patients from different geographic origins in randomized clinical trials.

Thrombin activity throughout the acute phase of acute ST-elevation myocardial infarction and the relation to outcome.

BACKGROUND: Thrombin and plasmin play a central role in ongoing thrombosis and platelet activation in patients with acute ST-elevation myocardial infarction (STEMI). Data of thrombin and plasmin activity in the early course of STEMI and the relation to outcome are scarce. METHODS: We included 68 consecutive patients (53 male, 59 +/- 11.4 years) with STEMI who underwent acute catheter-based reperfusion therapy within the first 12 h after onset of symptoms. Blood samples were taken at admission and after 4, 8, 12 and 24 h. Thrombin activity and generation was measured by changes in the thrombin/antithrombin-III complex (TAT) and prothrombin fragment (F1.2); plasmin was measured by changes in the plasmin-alpha(2)/antiplasmin complex (PAP). A follow-up with respect to the combined primary endpoint consisting of death, acute myocardial infarction or urgent need for revascularization up to 6 weeks post-discharge was carried out. RESULTS: TAT values showed no significant change over time in patients with and without the primary endpoint but there was a borderline difference between these groups at 4 h after admission (event group 9.0 vs no event group 4.7 microg l(-1), p = 0.057). F1.2 values were different between groups only after 24 h (event group 1.5 vs no event group 0.9 nmol l(-1), p = 0.028) and did not differ in serial sampling of 24 h. PAP values were higher in patients with events after 4 and 8 h and declined over time in the group without events (p <0.001). Odds ratios (OR) with respect to the primary endpoint were highest for TAT >4.8 microg l(-1) at 0 h and TAT >8.4 microg l(-1) at 4 h (OR 7.1, 95% confidence interval (CI) 1.5-34, p = 0.015 and OR 5.5, 95% CI 1.5-20.0, p = 0.01, respectively). The predictive value of plasmin concentrations were equally high after 4 h (PAP >962 microg l(-1); OR 6.8, 95% CI 1.8-26.2, p = 0.005) and 8 h (PAP >495 microg l(-1), OR 6.7, 95% CI 1.4-32.9, p = 0.024). Values for F1.2 were only predictive after 24 h (F1.2 >0.85 nmol l(-1), OR 13, 95% CI 1.4-117.8, p = 0.023). CONCLUSIONS: Markers of thrombin and plasmin activity in acute STEMI are related to outcome. The marker for thrombin generation F1.2 becomes a significant predictor of outcome at 24 h after admission, reflecting the potentially adverse effects of ongoing thrombin generation. This underlines the potential for direct thrombin inhibition and individualization of treatment by thrombin markers in STEMI.

The predictive performance of plasma neutrophil gelatinase-associated lipocalin (NGAL) increases with grade of acute kidney injury.

BACKGROUND: In adult cardiac surgery, the predictive value for AKI of neutrophil gelatinase-associated lipocalin (NGAL) appears to have wide variability. The choice of definition of acute kidney injury (AKI) might, at least in part, account for such variability. METHODS: In a prospective study of 100 adult cardiac surgery patients, we assessed the value of postoperative plasma NGAL in predicting AKI according to the degree of severity used for its definition. RESULTS: The predictive value of plasma NGAL varied according to the AKI definition used and was higher for more severe AKI (increase in creatinine >50%: mean AUC-ROC 0.79 +/- 0.01) compared to less severe AKI (>25%: mean AUC-ROC 0.65 +/- 0.02); P = 0.001. The discriminatory ability of NGAL for AKI also increased with increasing RIFLE classes (AUC-ROC R: 0.72, I: 0.79, F: 0.80) or AKIN stages (AUC-ROC 1: 0.75, 2: 0.78, 3: 0.81); P = 0.015. It was highest for the prediction of renal replacement therapy (AUC-ROC: 0.83). CONCLUSIONS: In adult cardiac surgery patients, the predictive value of NGAL increases with grade of AKI. This observation needs to be taken into account when interpreting any future studies of this biomarker.

Potent early immune response after kidney transplantation in patients of the European senior transplant program.

BACKGROUND: The increasing age of organ donors and the transplantation of older recipients have become clinical practice. Age-adapted immunosuppressive protocols considering these changes are currently not established. This study analyzed the age-dependent immune response after human kidney transplantation. METHODS: One hundred renal allograft recipients were prospectively evaluated from 2004 to 2005. Patients older than 65 years of the European Senior Program receiving kidneys from donors older than 65 years were compared with recipients younger than 65 years receiving kidneys from donors younger than 65 years. Age-dependent modifications of the immune response were evaluated before transplantation and 7 days and 6 months after grafting by flow cytometry analysis of lymphocyte surface markers in peripheral blood. The cytokine pattern was determined by Cytometric Bead Array, T-cell alloreactivity by enzyme-linked immunospot analysis. RESULTS: There were no differences between the groups regarding patient survival, graft survival, and function at 6 months after transplantation. Before transplantation, 7 days and 6 months thereafter recipients older than 65 years demonstrated significantly elevated numbers of memory T-cells while counts for naive T-cells were significantly reduced. Numbers of activated cytotoxic cells were elevated with increasing age before and 7 days after transplantation. T-cell alloreactivity was more pronounced in older recipients at all time points. Seven days after transplantation tumor necrosis factor-alpha (TNF-alpha) levels were significantly higher, whereas TNF-alpha and interleukin-10 (IL-10) concentrations were significantly reduced after 6 months in older recipients. CONCLUSIONS: Our data demonstrate an initially pronounced immune response in elderly recipients receiving grafts from elderly donors. This observation supports the concept of a donor and recipient age-adapted immunosuppression.

Anaemia management with subcutaneous epoetin delta in patients with chronic kidney disease (predialysis, haemodialysis, peritoneal dialysis): results of an open-label, 1-year study.

BACKGROUND: Anaemia is common in patients with chronic kidney disease (CKD) and can be managed by therapy with erythropoiesis-stimulating agents (ESAs). Epoetin delta (DYNEPO, Shire plc) is the only epoetin produced in a human cell line. The aim of this study was to demonstrate the safety and efficacy of subcutaneously administered epoetin delta for the management of anaemia in CKD patients (predialysis, peritoneal dialysis or haemodialysis) METHODS: This was a 1-year, multicentre, open-label study. Patients had previously received epoetin subcutaneously and were switched to epoetin delta at an identical dose to their previous therapy. Dose was titrated to maintain haemoglobin at 10.0-12.0 g/dL. The primary endpoint was mean haemoglobin over Weeks 12-24. Secondary analyses included long-term haemoglobin, haematocrit and dosing levels. Safety was assessed by monitoring adverse events, laboratory parameters and physical examinations. RESULTS: In total 478 patients received epoetin delta, forming the safety-evaluable population. Efficacy analyses were performed on data from 411 of these patients. Mean +/- SD haemoglobin over Weeks 12-24 was 11.3 +/- 1.1 g/dL. Mean +/- SD weekly dose over Weeks 12-24 was 84.4 +/- 72.7 IU/kg. Haemoglobin levels were maintained for the duration of the study. Epoetin delta was well tolerated, with adverse events occurring at rates expected for a CKD patient population; no patient developed anti-erythropoietin antibodies. CONCLUSION: Subcutaneously administered epoetin delta is an effective and well-tolerated agent for the management of anaemia in CKD patients, irrespective of dialysis status. TRIAL REGISTRATION: http://www.controlled-trials.com ISRCTN68321818.

Hyperosmotic stress enhances cytokine production and decreases phagocytosis in vitro.

INTRODUCTION: Hyperglycemia is associated with negative outcomes in various settings of critical illness; infectious complications, especially, seem to be increased. On the other hand, intensive insulin therapy (IIT) has been shown to improve outcome in clinical trials. Whether normoglycemia itself or the application of insulin is responsible for the observed findings is unknown. We therefore tested the effect of glucose and insulin on various immune functions in vitro. METHODS: Human peripheral blood mononuclear cells (PBMCs) were incubated ex vivo with low doses of lipopolysaccharide (LPS). PBMCs were incubated with various osmotic agents, insulin, or a combination of both. Interleukin (IL)-6 and IL-1 cytokine response was measured by enzyme-linked immunosorbent assay. In addition, we investigated the effects of glucose on phagocytosis and oxidative burst in human granulocytes. RESULTS: Increasing concentrations of both glucose and mannitol significantly enhanced LPS-induced cytokine production. Insulin alone did not alter cytokine production and had only a minor influence in combination with glucose. Phagocytosis and oxidative burst were significantly reduced with increasing concentrations of glucose and mannitol. CONCLUSION: Hyperglycemia may lead to inflammation by enhancing cytokine production via the direct effects of hyperosmotic stress. Impaired phagocytosis and oxidative burst under hyperglycemia may weaken defense mechanisms of the host. Our in vitro findings may help to explain the beneficial effects of IIT not only in diabetic but also in critically ill patients.

Activation of hypoxia-inducible factors ameliorates hypoxic distal tubular injury in the isolated perfused rat kidney.

BACKGROUND: Preconditional activation of HIF with specific prolyl-hydroxylase inhibitors (PHD-I) attenuates proximal tubular injury, induced by warm ischaemia/ reperfusion (Bernhardt, JASN, 2006). Distal tubular damage occurs in humans with acute kidney injury (AKI), in experimental contrast media-induced nephropathy (CIN), as well as in cell-free isolated perfused kidneys (IPKs). Since in the IPK distal tubular damage inversely correlates with HIF activation (Rosenberger, KI, 2005), we explored the potential of PHD-I to improve morpho-functional outcome in this model. METHODS: Male SD rats were randomly given the synthetic PHD-inhibitor FG-4497 (FibroGen, 50 mg/kg IV) or its vehicle (CTR, n = 10 per group). Six hours later, the right kidney was perfused for 90 min with cell-free oxygenated medium and subsequently perfusion-fixed for morphologic assessment. The left kidney was used for HIF immunostaining. RESULTS: As compared with CTR kidneys, at 6 h after FG-4497 HIF-alpha isoforms were markedly up-regulated in all renal zones: HIF-1alpha in tubules and in papillary interstitial cells (IC), HIF-2alpha in IC and vascular endothelial cells. FG-4497 treatment resulted in a higher perfusate flow rate (P < 0.04, ANOVA). Tubular injury to medullary thick ascending limbs (mTALs) was significantly attenuated in the treatment versus control group (38.9 +/- 7.4% versus 62.7 +/- 4.9% of mTALs in the mid-inner stripe (P < 0.02); 23.8 +/- 6.8% versus 45.6 +/- 7.4% in the innermost zone of the inner stripe (P < 0.05). CONCLUSIONS: These findings illustrate that PHD-I preconditioning attenuates hypoxic distal tubular injury produced in the IPK in the same fashion in which it protects proximal tubules. mTAL conservation may be related to the stabilization of cellular HIF, as well as to preserved endothelial function and microcirculation.

Biocompatibility of a bicarbonate-buffered amino-acid-based solution for peritoneal dialysis.

Amino-acid-based peritoneal dialysis (PD) fluids have been developed to improve the nutritional status of PD patients. As they may potentially exacerbate acidosis, an amino-acid-containing solution buffered with bicarbonate (Aminobic) has been proposed to effectively maintain acid-base balance. The aim of this study was to evaluate the mesothelial biocompatibility profile of this solution in comparison with a conventional low-glucose-based fluid. Omentum-derived human peritoneal mesothelial cells (HPMC) were preexposed to test PD solutions for up to 120 min, then allowed to recover in control medium for 24 h, and assessed for heat-shock response, viability, and basal and stimulated cytokine [interleukin (IL)-6] and prostaglandin (PGE(2)) release. Acute exposure of HPMC to conventional low-glucose-based PD solution resulted in a time-dependent increase in heat-shock protein (HSP-72) expression, impaired viability, and reduced ability to release IL-6 in response to stimulation. In contrast, in cells treated with Aminobic, the expression of HSP-72 was significantly lower, and viability and cytokine-producing capacity were preserved and did not differ from those seen in control cells. In addition, exposure to Aminobic increased basal release of IL-6 and PGE(2). These data point to a favorable biocompatibility profile of the amino-acid-based bicarbonate-buffered PD solution toward HPMC.

Development of an optimized multimarker strategy for early risk assessment of patients with acute coronary syndromes.

BACKGROUND: A multitude of biomarkers have been suggested for early risk-assessment in patients admitted to the emergency department with suspected acute coronary syndromes. We used logistic regression synergistically with classification and regression tree (CART) analysis to define a multimarker strategy and the cut-off values and sequencing needed to optimize risk stratification in a low to moderate risk population of the emergency department. METHODS: 432 unselected patients (59.7+/-14.5 y, 60.4% male) admitted to the emergency department (ED) with acute coronary syndromes (ACS) were enrolled. Cardiac troponin I (cTnI), N-terminal pro-B-Type natriuretic peptide (NT-proBNP), high sensitivity C-reactive protein (hsCRP), placental growth factor (PlGF), lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and D-dimers were measured by immunoassay and whole blood choline (WBCHO) and plasma choline (PLCHO) were measured using LC/MS from baseline samples. Logistic regression and CART analysis were used to define the importance of the various biomarkers tested and to define their hierarchy with respect to the prediction of major adverse cardiac events (MACE; cardiac death, non-fatal MI, unstable angina, CHF requiring admission, urgent PCI and CABG) over the 42-day follow-up period. RESULTS: A combination of NT-proBNP, WBCHO and Lp-PLA2 with cutoffs identified by CART-analysis was optimal for risk-stratification and superior to all other possible combinations of markers. Increased concentrations of both NT-proBNP (>1400 ng/l) and WBCHO (>21 micromol/l) identified patients with very high risk (RR=2.4, 39% primary endpoint) while low concentrations of NT-proBNP (< or = 1400 ng/l), WBCHO (< or = 17 micromol/l) and LP-PLA2 (< or = 210 microg/l) indicated very low risk (0% primary endpoint). WBCHO > 17 micromol/l additionally identified a subgroup with intermediate risk (RR=3.0, 13.5% primary endpoint) in patients with NT-proBNP concentrations < or = 1400 ng/l. Troponin when increased was highly prognostic but was not often positive in this early cohort. CONCLUSIONS: A multimarker strategy defined synergistically by logistic regression and by classification and regression tree (CART) analysis can stratify patients into risk groups ranging from very low risk (0% MACE) to very high risk (39.5% MACE) based on admission values.