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Frei U, Daloze P, Vítko Š, Klempnauer J, Reyes-Acevedo R, Titiz I, Fricke L, Bernasconi C, Ekberg H. Acute rejection in low-toxicity regimens: clinical impact and risk factors in the Symphony study. Clin Transplant 2010: 24: 500–509. © 2009 John Wiley & Sons A/S. 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. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Antibodies against MICA antigens and kidney-transplant rejection," by Y. Zou, P. Headings Stastny, C. Süsal, B. Döhler, and G. Opelz in the September 27, 2007 issue.

Cyclosporine (CsA) is a critical-dose drug for which a minor change in absorption can have important clinical implications. Generic formulations of CsA are becoming more widely available, but standard criteria for bioequivalence require only that a single study in healthy volunteers demonstrate that mean pharmacokinetic parameters fall within 80–125% of the mean values for Neoral, the reference formulation of CsA. However, CsA absorption is known to differ between healthy volunteers and transplant patients and between different types of transplant patients, such that standard bioequivalence testing may be inadequate to ensure interchangeability of CsA formulations in all patients. The limited available clinical evidence has shown that stable renal transplant patients receiving Neoral have a significant reduction in mean CsA trough level after transfer to the Cicloral formulation. Mean pharmacokinetic values have been reported as equivalent following transfer to Gengraft in one study, but mean CsA trough fell and mean serum creatinine rose significantly in a separate trial. The only clinical outcomes data available are from a retrospective study of de novo renal transplant patients, which reported a significantly higher incidence of biopsy-proven acute rejection in patents receiving Gengraf versus Neoral (39% versus 25%, P<0.05). Until robust clinical data demonstrate that different formulations of CsA are interchangeable, it is advisable to prescribe CsA by brand, and any transfer to a different CsA formulation should be undertaken with close supervision and only at the direction of the transplant physician. [ABSTRACT FROM AUTHOR]

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. [Copyright &y& Elsevier]

Background: In older adults, current equations to estimate glomerular filtration rate (GFR) are not validated and may misclasslfy 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: lohexol 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 mlsclasslficatlon 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 misclassrfication rate (17.2%), followed by the Chronic Kidney Disease Epidemiology Collaboration equation (20.4%). Limitation: There was no validation by an external data set. ..ASA-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 Nierentrans-platation (KfH) Foundation of Preventive Medicine. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

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-α2/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 μg 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 μg l−1 at 0 h and TAT >8.4 μg 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 μg l−1; OR 6.8, 95% CI 1.8–26.2, p = 0.005) and 8 h (PAP >495 μg 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

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 (PGE2) 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 PGE2. These data point to a favorable biocompatibility profile of the amino-acid-based bicarbonate-buffered PD solution toward HPMC. [ABSTRACT FROM AUTHOR]

Abstract: 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 A2 (Lp-PLA2) 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 μmol/l) identified patients with very high risk (RR=2.4, 39% primary endpoint) while low concentrations of NT-proBNP (≤1400 ng/l), WBCHO (≤17 μmol/l) and LP-PLA2 (≤210 μg/l) indicated very low risk (0% primary endpoint). WBCHO >17 μmol/l additionally identified a subgroup with intermediate risk (RR=3.0, 13.5% primary endpoint) in patients with NT-proBNP concentrations ≤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. [Copyright &y& Elsevier]

Background: Immunosuppressive regimens with the fewest possible toxic effects are desirable for transplant recipients. This study evaluated the efficacy and relative toxic effects of four immunosuppressive regimens. Methods: We randomly assigned 1645 renal-transplant recipients to receive standard-dose cyclosporine, mycophenolate mofetil, and corticosteroids, or daclizumab induction, mycophenolate mofetil, and corticosteroids in combination with low-dose cyclosporine, low-dose tacrolimus, or low-dose sirolimus. The primary end point was the estimated glomerular filtration rate (GFR), as calculated by the Cockcroft–Gault formula, 12 months after transplantation. Secondary end points included acute rejection and allograft survival. Results: The mean calculated GFR was higher in patients receiving low-dose tacrolimus (65.4 ml per minute) than in the other three groups (range, 56.7 to 59.4 ml per minute). The rate of biopsy-proven acute rejection was lower in patients receiving low-dose tacrolimus (12.3%) than in those receiving standard-dose cyclosporine (25.8%), low-dose cyclosporine (24.0%), or low-dose sirolimus (37.2%). Allograft survival differed significantly among the four groups (P=0.02) and was highest in the low-dose tacrolimus group (94.2%), followed by the low-dose cyclosporine group (93.1%), the standard-dose cyclosporine group (89.3%), and the low-dose sirolimus group (89.3%). Serious adverse events were more common in the low-dose sirolimus group than in the other groups (53.2% vs. a range of 43.4 to 44.3%), although a similar proportion of patients in each group had at least one adverse event during treatment (86.3 to 90.5%). Conclusions: A regimen of daclizumab, mycophenolate mofetil, and corticosteroids in combination with low-dose tacrolimus may be advantageous for renal function, allograft survival, and acute rejection rates, as compared with regimens containing daclizumab induction plus either low-dose cyclosporine or low-dose sirolimus or with standard-dose cyclosporine without induction. (ClinicalTrials.gov number, NCT00231764.) N Engl J Med 2007;357:2562-75. [ABSTRACT FROM AUTHOR]

As cytomegalovirus (CMV) infection frequently occurs in simultaneous pancreas kidney transplantation (SPKT), most centers use general ganciclovir prophylaxis. The aim of the study was to analyze the impact of CMV in a patient cohort with preemptive therapy only. Incidence, course and risk factors of CMV infection were retrospectively analyzed in 94 adult SPK recipients without prophylaxis. Patients with asymptomatic pp65-antigenemia were treated preemptively with intravenous ganciclovir for 14 days. Survival rates after 1, 3, and 5 years were 98%, 97%, and 94% for patients, 96%, 94%, and 88% for renal grafts and 88%, 85%, and 82% for pancreas grafts. CMV infections occurred in 51% of patients and CMV syndrome in 16%. No tissue-invasive disease was observed. Thirty-eight per cent of patients with CMV infection developed a recurrence. Risk factors for CMV in multivariate analysis were the D+/R− constellation, acute rejections, anti-rejection therapy and coronary heart disease. CMV had no impact on patient or graft survival, occurrence of acute or chronic rejection and bacterial infections. Preemptive therapy seems to be safe and effective in SPK recipients, but as the present study was retrospective, prospective randomized studies are needed to confirm our results. [ABSTRACT FROM AUTHOR]

Angiogenesis induced by vascular endothelial growth factor (VEGF) plays an important role in psoriasis. Hypoxic adaptation is conferred through hypoxia-inducible transcription factors (HIFs). VEGF and its receptor Flt-1 are HIF target genes. Growth factors and inflammatory cytokines activate the phosphoinositol-3 kinase pathway, and via activated protein kinase B (phospho-Akt) augment HIF activity. Here, we demonstrate that the major oxygen-dependent HIF isoforms are strongly upregulated in psoriatic skin: HIF-1α mainly in the epidermis, in an expression pattern similar to VEGF mRNA; HIF-2α in both the epidermis and in capillary endothelial cells of the dermis. In contrast, normal human skin shows low expression of HIF-α proteins, with the exception of hair follicles, and glands, which strongly express HIF-1α. In normal human skin, phospho-Akt appeared in the basal epidermal layer, in hair follicles, and in dermal glands. In contrast, in psoriasis, phospho-Akt expression was low in the epidermis, but markedly enhanced in the dermal capillaries and in surrounding interstitial/inflammatory cells. Our data suggest that hypoxia initiates a potentially self-perpetuating cycle involving HIF, VEGF, and Akt activation, which could drive physiologic growth of hair follicles and skin glands. Furthermore, such a cycle may exist in psoriasis in dermal capillaries and contribute to disease progression.Journal of Investigative Dermatology (2007) 127, 2445–2452; doi:10.1038/sj.jid.5700874; published online 10 May 2007 [ABSTRACT FROM AUTHOR]

Abstract: Background: Whole blood choline (WBCHO) and plasma choline (PLCHO) concentrations increase rapidly after stimulation of phospholipase D in acute coronary syndromes (ACS). Early risk-stratification was analyzed in 217 patients with suspected ACS and a negative admission troponin T (<0.03 μg/L). Methods: WBCHO and PLCHO were measured using high-performance-liquid-chromatography mass spectrometry. Major cardiac events (MACE) were defined as cardiac death/arrest, coronary intervention or myocardial infarction (MI). Results: WBCHO (≥28.2 μmol/L) was predictive for MACE (hazard ratio [HR] 2.7; p <0.001), cardiac death/arrest (HR 4.2; p =0.015), heart failure (HR 2.8; p =0.003), coronary intervention (HR 2.1; p =0.01) and MI (HR 8.4; p =0.002) after 30 days. PLCHO (≥25.0 μmol/L) was predictive for MACE (HR 2.6; p =0.005), cardiac death/arrest (HR 15.7; p <0.001), heart failure (HR 6.0; p <0.001) but not for coronary intervention and MI. WBCHO and PLCHO were predictive for MACE in multivariate analysis (Odds ratio [OR] 2.7, p =0.009 and OR 3.3, p =0.03) independently of age, gender, prior MI, coronary risk factors and ECG. Conclusions: WBCHO and PLCHO are significant and independent predictors of major cardiac events in admission troponin T negative acute coronary syndromes. Both are predictive for events related to tissue ischemia and WBCHO is capable of detecting risks associated with coronary plaque instability. [Copyright &y& Elsevier]

Background: Long-term survival after heart (HTx) or lung (LuTx) transplantation increases the risk for end-stage renal disease (ESRD). After HTx ESRD was reported to enhance mortality, and kidney transplantation (KTx) was shown to improve survival. However, prognostic factors in ESRD after HTx or LuTx are largely unknown. Methods: Single-center observational study in HTx and LuTx patients who accessed the KTx waiting list; baseline characteristics were correlated with mortality. Results: KTx was performed in 15 of 65 study patients. Survival was comparable on the KTx waiting list and in reference patients from the same center without ESRD. KTx significantly improved survival (5 years’ survival 84.6% with KTx vs. 56.5% on the KTx waiting list, p = 0.030). None of the baseline parameters predicted mortality in the KTx group. Only on the KTx waiting list BMI (median 24.7 vs. 20.7; p < 0.05) and left ventricular ejection fraction (LVEF, median 63 vs. 53%, p < 0.008) significantly correlated with survival. Conclusions: The risk for mortality after HTx or LuTx is not increased by ESRD, provided that patients meet access criteria for the KTx waiting list. KTx improves survival in ESRD after HTx or LuTx. BMI and LVEF may predict outcome in HTx/LuTx patients on the KTx waiting list. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The transcription factor HIF-1α has been identified as a key regulator in the cellular and systemic response to hypoxia. Because hypoxia is frequently associated with acidosis, like in ischemia or tumour growth, we studied the impact of acidosis on the expression of the HIF-1α and HIF-2α proteins and that of the three HIF target genes carbonic anhydrase-9 (CA-9), glucose transporter-1 (Glut-1) and erythropoietin (EPO). Since the HIF-prolyl hydroxylases (PHD) modulate cellular HIF-α protein levels we also investigated changes in PHD mRNA expression under hypoxia and acidosis. HIF-1α immunoblots revealed, depending on the cell line investigated, a moderate induction of HIF-α protein levels by acidosis in normoxia (Hep3B cells) or hypoxia (HeLa cells). Concordantly, the activity of HIF-driven luciferase reporters was slightly enhanced at pH 7.0. In contrast, HIF target genes exhibited divergent responses to acidosis: basal and hypoxia-induced CA-9 mRNA levels were further increased, whereas hypoxic EPO mRNA induction was attenuated, and Glut-1 mRNA levels were not altered by acidosis. Except from a small increase of hypoxia-induced PHD3 mRNA levels in HeLa cells, there was also no significant effect of acidosis on PHD expression. In conclusion, albeit HIF protein levels slightly induced by acidosis and the inconsistent regulation of HIF target genes under acidosis suggest additional, yet unidentified pH-sensitive factors to be involved in the regulation of these genes. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the effect of low-dose hydrocortisone on time to shock reversal, the cytokine profile, and its relation to adrenal function in patients with early septic shock.Design: Prospective, randomized, double-blind, single-center study.Setting: Medical intensive care unit of a university hospital.Patients: Forty-one consecutive patients with early hyperdynamic septic shock.Interventions: After inclusion and a short adrenocorticotropic hormone test, all patients were randomized to receive either low-dose hydrocortisone (50-mg bolus followed by a continuous infusion of 0.18 mg/kg body of weight/hr) or matching placebo. After shock reversal, the dose was reduced to 0.06 mg/kg/hr and afterward slowly tapered. Severity of illness was estimated using Acute Physiology and Chronic Health Evaluation II score and Sequential Organ Failure Assessment score.Measurements and Main Results: Time to cessation of vasopressor support (primary end point) was significantly shorter in hydrocortisone-treated patients compared with placebo (53 hrs vs. 120 hrs, p < .02). This effect was more profound in patients with impaired adrenal reserve. Irrespective of endogenous steroid production, cytokine production was reduced in the treatment group with lower plasma levels of interleukin-6 and a diminished ex vivo lipopolysaccharide-stimulated interleukin-1 and interleukin-6 production. Interleukin-10 levels were unaltered. Adverse events were not more frequent in the treatment group.Conclusions: Treatment with low-dose hydrocortisone accelerates shock reversal in early hyperdynamic septic shock. This was accompanied by reduced production of proinflammatory cytokines, suggesting both hemodynamic and immunomodulatory effects of steroid treatment. Hemodynamic improvement seemed to be related to endogenous cortisol levels, whereas immune effects appeared to be independent of adrenal reserve. [ABSTRACT FROM AUTHOR]

The association between renal hyperparathyroidism (HPT) and differentiated thyroid carcinoma is discussed. To determine the prevalence and potential risk factors, we performed a retrospective analysis of our patients (1998–2004) and compared the data with the data from other surgical and autopsy studies. At our hospital, a total of 347 parathyroidectomies in 339 patients with renal HPT were performed. Most patients underwent preoperative ultrasound investigation of the thyroid gland and, if indicate, thyroid scintigraphy. Intraoperatively, both thyroid lobes were mobilized and palpated. Detected thyroid nodules were adequately resected and investigated histologically. A systematic analysis of the international literature was performed using the PubMed/MEDLINE system to identify publications on the prevalence of papillary thyroid carcinoma (PTC) in patients with renal HPT and in the overall population. Altogether, 133 patients (39.2%) underwent simultaneous thyroid surgery. The initial operation was hemithyroidectomy in 55 (16.2%), Dunhill operation in 36 (10.6%), unilateral subtotal resection in 17 (5.0%), bilateral subtotal resection in 5 (1.5%), and enucleation of a thyroid nodule in 18 (5.3%). A PTC was found in 8 of 339 patients (2.4%) and a follicular thyroid carcinoma in 1. Among 311 patients with primary cervical operation, 6 (1.9%) had a papillary thyroid carcinoma. All papillary tumors were classified as pT1 with a diameter of 1 to 12 mm; three were bifocal, and only one patient had positive lymph nodes. None of the analyzed factors showed a significant correlation with the occurrence of thyroid carcinoma. Depending on the screening method, the prevalence of occult PTC in European autopsy studies ranged from 5% to 9% and was markedly higher in almost all studies than in the present one. The prevalence of PTC in the present study makes an etiologic association between renal HPT and PTC unlikely. The clinical significance of these tumors remains unclear becauses all incidental tumors were small. However, if easily and safely feasible, relevant thyroid nodules should be removed during parathyroid surgery. [ABSTRACT FROM AUTHOR]

Abstract Background and aims: In contrast to that in patients with primary hyperparathyroidism, the value of intra operative intact parathyroid hormone (iPTH) measurement is still unclear in patients with renal hyper- parathyroid ism and was, therefore, evaluated in a large cohort of patients. Patients: Intra operative iPTH mea- surmount was performed in 153 patients with renal hyperparathyroidism (129 with terminal renal failure and 24 with frmnctioning kidney graft). Subtotal and total parathyroidectomy were performed in 123 and 13 patients, respectively, during initial surgery. In patients with recurrent disease (17), the respective hyper- functioning tissue was removed. Intra operative blood samples were obtained by puncture of the internal jugular vein before preparation of the parathyroids (PTH0) and 15 mm after parathyroidectomy (PTH15). iPTH was measured with the Elecsys 2010 system. Postoperative iPTH levels (PTHPOSI) were determined at postoperative days 1 to 3 and at week 2. Patients were arbitrarily divided in four groups according to the po stop ergative iPTH values: 0-25 pg/ml (group 1), 26-65 pg/ml (group 2), 66-150 pg/ml (group 3) and more than 150 pg/ml (group 4). Results: The mean PTH0 value was 869±57 pg/ml, which decreased to 167±15 pg/ml at PTH15. The mean relative PTH15 value was 2 1.6±1.7%. Postoperatively, iPTH decreased to 42±9 pg/ml. The postoperative iPTH value of the 129 patients with terminal renal failure was 25 pg/ml or less in 99 patients, 26-65 pg/ml in 11 patients, 66-150 pg/ml in eight patients and higher than 150 pg/ml in 11 patients. Two successive criteria of iPTH de- crease were used: first, a PTH15 of s150 pg/ml or, second, a relative PTH15 of S30% less was used. Fifteen patients did not fulfil both criteria. In 13 of them (86.7%) iPTHPOSt was higher than 65 pg (true failure to decline). Of 114 patients who fulfilled the criteria, 108 (94.7%) had normal postoperative iPTH values (true de- cline). Absolute PTH15 values of less than 150 pg/ml predicted normal postoperative iPTH levels in 77 of 78 patients. Conclusion: A PTH15 value of 150 pg/ml or less predicts operative success in patients with renal failure in 98.7% of cases, independently of the relative decay. In contrast, if the relative PTH15 is higher than 30%, high postoperative PTH values are predicted with a probability of 8 6.7%. Although there remain some borderline cases, intraoperative iPTH measurement is accurate and also can be useful in patients with renal hyperparathyroidism. [ABSTRACT FROM AUTHOR]

Background: Medullary hypoxia is believed to play an important role in the pathogenesis of acute renal failure (ARF). Hypoxia-inducible transcription factors (HIF) are recognized as master regulators of hypoxic adaptation, but little is known about their role in renal disease.Methods: A multi-insult rat model of ARF combining the application of contrast medium with nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibition was used to study chronology and distribution of the oxygen regulated HIF isoforms HIF-1alpha and HIF-2alpha in comparison with the hypoxia-marker pimonidazole between 10 minutes and 48 hours after injury induction. Treatment with furosemide was used to study HIF expression under conditions of ameliorated tissue injury.Results: Contrast medium in combination with NOS and COX inhibition resulted in widespread induction of HIF in the outer and inner medulla that was initiated within 10 minutes, reached the highest levels at 2 hours and diminished 8 hours to 24 hours thereafter. HIF isoforms were expressed in a cell type-specific fashion: HIF-1alpha in tubular and HIF-2alpha in interstitial and endothelial cells. The degree of HIF-1alpha accumulation varied between nephron segments, being much stronger in collecting ducts than in medullary thick ascending limb of the loop of Henle (mTAL). Comparison with pimonidazole staining and the effect of furosemide indicated that HIF induction in mTAL is maximal with moderate hypoxia and declines with increasing severity of hypoxia.Conclusion: A complex pattern of HIF activation appears to play an important role in tissue preservation as a response to regional renal hypoxia. The limited capacity of mTAL cells for HIF activation may explain their susceptibility to injury. [ABSTRACT FROM AUTHOR]

Background: Hypoxia is believed to play an important role in the pathogenesis of acute and chronic kidney disease. However, the impact of low oxygen tensions on cellular functions in the kidney and potential adaptive responses are poorly understood. Methods: In order to assess the effects of regional hypoxia, we induced large segmental renal infarcts in rats by renal artery branch ligation to create an oxygen gradient vertical to the corticomedullary axis and studied the effects on cell morphology, the induction of hypoxia-inducible transcription factors (HIF), the expression of HIF target genes, and cell proliferation. Results: Pimonidazol protein adduct immunohistochemistry, a marker for severe tissue hypoxia, verified a continuous area of hypoxic renal tissue extending from the cortex to the papilla, in which tubular necrosis developed subsequently. Within this area local sparing of pimonidazol staining and tissue preservation was found around arcuate veins, indicating regional oxygen supply via diffusion from venous blood. HIF-1alpha was up-regulated within 1 hour and for up to 7 days predominantly in the border zone of the infarct in tubular cells, glomerular cells, resident interstitial cells, capillary endothelial cells, and infiltrating macrophages. HIF-2alpha expression was less prominent and confined to resident and infiltrating peritubular cells in the cortex. HIF expression was colocalized with regional up-regulation of the hypoxia-inducible genes heme oxygenase-1 and vascular endothelial growth factor (VEGF), and was followed by capillary and tubular proliferation. Conclusion: Our findings illustrate a marked potential of renal tissue to respond to regional ischemia and initiate adaptive reactions, including angiogenesis. [ABSTRACT FROM AUTHOR]

Hypertension increases expression of growth factors and MHC II in chronic allograft nephropathy. Background. Hypertension of the recipient is strongly associated with chronic allograft nephropathy. It is unclear, however, whether hypertension is the cause or the consequence of chronic allograft nephropathy. Methods. The present study was performed in the Fisher to Lewis rat kidney transplant model. Transplanted rats (N = eight in each group) received either no treatment or were made hypertensive by administration of deoxycorticosteron acetate (DOCA) and salt. Proteinuria and systolic blood pressure was measured monthly, grafts were harvested at 3 and 6 months for semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and for immunohistology. Results. Systolic blood pressure was markedly elevated in rats receiving DOCA/salt. Allografts of hypertensive animals contained significantly more cells expressing the proliferating cell nuclear antigen compared to isografts and to allografts from normotensive animals (P < 0.05). Histologic staining and mRNA expression of major histocompatibility complex (MHC) II was markedly increased in allografts of hypertensive animals compared to all other groups (P < 0.05). Expression of mRNA for platelet-derived growth factor-B (PDGF-B), transforming growth factor-β (TGF-β) and collagen was higher in allografts than in isografts and was highest in hypertensive animals. Conclusion. We conclude that hypertension augments the expression of growth factors in the allograft possibly aggravating the intimal hyperplasia observed in chronic allograft nephropathy. By increasing the expression of MHC II antigens, hypertension may render the allograft more susceptible to alloantigen-dependent damage. Hypertension and alloantigen-dependent factors appear to exert additive or synergistic effects on inflammatory pathways leading to graft injury. [ABSTRACT FROM AUTHOR]

Troponins I and T represent the current biomarker standard for diagnosis of myocardial infarction. Even small increases of cardiac troponins have prognostic implications, but not all patients at risk are correctly classified, particularly at admission. We identified elevated whole-blood choline as a promising marker and performed a prospective study of 327 patients with a suspected acute coronary syndrome that focused on the analysis of troponin-negative patients. Diagnostic classification of patients and the definition of troponin cutoffs were performed according to the new European Society of Cardiology/American College of Cardiology criteria. Blood was sampled serially and choline was measured using high-performance liquid chromatography mass spectrometry in whole blood. Patients were followed for 30 days. In patients with negative troponin I test results at admission (n = 250), choline was a predictor of cardiac death and nonfatal cardiac arrest (hazard ratio 6.0, p = 0.003), life-threatening arrhythmias (hazard ratio 3.75, p = 0.004), heart failure (hazard ratio 2.87, p = 0.002), and coronary angioplasty (hazard ratio 2.57, p = 0.001). In multivariate analysis of troponin-negative patients, choline was the strongest predictor of cardiac death or arrest (odds ratio 6.05, p = 0.01). Choline was not a marker for myocardial necrosis but indicated high-risk unstable angina in patients without acute myocardial infarction (sensitivity 86.4%, specificity 86.2%). Thus, an increased concentration of choline at hospital admission is a predictor of adverse cardiac events in patients with suspected acute coronary syndromes. Whole blood choline may be useful for early risk stratification of these patients, particularly if troponin results are negative on admission. [ABSTRACT FROM AUTHOR]

Troponins I and T represent the current biomarker standard for diagnosis of myocardial infarction. Even small increases of cardiac troponins have prognostic implications, but not all patients at risk are correctly classified, particularly at admission. We identified elevated whole-blood choline as a promising marker and performed a prospective study of 327 patients with a suspected acute coronary syndrome that focused on the analysis of troponin-negative patients. Diagnostic classification of patients and the definition of troponin cutoffs were performed according to the new European Society of Cardiology/American College of Cardiology criteria. Blood was sampled serially and choline was measured using high-performance liquid chromatography mass spectrometry in whole blood. Patients were followed for 30 days. In patients with negative troponin I test results at admission (n = 250), choline was a predictor of cardiac death and nonfatal cardiac arrest (hazard ratio 6.0, p = 0.003), life-threatening arrythmias (hazard ratio 3.75, p = 0.004), heart failure (hazard ratio 2.87, p = 0.002), and coronary angioplasty (hazard ratio 2.57, p = 0.001). In multivariate analysis of troponin-negative patients, choline was the strongest predictor of cardiac death or arrest (odds ratio 6.05, p = 0.01). Choline was not a marker for myocardial necrosis but indicated high-risk unstable angina in patients without acute myocardial infarction (sensitivity 86.4%, specificity 86.2%). Thus, an increased concentration of choline at hospital admission is a predictor of adverse cardiac events in patients with suspected acute coronary syndromes. Whole blood choline may be useful for early risk stratification of these patients, particularly if troponin results are negative on admission. [Copyright &y& Elsevier]

A possible diagnostic role of procalcitonin (PCT) as a marker for ventilator associated pneumonia (VAP) in patients with an already triggered acute phase response after successful cardiopulmonary resuscitation (CPR) was investigated. In 28 patients with return of spontaneous circulation (ROSC) after out of hospital CPR, measurements of PCT, C-reactive protein (CrP), white blood cell count (WBC) and body temperature were compared with the clinical course of the patients. In this setting, PCT was the only marker to differentiate between patients with and without VAP (median value on day 1, 6.0 vs. 0.5 ng/ml; P<0.001). Using a cut off value of 1 ng/ml during the first 7 days after ROSC PCT had a sensitivity of 100% and a specificity of 75% to indicate VAP. PCT was elevated a median of 2 days earlier than the clinical diagnosis of VAP. Elevations in PCT can, therefore, indicate bacterial complications in cardiac arrest patients with a non-infectious acute phase response. [Copyright &y& Elsevier]

Background: Changes in renal blood flow are considered to play a significant role in the induction and maintenance of kidney failure, but are difficult to monitor with currently available techniques. The objective was to validate renal flow measurements with Doppler guidewires and to apply this technique to assess dose and time dependency of the renal vascular effects of norepinephrine (NE). Methods: In 10 anesthetized pigs, flow velocity in renal arteries (FVart) and veins (FVvein) and volumetric renal blood flow (VBF) were measured before and after intravenous bolus application of incremental doses of NE (2 to 200 microg). Results: FVart curves exactly reflected the changes in VBF. Beat-to-beat analysis revealed a strong linear correlation over a mean VBF range of less than 0.05 to 0.35 L/min (median correlation coefficient with FVart, r = 0.998), and significant but less close relationships were also found between VBF and FVvein. Ten seconds after the administration of 200 microg NE, FVart dropped from 71 to 6 cm/sec and was 90% reversible after 48 seconds. Similarly, the renal vascular resistance temporarily rose from 988 to 13711 mm Hg. min/L. In contrast, NE-induced increases in systemic vascular resistance were on average a maximum of 1.5-fold but persisted for more than 60 seconds. Conclusions: Doppler flow measurements in the renal artery provide an excellent surrogate of volumetric blood flow, which may be useful for continuous monitoring of renal hemodynamics. The renal vasculature is more sensitive when compared with the systemic vasculature, but also appears to evoke more efficient counter-regulatory mechanisms in response to NE. [ABSTRACT FROM AUTHOR]

Focuses on a study on the effect of bicarbonate buffered peritoneal dialysis fluids (PDF) in peritoneal cell function. Information on peritoneal dialysis; Effect of lactate buffered PDF; Comparison of effects between the two buffered PDF.

Presents a study which examined the temporo-spatial pattern of induction of the oxygen-regulated subunits of mediators of adaptation to critically low oxygen levels, hypoxia-inducible transcription factors-1 and -2, after myocardial infarction compared with systemic hypoxia. Methodology; Findings and its implications.

Presents a study which determined the functional differences between hypoxia-inducible factor (HIF)-1α and HIF-2α in different human cell lines by using RNA interference. Brief background on HIF; Methodology; Key findings.

We describe a young woman whose initial presentation was dominated by acute diarrhoea. Life-threatening multiorgan failure rapidly ensued and necessitated mechanical ventilation and dialysis treatment. An initially elongated activated partial thromboplastin time prompted further coagulation tests that led to the detection of positive lupus anticoagulant, a highly elevated IgG-anticardiolipin (aCL) antibody titre, and prolonged dilute Russell's viper venom time. Histological examination of samples obtained during endoscopy revealed widespread intestinal thrombotic microangiopathy. In view of these serologic and histologic features, a diagnosis of the malignant variant of the antiphospholipid syndrome (APS), also termed 'catastrophic APS', was established. In spite of this syndrome's grim prognosis, the patient recovered following intensive anticoagulation and adjunct treatment with steroids and immunoglobulins. [ABSTRACT FROM AUTHOR]