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Background: Thiazide diuretics are a mainstay in the management of hypertension and often associated with dyselectrolytemias. We investigated the prevalence of and risk factors for hyponatremia and hypokalemia in thiazide users, substance-specific differences, and the association of thiazides with syncope and falls. Methods: In this cross-sectional analysis all patients admitted to an interdisciplinary emergency department in Switzerland between January 1, 2017, and December 31, 2018, with measurements of serum sodium and potassium were included. Data regarding serum electrolytes and creatinine were analyzed to classify for dysnatremias, dyskalemias, and acute kidney injury. Chart reviews were performed to screen for syncope or falls. Results: A total of 1604 patients (7.9%) took thiazides. Acute kidney injury was significantly more common in thiazide users (22.1 vs 7%, P < .0001). Hyponatremia (22.1 vs 9.8%, P < .0001) and hypokalemia (19 vs 11%, P < .0001) were more frequent with thiazides. Thiazide use together with higher age and female sex were independent predictors of hyponatremia and hypokalemia. A dose-dependent effect was found for electrolyte disorders, and there was a variance in risk between the investigated substances with chlorthalidone bearing the highest and hydrochlorothiazide the lowest risk. Patients taking thiazide diuretics had significantly more episodes of syncope and falls. Conclusions: Thiazide use is a clear risk factor for hyponatremia and hypokalemia. The effect appears to be dose-dependent and highly variable depending on the substance. Syncope and falls seem to be causally related to thiazide use. Especially in patients who are elderly, female, and prone to falls, the use of thiazide diuretics should be thoroughly questioned.

Purpose We aimed to investigate the prevalence, risk factors and outcome of hypo- and hypernatremia in emergency patients with acute kidney injury (AKI). Methods In this cross-sectional analysis all emergency patients between January 1st 2017 and December 31st 2018 with measurements of creatinine and sodium were included. Baseline characteristics, medication and laboratory data were gathered. Chart reviews were performed to identify patients with a diagnosis of chronic kidney disease (CKD) and to extract baseline creatinine. For all other patients the ADQI backformula was used to calculate baseline creatinine. AKI was graduated using creatinine criteria of the acute kidney injury network. Binary logistic regression analysis was used to identify risk factors for appearance of dysnatremias and outcome. Results AKI was found in 8% of patients. 392 patients (23.16%) had hyponatremia, 24 (1.4%) had hypernatremia. Use of potassium sparing diuretics, a medical cause for emergency referral, use of thiazide diuretics and AKI stage were the strongest risk factors for hyponatremia. Loop diuretics, a medical cause for emergency referral and AKI stage were risk factors for hypernatremia. In patients with all classes of hyponatremia, length of hospital stay was significantly longer compared to patients with a normal serum sodium. In the binary logistic regression analysis with death as outcome, hyponatremia as well as severe hypernatremia were independent risk factors for mortality. Conclusions Dysnatremias are common in emergency patients with AKI. Diuretic medication is a major risk factor for hypo- and hypernatremia. Both hyponatremia and severe hypernatremia were independent risk factors for adverse outcome.

Hypervitaminosis D is a rare reason for hypercalcemia and associated with acute kidney injury. We report on two cases of hypercalcemia and acute kidney injury because of vitamin D intoxication successfully treated with denosumab. Case 1 is an 83-year-old woman, who was initially treated for 2 weeks with intravenous hydration, steroids and thereafter with furosemide without any effect on serum calcium levels and renal function. Because acute renal failure discouraged us to use intravenous bisphosphonate therapy, we applicated 60 mg denusomab subcutaneously. This led to a prompt reduction in serum calcium levels and improvement of renal function within 1 week. Case 2 is a 45-year-old athletic woman, who refused the standard therapy of steroids and forced diuresis for vitamin D intoxication. After 1 day of rehydration therapy, she received 60 mg denusomab. Similar to case 1 serum calcium declined and renal function improved within 7 days.

BACKGROUND Acid base and electrolyte disorders are frequently reported in the early period after renal transplantation. No comprehensive data exist on the prevalence and patterns of, and contributing factors to, electrolyte disturbances in patients with stable long-term allograft function. METHODS We analysed 576 renal transplant recipients (serum creatinine level

Background No data concerning the prevalence and risk factors of dyskalemia in acute kidney injury (AKI) exist. We investigated (a) prevalence rates, (b) risk factors and (c) outcome of hypo- and hyperkalemia in emergency patients. Methods In this cross-sectional analysis, all patients admitted to the emergency department of a large public hospital in Switzerland between January 1st 2017 and December 31st 2018 with measurements of creatinine and potassium were included. Baseline characteristics, medication and laboratory data were extracted. Chart reviews were performed to identify patients with a diagnosis of chronic kidney disease (CKD) and to extract their baseline creatinine. For all other patients, the ADQI backformula was used in order to calculate baseline creatinine. AKI was graduated using creatinine criteria of the acute kidney injury network. Binary logistic regression analysis was used to identify risk factors for appearance of hyperkalemia and outcome. Results AKI was found in 8% of patients. Hyperkalemia was present in 13% and hypokalemia in 11% of patients with AKI. AKI stage, potassium-sparing diuretics, ACE inhibitors and underlying CKD were the strongest risk factors for hyperkalemia. Hyperkalemia as well as profound hypokalemia were independently associated with prolonged length of stay and in-hospital mortality. The study is limited by its dependency on chart review data in order to identify patients with chronic kidney disease and by limitations of the ADQI backformula to calculate baseline creatinine. Conclusions Dyskalemias are common in emergency patients with AKI and are independent risk factors for adverse outcomes. Potassium-sparing diuretics, ACE-inhibitors, AKIN stage and CKD are predictors of hyperkalemia in AKI.

Resection margin status is a known prognosticator in patients who undergo resection for hilar cholangiocarcinoma. However, the influence of an isolated positive circumferential margin on clinical outcome is unclear.Patients with resected de novo hilar cholangiocarcinoma from two European hepatobiliary centres (Medical University of Vienna and Aintree University Hospital, 2006-2016) were classified according to resection margin status (negative, surgically positive, isolated circumferentially positive) and investigated with respect to overall survival (OS), recurrence-free survival (RFS) and recurrence pattern.Eighty-three (48 male/35 female) patients were enrolled. The median age was 64 years (range 33-80). The median follow-up was 21.7 months (range 0.3-92.4). Forty (48%) patients had negative resection margins, 25 (30%) had an isolated positive circumferential margin and 18 (22%) had a positive surgical margin. The 5-year OS rates in patients with negative, isolated positive circumferential and positive surgical resection margins were 47%, 33% and 0%, respectively. Median OS was 45.6, 32.7 and 14.5 months, respectively (log rank, P = 0.011). Upon multivariable Cox regression analysis, resection margin status and lymph node status remained statistically significant (P 0.05). No difference with respect to RFS and recurrence pattern was found between the groups (P 0.05).Our data show that these three resection margin types were associated with different clinical outcomes. Circumferential margin status may therefore serve as a novel prognostic biomarker.

Background The value of liver resection (LR) for metachronous pancreatic ductal adenocarcinoma (PDAC) metastases remains controversial. However, in light of increasing safety of liver resections, surgery might be a valuable option for metastasized PDAC in selected patients. Methods We performed a retrospective, multicenter study including patients undergoing hepatectomy for metachronous PDAC liver metastases between 2004 and 2015 to analyze postoperative outcome and overall survival. All patients were operated with curative intent. Patients with oligometastatic metachronous liver metastasis with definitive chemotherapy (n = 8) served as controls. Results Overall 25 patients in seven centers were included in this study. The median age at the time of LR was 63.8 years (56.9–69.9) and the median number of metastases in the liver was 1 (IQR 1–2). There were eight non-anatomical resections (32%), 15 anatomical minor (60%) and 2 major LR (8%). Postoperative complications occurred in eleven patients (eight Clavien-Dindo grade I complications (32%) and three grade IIIa complications (12%), respectively). The 30-day mortality was 0%. The median length of stay was 8.6 days (IQR 5–11). Median overall survival following LR was 36.8 months compared to 9.2 months in patients with metachronous liver metastasis with chemotherapy (p = 0007). Discussion Liver resection for metachronous PDAC metastasis is safe and feasible in selected patients. To address general applicability and to find factors for patient selection, larger trials are urgently warranted.

Background The impact of major liver resection (LR) on the detoxifying function of the remaining liver tissue as represented by CYP3A activity has yet to be assessed. Therefore, this study evaluates the changes in CYP3A activity between preoperative values and after liver resection. Material and methods To determine CYP3A activity, midazolam (MDZ) was used as a marker substance, 3 μg were applied intravenously one day before surgery and on the 3rd day after surgery. Subsequently blood was withdrawn at 0, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3, 4 and 6 h post application of the study drug. Plasma MDZ and 1-OH-MDZ concentration was assessed using a LC-MS/MS method. Volumetric analysis of the resected liver was done by syngo.CT liver analysis software (Siemens Healthineers) using preoperative multidetector computed tomography. Results N = 13 (8 male/5 female) patients were included in this study and received preoperative evaluation, 11 patients were studied also after liver resection. The mean age was 62 (±15.3) years with a mean BMI of 23.6 ± 4.8 kg/m2. No patient suffered from acute liver dysfunction postoperatively. None of the pharmacokinetic parameters assessed were significantly altered by liver resection. CYP3A activity over time was not significantly reduced by major liver resection. Conclusion This study gives first time data on the impact of major liver resection on CYP3A activity. It was shown that MDZ clearance representing in vivo CYP3A activity is not altered by major liver resection. This suggests no dose adjustment of commonly applied drugs which are CYP3A substrates needs to be carried out.

Background Open abdomen (OA) may be required in patients with abdominal trauma, sepsis or compartment syndrome. Vacuum-assisted wound closure and mesh-mediated fascial traction (VAWCM) is a widely used approach for temporary abdominal closure to close the abdominal wall. However, this method is associated with a high incidence of re-operations in short term and late sequelae such as incisional hernia. The current study aims to compare the results of surgical strategies of OA with versus without permanent mesh augmentation. Methods Patients with OA treatment undergoing vacuum-assisted wound closure and an intraperitoneal onlay mesh (VAC-IPOM) implantation were compared to VAWCM with direct fascial closure which represents the current standard of care. Outcomes of patients from two tertiary referral centers that performed the different strategies for abdominal closure after OA treatment were compared in univariate and multivariate regression analysis. Results A total of 139 patients were included in the study. Of these, 50 (36.0%) patients underwent VAC-IPOM and 89 (64.0%) patients VAWCM. VAC-IPOM was associated with reduced re-operations (adjusted incidence risk ratio 0.48 per 10-person days; CI 95% = 0.39–0.58, p

To compare the value of functional future liver remnant (functFLR) to established clinical and imaging variables in prediction of post-hepatectomy liver failure (PHLF) after major liver resection. This retrospective, cross-sectional study included 62 patients, who underwent gadoxetic acid enhanced MRI and MDCT within 10 weeks prior to resection of ≥ 4 liver segments. Future liver remnant (FLR) was measured in MDCT using semi-automatic software. Relative liver enhancement for each FLR segment was calculated as the ratio of signal intensity of parenchyma before and 20 min after i.v. administration of gadoxetic acid and given as mean (remnantRLE). Established variables included indocyanine green clearance, FLR, proportion of FLR, weight-adapted FLR and remnantRLE. functFLR was calculated as FLR multiplied by remnantRLE and divided by patient’s weight. The association of measured variables and PHLF was tested with univariate and multivariate logistic regression analysis and receiver operator characteristics (ROC) curves compared with the DeLong method. Sixteen patients (25.8%) experienced PHLF. Univariate logistic regression identified FLR (p = 0.015), proportion of FLR (p = 0.004), weight-adapted FLR (p = 0.003), remnantRLE (p = 0.002) and functFLR (p = 0.002) to be significantly related to the probability of PHLF. In multivariate logistic regression analysis, a decreased functFLR was independently associated with the probability of PHLF (0.561; p = 0.002). Comparing ROC curves, functFLR showed a significantly higher area under the curve (0.904; p < 0.001) than established variables. functFLR seems to be superior to established variables in prediction of PHLF after major liver resection. • functFLR is a parameter combining volumetric and functional imaging information, derived from MDCT and gadoxetic acid enhanced MRI. • In comparison to other established methods, functFLR is superior in prediction of post-hepatectomy liver failure. • functFLR could help to improve patient selection prior major hepatic surgery.

Kidney transplantation represents the treatment of choice for end-stage renal disease (ESRD). However, nephrectomy bears certain short- as well as long-term risks for the healthy, voluntary donor. As obesity is increasing and is a known risk factor for surgical complications, we wanted to assess the impact of BMI on perioperative complication rates and renal function.We retrospectively assessed patients undergoing living donor kidney nephrectomy at our institution. We identified 289 donors that underwent unilateral nephrectomy between January 2006 and December 2015. Donors were categorized according to their BMI (BMI25 kg/m126 donors (43.6%) had a BMI25 while 120 (41.5%) had a BMI ≥25/30 and 43 (14.9%) were obese with a BMI ≥30. BMI had no statistically significant influence on the percentage of laparoscopic approach (86.5% vs. 83.3% vs. 88.4%, p = 0.6564), on conversion rates (0% vs. 2.0% vs. 2.6%, p = 0.2879) or postoperative complication rates defined as Clavien Dindo ≥ II (8.7% vs. 13.3% vs. 14.0%, respectively; p = 0.4474). Notably, there were no Grade III or higher complications in any group. There was no difference in pre-operative kidney function, postoperative surgical site infection or systemic infection. BMI and male sex had a statistically significant influence on short-term decline of eGFR.Obese donors do not suffer from an increased risk of intraoperative or perioperative complication rates. However, male sex and high BMI are associated with a more pronounced short-term decline in renal function. The impact of BMI on long-term consequences for kidney donors needs to be defined in larger prospective cohorts.

Background While the number of laparoscopic liver resections (LLRs) is increasing worldwide, its impact on physical recovery remains unclear. We hypothesized that LLR is associated with better physical recovery than open liver resection (OLR). To address this question, we investigated the impact of laparoscopic liver resection compared to open liver resection on physical recovery in a prospective trial. Methods Twenty-one patients who underwent LR were included in this study (11 OLR (52.4%) and 10 LLR (47.6%), respectively). Physical recovery was measured by bicycle stress testing at months 1 and 6 after surgery and compared to preoperative stress testing. Standardized performance for bicycle stress testing was calculated based on age, sex, height and weight. Physical recovery was compared between groups as change of performance (%). Results Median age was 58 years (Inter Quartile Range (IQR): 44–68), and the main indications for LR were colorectal liver metastases (n = 10; 45%) and hepatocellular carcinoma (n = 6; 27%). The one-month change of performance level was −8% (IQR: -12-1) compared to the preoperative level with no significant difference between open and laparoscopic LR (LLR: -8% (-11 – 1); OLR: -6% (-12 – 4), p = 0.833). Furthermore, 6 months postoperatively, patients in both groups had not reached back their preoperative performance level (LLR: -5.7% (−8.4 - 18.6); OLR -4. 8% (−12.6 - 1.9), p = 0.833). Conclusion In this study, we report an impaired physical recovery after LR that was not fully restored 6 months after surgery. There was no significant difference between open and laparoscopic LR in terms of bicycle stress testing. Limitations of the study include the limited sample size and differences, albeit non-statistically significant, in the baseline characteristics of the two groups. To rule out a possible role of age or underlying indication for liver resection on physical recovery, future randomized controlled trials need to be performed.

Tolerance induction through simultaneous hematopoietic stem cell and renal transplantation has shown promising results, but it is hampered by the toxicity of preconditioning therapies and graft‐versus‐host disease (GVHD). Moreover, renal function has never been compared to conventionally transplanted patients, thus, whether donor‐specific tolerance results in improved outcomes remains unanswered. We collected follow‐up data of published cases of renal transplantations after hematopoietic stem cell transplantation from the same donor and compared patient and transplant kidney survival as well as function with caliper‐matched living‐donor renal transplantations from the Austrian dialysis and transplant registry. Overall, 22 tolerant and 20 control patients were included (median observation period 10 years [range 11 months to 26 years]). In the tolerant group, no renal allograft loss was reported, whereas 3 were lost in the control group. Median creatinine levels were 85 μmol/l (interquartile range [IQR] 72‐99) in the tolerant cohort and 118 μmol/l (IQR 99‐143) in the control group. Mixed linear‐model showed around 29% lower average creatinine levels throughout follow‐up in the tolerant group (P, A long‐term follow‐up analysis shows stable renal graft function without immunosuppression and no graft loss in patients receiving renal transplantation after hematopoietic stem cell transplantation from the same donor.

Postoperative liver dysfunction remains a major concern following hepatic resection. In order to identify patients who are at risk of developing liver dysfunction, indocyanine green (ICG) clearance has been proposed to predict postoperative liver function. All patients who underwent liver resection at the Medical University Vienna, Austria between 2006 and 2015 with preoperative ICG clearance testing (PDR, R15) were analyzed in this study. Postoperative liver dysfunction was analyzed as defined by the International Study Group of Liver Surgery. Overall, 698 patients (male: 394 (56.4%); female: 304 (43.6%)) with a mean age of 61.3 years (SD: 12.9) were included in this study, including 313 minor liver resections (44.8%) and 385 major liver resections (55.2%). One hundred and seven patients developed postoperative liver dysfunction after liver resection (15.3%). Factors associated with liver dysfunction were: male sex (p = 0.043), major liver resection (p 5.6%. To the best of our knowledge, this is the largest study analyzing the predictive value of preoperative ICG clearance assessment in patients undergoing liver resection. ICG clearance is useful to identify patients at risk of postoperative liver dysfunction.

Background Several clinical risk scores for patients with colorectal liver metastases (CLM) were established in cohorts of patients undergoing liver resection (LR) without neoadjuvant chemotherapy (NAC). The purpose of the study was to evaluate the predictive values of four common risk scores in the setting of NAC and the impact of score changes during NAC. Methods Risk scores (Fong, Nordlinger, Nagashima, and Konopke) were retrospectively calculated for 336 patients undergoing LR for CLM, including 109 patients without and 227 patients with NAC. In patients with NAC, the scores were calculated before and after NAC. Results In patients without NAC (n = 109), all risk scores except the Konopke score showed a significant correlation with disease-free survival (DFS). Only the Nagashima score also was predictive for overall survival (OS). In patients with NAC (n = 227), all scores except the Konopke score were predictive for DFS and OS before and after NAC. Score changes in the Fong and the Nagashima score showed a significant correlation with DFS and OS. Conclusions Nagashima score was the most universally applicable score and predicted prognosis in all tested scenarios.

The B7/CD28/CTLA4 signaling cascade is the most thoroughly studied costimulatory pathway and blockade with CTLA4Ig (abatacept) or its derivative belatacept has emerged as a valuable option for pharmacologic immune modulation. Several clinical studies have ultimately led to the approval of belatacept for immunosuppression in kidney transplant recipients. Areas covered: This review will discuss the immunological background of costimulation blockade and recent preclinical data and clinical results of CTLA4Ig/belatacept. Expert commentary: The development of belatacept is a major advance in clinical transplantation. However, in spite of promising results in preclinical and clinical trials, clinical use remains limited at present, in part due to increased rates of acute rejection. Recent efforts showing encouraging progress in refining such protocols might be a step toward harnessing the full potential of costimulation blockade-based immunosuppression.

Background Selective interleukin-2 receptor (IL2R) blockade is one option to decrease acute rejection rates in kidney transplant recipients. However, there are little data on the impact of basiliximab in a triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and low-dose steroids). Thus, this analysis aims at investigating the impact of basiliximab induction on rejection rates and immediate graft function following kidney transplantation. Methods Basiliximab was introduced in our center according to our center's policy in the beginning of 2011. Patients who received basiliximab (n = 83) were compared with patients without induction therapy (n = 65) transplanted before the introduction of IL2R antibody induction. Results The use of basiliximab as induction therapy decreased the incidence of biopsy-proven acute rejection (BPAR) within the 1st year after transplantation (21.5% vs 14.5%; P = .283). Overall rejection episodes (including BPAR and borderline rejection) were significantly reduced in patients with basiliximab compared with patients without (41.5% vs 24.1%; P = .033). However, graft function (incidence of delayed graft function, primary nonfunction, slow graft function, and serum creatinine decline) and overall outcome (patient and graft survivals) were similar in both groups. Conclusions We found a favorable impact of basiliximab induction therapy on early acute rejection rate. The impact on long-term outcome must be addressed in further randomized controlled trials.

Traditionally, abdominal drainage (AD) is routinely inserted in patients after liver transplantation (LT) to drain ascites and to detect postoperative hemorrhage and bile leakage. However, the benefit of this surgical practice remains a matter of debate regarding potential drainage-associated morbidities. In a retrospective pair-matched analysis in a 1:1 ratio, 116 patients after LT were assessed with regards to benefits and risks of abdominal drainage under immunosuppression, respecting model for end-stage liver disease (MELD), age, and gender. The indications for LT were comparable between the drain and the no-drain group. There was an increased rate of early bile leakage in patients with abdominal drainage (13.8 vs. 1.7 %, p = 0.032). In addition, a significantly higher incidence of infections requiring antibiotic therapy was observed in the drain group (63.8 vs. 39.7 %, p = 0.015). The contribution of drains as a diagnostic tool was marginal, as in the drain group, other diagnostic tools than the drain itself confirmed 50 % of all early bile leakages and 60 % of postoperative hemorrhages. Overall, there was no difference regarding the incidence of incisional hernia after LT (8.6 vs. 10.3 %, p = 1.000), length of hospital stay (22.9 ± 18.7 vs. 18.6 ± 18.6 days, p = 0.215), and 1- and 5-year patient (p = 0.981) and graft survival (p = 0.092). Equal results can be achieved with or without an abdominal drain in recipients with whole-liver grafts in spite of an increased risk of postoperative infection and biliary leakage in the former group. A benefit of AD as a diagnostic tool could not be demonstrated.

Background Allogeneic hematopoietic stem cell transplantation (HSCT) can lead to donor-specific tolerance. Patients reported in the literature that underwent kidney transplantation (KT) after a previous HSCT from the same haploidentical donor typically received short-term immunosuppression, mainly for safety reasons and concerns of triggering graft-versus-host disease. Methods We describe the case of a 22-year-old patient who developed chronic kidney failure after receiving haploidentical HSCT from his father for the treatment of metastatic rhabdomyosarcoma. Five years after HSCT, he received a preemptive kidney transplant from his father. Steroid treatment, which had been prescribed for the underlying kidney disease, was withdrawn within 2 months posttransplant, and no de novo immunosuppression was given. Donor-specific tolerance was assessed with mixed lymphocyte reaction and INF-γ ELISPOT before (D0) and after KT (D9). Furthermore, the exact level of donor-derived T cells was measured with real-time polymerase chain reaction before and 1 year after KT. Results In vitro assays (mixed lymphocyte reaction and ELISPOT) revealed donor-specific tolerance before and after transplantation, respectively. The number of recipient-derived T cells was low before KT and virtually did not change over time (0.0139% ± 0.0039 and 0.0120% ± 0.0067; P = NS). Graft function was excellent throughout the follow-up (36 months post KT: serum creatinine, 1.18 mg/dL). Protocol biopsies performed 1 and 12 months after transplantation confirmed the absence of rejection. Conclusions This is one of the first cases of kidney transplantation from the same donor after previous haploidentical HSCT with a corticosteroid taper alone. Our results suggest that immunosuppression can be avoided in such cases.

Background The value of microscopic biliary and perineural invasion as prognostic biomarkers in patients with resectable colorectal liver metastases (CLM) who undergo neoadjuvant chemotherapy and liver resection is still unclear. This retrospective study was performed to elucidate this issue. Methods Histologic slides of resected CLM of patients who underwent neoadjuvant bevacizumab-based chemotherapy and liver resection were investigated with respect to biliary and perineural invasion. Presence of invasion was correlated with radiologic and histologic response, recurrence-free survival (RFS) and overall survival (OS). Results One hundred forty-one patients were enrolled. There was a significant association between biliary and perineural invasion, respectively (P = 0.001). Moreover, both biliary and perineural invasion were associated with bilobar metastatic spread and higher number of metastases, while perineural invasion was also associated with a higher Fong score. No significant association was found with response. In univariable analysis, biliary and perineural invasion were associated with shorter RFS (median 10.1 vs. 13.5 months, HR 2.09, P = 0.010 and 7.6 vs. 14.0, HR 2.23, P = 0.001, respectively). Biliary invasion was also associated with shorter OS (median 32.8 months vs. not reached, HR 2.78, P = 0.010), however these results did not remain significant in multivariable analysis. Conclusions In patients with resectable colorectal liver metastases undergoing neoadjuvant bevacizumab-based chemotherapy and liver resection, biliary and perineural invasion are associated with higher tumor load but may not be prognostic biomarkers.

Belatacept was recently evaluated in liver transplantation (LT) in a phase II multicenter trial, which was terminated prematurely. Patients were more than two yr post-LT at the time. As high rates of spontaneous tolerance after LT have been reported and as belatacept has marked immunomodulatory effects, we decided to maintain the belatacept patients enrolled at our center (n = 4) on MMF monotherapy. All belatacept patients on MMF monotherapy developed graft dysfunction consistent with acute rejection after a mean period of 10.3 (7-14) wk. Patients were therefore switched to triple therapy with CNI, MMF, and corticosteroids. Graft dysfunction resolved within 1-3 wk after switch. At the time of belatacept discontinuation, mean eGFR was 105.1 mL/min/1.73 m² (92.1-118.9) in belatacept patients compared to 58 mL/min/1.73 m² (36.1-98.2) in controls (p = 0.022). One yr after the switch to CNI therapy, eGFR had declined by 27.4 mL (19.2-39.3; p = 0.008). Thus, LT patients treated with belatacept show superior kidney function that declines upon institution of CNIs. MMF monotherapy following withdrawal of belatacept is associated with a high incidence of graft dysfunction. Belatacept has no obvious immunomodulatory effects in LT recipients that would be sufficient to allow drug withdrawal with a high rate of success.

Hyponatremia is a complication of diuretic treatment and has been recently identified as a novel factor associated with osteoporosis and fractures. The impact of diuretic-associated electrolyte disorders on osteoporotic fractures (OF) has rarely been studied systematically.We conducted a study in patients presenting to the emergency department at the University Hospital Bern. In this retrospective case series analysis of prospectively gathered data, over a 2-year period we identified 10,823 adult (≥50 years) outpatients with a measured baseline serum sodium, at admission to the hospital. OF patients were compared to a control group without fractures using standard statistical methods.Four hundred and eighty (5%) patients had 547 OF. The OF group had a higher mean age (73 vs. 68 years, p0.0001), smaller proportion of men (37% vs. 58%, p0.0001), higher hospitalisation rate (83% vs. 62%, p0.0001) and longer hospital stay (8 vs. 6 days, p0.0001). Any diuretic agent (p0.0001), loop diurietics (p=0.02), spironolactone (p=0.02) and amiloride (p0.01) were used significantly more in OF patients, but not thiazides (p=0.68). The prevalence of hyponatremia increased significantly (p0.0001) with the number of diuretics taken. Advanced age (odds ratio [OR] 1.04, p0.0001), hyponatremia (OR 1.46, p=0.011) higher serum creatinine (OR 1.53, p=0.0001), furosemide use alone (OR 1.40, p=0.01) and co-treatment with amiloride (OR 2.22, p=0.02) were associated with a higher risk for OF.This study highlights the clinical association of hyponatremia during the use of certain diuretics (i.e. furosemide or in combination, i.e. amiloride) with an increased risk of osteoporosis associated fractures. Although evidence-based data is currently lacking a pragmatic approach concerning hyponatremia monitoring and correction appears reasonable in selected groups of patients.

Purposes The aim of the study was to describe the prevalence, demographic, and clinical characteristics and etiologies of hypercalcemia in emergency department patients. Basic procedures In this retrospective cross-sectional descriptive study, all patients admitted between April 1, 2008, and March 31, 2011, to the emergency department of Inselspital, University Hospital Bern, were screened for the presence of hypercalcemia, defined as a serum calcium exceeding 2.55 mmol/L after correction for serum albumin. Demographic, laboratory, and outcome data were gathered. A detailed medical record review was performed to identify causes of hypercalcemia. Main findings During the study period, 14 984 patients (19% of all admitted patients) received a measurement of serum calcium. Of these, 116 patients (0.7%) presented with hypercalcemia. Median serum calcium was 2.72 mmol/L (first quartile, 2.64; third quartile, 2.88), with 4.3 mmol/L being the maximum serum calcium value observed. Underlying malignancy in 44% of patients and hyperparathyroidism in 20% (12% secondary and 8% primary) were the leading causes of hypercalcemia. Twenty-six percent of patients presented with symptomatic hypercalcemia. Weakness was the most common symptom of hypercalcemia, followed by nausea and disorientation. Principal conclusions Hypercalcemia is a rare but harmful electrolyte disorder in emergency department patients. Unspecific symptoms such as a change in mental state, weakness, or gastrointestinal symptoms should prompt physicians to order serum calcium measurements, at least in patients with known malignancy or renal insufficiency.

Background: Calculation of electrolyte-free water clearance (EFWC) allows for quantification of renal losses of free water and was shown to be helpful in the differential diagnosis of dysnatremias and might help in the correction of the electrolyte disorders. A modified EFWC formula (MEFWC) was described to be more accurate than the conventional one; however, it has never been evaluated clinically. Methods: In order to evaluate the performance of MEFWC compared to EFWC under clinical circumstances, we gathered data from a total of 912 patient days of 138 critically ill patients. EFWC and MEFWC were calculated on the basis of these data. Additionally, from data of critically ill patients, we calculated a prediction of serum sodium based on the Edelman equation using either EFWC or MEFWC and compared results. Results: Altogether, 343 normonatremic, 124 hyponatremic and 445 hypernatremic days were analyzed. Results for EFWC and MEFWC correlated significantly (R = 0.98). In patients with hyponatremia, the absolute difference between EFWC and MEFWC was significantly larger than in patients with normonatremia (437 vs. 256 ml, p < 0.01). The absolute difference between EFWC and MEFWC correlated significantly with the level of serum sodium (R = –0.41). The mean difference in the prediction of serum sodium change as calculated based on the Edelman equation between the formula using EFWC and the formula using MEFWC was 0.7 mmol/l (SD 0.68) and was highest in hyponatremia and lowest in hypernatremia. Conclusion: Results of EFWC and MEFWC were comparable in critically ill patients. Under normal circumstances, the use of the more complicated MEFWC is not justified. In hyponatremia, the difference between EFWC and MEFWC is larger and thus might justify the use of the more complicated formula.

Hypernatremia is common in the medical Intensive Care Unit (ICU) and has been described as an independent risk factor for mortality. Hypernatremia has not yet been studied in a collection of ICU patients after cardiothoracic surgery. Therefore, we wanted to determine the incidence of hypernatremia in a surgical ICU and its association with outcomes of critically ill surgical patients.In this retrospective cohort study performed at a surgical ICU of a university hospital in Vienna, patients were admitted to the ICU after major cardiothoracic surgery between May 1999 and October 2007. Data on serum sodium in the ICU, ICU mortality, hospital mortality, and length of ICU stay were collected prospectively.2,699 patients underwent surgery during the study period, and 2,314 patients were included in the study. Two hundred twenty-one (10%) patients acquired hypernatremia during their ICU stay. Median onset of hypernatremia was on day 4 (2-7). Patients with ICU-acquired hypernatremia had a higher ICU mortality (19%) compared to patients without hypernatremia (8%; p0.01). Length of ICU stay was increased in patients with hypernatremia (17 vs. 3 days; p0.01). In a multivariate Cox regression, ICU-acquired hypernatremia was an independent risk factor for ICU mortality within 28 days.Hypernatremia is a common event early in the course of critical illness after major cardiothoracic surgery and is independently associated with ICU mortality within 28 days. Future research should focus on the impact of hypernatremia on physiological functions as well as adequate and safe treatment of the electrolyte disorder.

Background Hypernatremia is a serious electrolyte disturbance and an independent risk factor for mortality in critically ill patients. In many cases, hypernatremia is an iatrogenic problem that develops in the intensive care unit (ICU). Study Design Case series. Setting & Participants 45 patients were studied in a medical ICU. For inclusion in the study, patients needed to show an increase in serum sodium concentration to greater than 149 mEq/L from an initial concentration of less than 146 mEq/L. Outcomes Solute balance, fluid balance, and both. Causes of hypernatremia. Measurements The daily mass balance of sodium, potassium, and water over 1- to 3-day intervals was measured while serum sodium levels were increasing. Results During the study period, 69 of 981 patients (7%) acquired hypernatremia after admission to the ICU. Of these, 45 had sufficient data for evaluation. Maximum serum sodium levels were 150 to 164 mEq/L. The average duration of hypernatremia was 2 days (range, 1 to 10 days), with an average onset on day 5.9 ± 4.3 of the ICU stay. Patients were classified as having a positive solute balance (n = 17; 38%), negative fluid balance (n = 20; 44%), or both (n = 8; 18%). The most important extrarenal factors contributing to hypernatremia were fever (45%) and diarrhea (18%). Polyuria was observed in 38% of patients and 35% had acute renal failure. Hypertonic solutions were administered to 27% of patients. Limitations Retrospective analysis; lack of daily measurement of body weight. Conclusion ICU-acquired hypernatremia is associated with multiple factors associated with negative fluid and positive solute balance.

Summary Although chronological donor age is the most potentpredictor of long-term outcome after renal transplantation,it does not incorporate individual differences of the aging-process itself. We therefore hypothesized that an estimateof biological organ age as derived from markers of cellularsenescence in zero hour biopsies would be of higherpredictive value. Telomere length and mRNA expressionlevels of the cell cycle inhibitors CDKN2A (p16INK4a) andCDKN1A (p21WAF1) were assessed in pre-implantationbiopsies of 54 patients and the association of these andvarious other clinical parameters with serum creatinineafter 1 year was determined. In a linear regression analysis,CDKN2A turned out to be the best single predictorfollowed by donor age and telomere length. A multiplelinear regression analysis revealed that the combinationof CDKN2A values and donor age yielded even higherpredictive values for serum creatinine 1 year after trans-plantation. We conclude that the molecular aging markerpredict renal allograft function after 1 year significantlybetter than chronological donor age alone.Key words: biological organ age, CDKN1A, CDKN2A, kidneytransplantation, long-term allograft function, telomerelength, zero hour biopsy.

Hypernatremia is common in the intensive care unit (ICU). We assessed the prevalence of hypernatremia and its impact on mortality and ICU length of stay (LOS).Retrospective analysis.All patients admitted to a medical ICU of a university hospital during a 35-month observation period.Hypernatremia (serum sodium149 mmol/L) after admission to the ICU.Main outcomes were 28-day hospital mortality and ICU LOS. Demographic factors, main diagnosis, and severity of illness. Cox proportional hazards regression models were used for data analysis.Of 981 patients, 90 (9%) had hypernatremia, on admission to the ICU in 21 (2%) and developed during the ICU stay in 69 patients (7%). Of these 981 patients, 235 (24%) died; LOS was 8 +/- 9 (SD) days. Mortality rates were 39% and 43% in patients with hypernatremia on admission or that developed after admission compared with 24% in patients without hypernatremia (P0.01). LOS was 20 +/- 16 days in patients with hypernatremia compared with 8 +/- 10 days in patients without hypernatremia (P0.001). In multivariable analysis, hypernatremia was an independent risk factor for mortality (relative risk, 2.1; 95% confidence interval, 1.4 to 3.3).Retrospective design, absence of data for long-term mortality.Most cases of hypernatremia in the ICU developed after admission, suggesting an iatrogenic component in its evolution. Hypernatremia is associated with increased mortality. Strategies for preventing hypernatremia in the ICU should be encouraged.

Background. Donor factors such as age profoundly influence long-term graft function after cadaveric renal transplantation, but the molecular signature of these aspects in the allograft remains unknown. Methods. We analyzed the genome-wide gene expression signature of donor kidney biopsies of different ages obtained before transplantation. Subsequent analysis compared expression profiles from allografts with excellent function versus impaired function at 1 yr after engraftment. Differential expression profiles were analyzed on the level of molecular function and biologic role, as well as by analysis of co-regulation through transcription factors, regulatory networks, and protein-protein interaction data utilizing extended bioinformatics. Results. The 15 subjects with excellent transplant function defined as calculated GFR≥45 mL/min/1.73 m 2 at 1 yr exhibited a distinctly different gene expression profile than the matched 16 subjects with impaired function defined as calculated GFR

BACKGROUND Parenchymal transection represents a crucial step during liver surgery and many different techniques have been described so far. Stapler resection is supposed to be faster than CUSA resection. However, whether speed impacts on the inflammatory response in patients undergoing liver resection (LR) remains unclear. MATERIALS AND METHODS This is a randomized controlled trial including 40 patients undergoing anatomical LR. Primary endpoint was transection speed (cm2/min). Secondary endpoints included the perioperative change of pro- and anti-inflammatory cytokines, overall surgery duration, length of hospital stay, morbidity and mortality. RESULTS Mean transection speed was significantly higher in patients undergoing stapler hepatectomy compared to CUSA resection (CUSA: 1 (0.4) cm2/min vs. Stapler: 10.8 (6.1) cm2/min; p

Establishing donor-specific immunological tolerance could improve long-term outcome by obviating the need for immunosuppressive drug therapy, which is currently required to control alloreactivity after organ transplantation. Mixed chimerism is defined as the engraftment of donor hematopoietic stem cells in the recipient, leading to viable coexistence of both donor and recipient leukocytes. In numerous experimental models, cotransplantation of donor bone marrow (BM) into preconditioned (e.g., through irradiation or cytotoxic drugs) recipients leads to transplantation tolerance through (mixed) chimerism. Mixed chimerism offers immunological advantages for clinical translation; pilot trials have established proof of concept by deliberately inducing tolerance in humans. Widespread clinical application is prevented, however, by the harsh preconditioning currently necessary for permitting BM engraftment. Recently, the immunological mechanisms inducing and maintaining tolerance in experimental mixed chimerism have been defined, revealing a more prominent role for regulation than historically assumed. The evidence from murine models suggests that both deletional and regulatory mechanisms are critical in promoting complete tolerance, encompassing also the minor histocompatibility antigens. Here, we review the current understanding of tolerance through mixed chimerism and provide an outlook on how to realize widespread clinical translation based on mechanistic insights gained from chimerism protocols, including cell therapy with polyclonal regulatory T cells.

Gitelman syndrome is a rare hereditary disorder of the thiazide-sensitive NaCl transporter in the distal renal tubular cells, but mimicking of such hereditary tubular disorders has been described in different autoimmune diseases (Sjögren syndrome, SLE, ...). A 62-year-old woman with painful red eyes and sicca syndrome presented at the ophthalmological department. The diagnostic evaluation identified a Sjögren syndrome with early endophthalmitis as the reason for the red eyes. Results of laboratory examination indicated severe hypokalemia, metabolic alkalosis and hypomagnesemia, although this had not been seen years earlier. Together with the urine analysis, a rare case of an acquired Gitelman syndrome was diagnosed. Substitution with potassium and magnesium improved the initial symptoms of weakness, but renal electrolyte wasting persisted even after treatment of Sjögren syndrome. In patients with autoimmune disease, laboratory analysis of serum electrolytes should be performed because different acquired tubular disorders can lead to severe hypokalemia.

Background. Bone loss remains a serious problem after kidney transplantation and is most pronounced during the first months after engraftment. Bisphosphonates are frequently used to treat posttransplant osteodystrophy, but data of large randomized controlled trials (RCTs) are missing. Methods. We, therefore, conducted this systematic review of the literature, searching electronical databases, reference lists and abstracts from scientific meetings to identify RCTs in all languages. The primary outcome assessed was the change in bone mineral density (BMD) during the early posttransplantation period. Based on the mean BMD change presented in the identified publications, the authors were asked for the individual BMD results of all randomized patients, determined at lumbar spine and femoral neck before and after bisphosphonate therapy. Data were pooled for summary estimates by using weighted mean differences of absolute change in BMD. An analysis of covariance was performed, adjusted for individual baseline values, treatment arm and individual trial. Results. Five studies involving 180 participants were included in our meta-analysis. Treatment with bisphosphonates showed a substantial effect in preventing post-transplant osteodystrophy. BMD decline at the lumbar spine within 6–12 months after transplantation was significantly reduced by 0.06 g/cm 2 in patients treated with bisphosphonates (95% CI 0.05–0.08 g/cm 2 ). At the femoral neck, the loss of BMD was reduced by 0.05 g/cm 2 during this period (95% CI 0.0–0.11 g/cm 2 ), reaching just non-statistical significance. This benefit of bone loss prevention could be reached without major side effects. Conclusion. Bisphosphonates are effective in preventing bone loss in the early post-transplant period.

Roughly 25% of cadaveric, but rarely living donor renal transplant recipients, develop postischemic acute renal failure, which is a main risk factor for reduced long-term allograft survival. An accurate prediction of recipients at risk for ARF is not possible on the basis of donor kidney morphology or donor/recipient demographics. We determined the genome-wide gene-expression pattern using cDNA microarrays in three groups of 36 donor kidney wedge biopsies: living donor kidneys with primary function, cadaveric donor kidneys with primary function and cadaveric donor kidneys with biopsy proven acute renal failure. The descriptive genes were characterized in gene ontology terms to determine their functional role. The validation of microarray experiments was performed by real-time PCR. We retrieved 132 genes after maxT adjustment for multiple testing that significantly separated living from cadaveric kidneys, and 48 genes that classified the donor kidneys according to their post-transplant course. The main functional roles of these genes are cell communication, apoptosis and inflammation. In particular, members of the complement cascade were activated in cadaveric, but not in living donor kidneys. Thus, suppression of inflammation in the cadaveric donor might be a cheap and promising intervention for postischemic acute renal failure.

Measurement of access blood flow is the preferred noninvasive screening test for hemodialysis arteriovenous (AV) fistula stenosis. However, performance characteristics of the 2 most frequently used ultrasound techniques compared with fistulography remain elusive.We evaluated 59 hemodialysis patients with native forearm AV fistulae who underwent all 3 measurements in a prospective order: the ultrasound dilution technique (UDT), color Doppler ultrasonography (CDUS), and fistulography. Patients with angiographically diagnosed access stenosis underwent angioplasty and were followed up by means of monthly UDT measurements until restenosis occurred within the first 6 months.Both ultrasound techniques predicted access stenosis (P0.01). Performance was similar between both techniques, evaluated by receiver operating characteristic curves. Areas under the curve averaged 0.79 (95% confidence interval [CI], 0.66 to 0.91) for UDT and 0.80 (95% CI, 0.65 to 0.94) for CDUS. Correlation between measured UDT and CDUS blood flow rates was 0.37 (Spearman's rho, rho = 0.004). The calculated optimal cutoff value for the prediction of stenosis was 465 mL/min for the UDT and 390 mL/min for the CDUS technique. Access stenosis was diagnosed in 41 patients who subsequently underwent percutaneous angioplasty (PTA), which was successful in 34 patients. Restenosis occurred in 13 patients within the first 6 months after PTA. UDT access blood flow after PTA was significantly lower in these 13 patients compared with the other 21 patients.Our data suggest that blood flow monitoring of AV hemodialysis access by ultrasound provides a reasonable prediction of access stenosis and restenosis.

In renal transplantation, postischemic acute renal failure (ARF) develops in more than 20% of patients. We investigated whether tubular epithelial cells obtained from donor kidneys without subsequent ARF express a different pattern of survival genes, compared with cells from kidneys exhibiting ARF. Donor kidney biopsy specimens were obtained before transplantation from eight recipients of cadaveric kidneys with primary graft function (CAD-PF), eight patients with biopsy-proven ARF without rejection (CAD-ARF), and eight recipients of living donor kidneys with primary graft function (LIV). One thousand proximal tubular epithelial cells per biopsy specimen were isolated by laser capture microdissection. Quantitative analysis of apoptosis and the apoptosis regulatory genes Bcl-2, Bcl-xL, and Bax were performed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling staining and real-time PCR, respectively. Primary cultures of human proximal tubular epithelial cells served as calibrator. The number of apoptotic cells was significantly higher in CAD-ARF compared with LIV and CAD-PF (1.5 +/- 1.1% [p0.05] vs. 0.3 +/- 0.2% vs. 0.4 +/- 0.2%; mean +/- SD). The apoptosis inhibitors Bcl-2 and Bcl-xL were significantly up-regulated in renal tubular cells of recipients without ARF compared with CAD-ARF. The ratios of Bcl-2/GAPDH normalized to calibrator were as follows: LIV 48 +/- 30, CAD-PF 38 +/- 55, and CAD-ARF 5 +/- 7 (p0.05). The corresponding ratios for Bcl-xL were as follows: LIV 6 +/- 6, CAD-PF 5 +/- 3, and CAD-ARF 1 +/- 1 (p0.05). No difference in the expression of the proapoptotic Bax could be observed. These data suggest that failure of proximal tubular cells to respond to injury by up-regulation of survival factors from the Bcl-2 family contributes to postischemic ARF in patients after cadaveric renal transplantation.

Immunosuppressant nephrotoxicity is among the major contributors to chronic renal allograft failure, which is the primary cause of graft loss. Because of a lack of alternatives to the inherently nephrotoxic calcineurin inhibitors for maintenance immunosuppression, long-term survival rates for renal allografts have not increased in proportion to the rise in short-term graft survival. Clinical studies have shown that mammalian target of rapamycin-based immunosuppression in combination with calcineurin inhibitors, mycophenolate mofetil, or azathioprine is safe and efficacious. These data suggest that a target of rapamycin antagonist (sirolimus/everolimus) should be used initially in combination with calcineurin antagonists in order to prevent early acute rejection. After 3-6 months, a maintenance immunosuppressive regimen can then be individually tailored to each patient on the basis of their clinical and histological status. Those patients at high immunological risk should remain on full-dose triple therapy. All other patients should receive either a calcineurin inhibitor or corticosteroid-sparing regimen, with a maintenance dose of a target of rapamycin inhibitor. This regimen should result in less immunosuppressant nephrotoxicity and a reduction in the serious side effects of steroids, such as diabetes and osteoporosis. Whether the proposed individually designed immunosuppressive regimen, based on protocol biopsies and mammalian target of rapamycin inhibition, will result in prolonged graft and patient survival remains to be determined.

Osteoprotegerin (OPG) has a profound inhibitory effect on osteoclast differentiation and bone resorption. Because high-turnover renal osteodystrophy (ROD) is characterized by increased osteoclast activity, serum OPG concentrations might be used to distinguish between forms of ROD. Twenty-six patients on maintenance hemodialysis therapy underwent a transiliac crest biopsy for evaluation of histopathologic characteristics and histomorphometric studies. ROD was diagnosed as type II (normal or low turnover) or type III (high turnover plus osteoidosis) disease. Bone mineralization density distribution (BMDD) was characterized by measuring the mean trabecular calcium concentration in the biopsy specimen with quantitative backscattered electron imaging. Patients underwent additional dual-energy x-ray absorptiometry (DEXA) of the spine and hip and measurement of such biochemical markers of bone turnover as OPG, intact parathyroid hormone (iPTH), osteocalcin, calcitonin, bone alkaline phosphatase, and cross-laps. OPG levels were significantly reduced in patients with ROD III compared with ROD II (118 +/- 38 versus 204 +/- 130 pg/mL; P < 0.05) and correlated with BMDD (r = 0.43; P < 0.05). Patients with ROD III showed significantly lower BMDD compared with healthy controls (21.42% +/- 0.12% versus 22.17% +/- 0.81% weight; P < 0.01). Besides iPTH, which showed significantly greater levels in patients with ROD III than ROD II (382 +/- 322 versus 136 +/- 156 pg/mL; P < 0.05), none of the serological markers or DEXA was useful in separation of the groups. Discriminant function analysis showed that a combination of OPG and iPTH correctly classifies ROD II in 72% and ROD III in 88% of patients. We conclude that OPG in combination with iPTH can be used as a marker for noninvasive diagnosis of ROD in hemodialysis patients. Furthermore, OPG serum levels might be used to estimate trabecular bone mineralization in these subjects.

Background Postoperative complications are still a major concern after liver resection (LR). Systemic inflammation and deregulated reactive oxygen species during major abdominal surgery may impair outcome after hepatectomy. Methods Patients undergoing LR were included in this study (n = 40). Oxidative stress (OS) was measured peri- and post-operatively as static oxidation-reduction potential markers (sORP) and antioxidant capacity ORP (cORP) by using the RedoxSYS Diagnostic system. Furthermore, Th1- and Th2-specific cytokines were assessed. Results Whereas there was no significant change in systemic sORP during LR and in the early postoperative course, there was a substantial decrease of cORP immediately post-surgery, and on postoperative days 1 and 3 (p

While belatacept has shown favorable short- and midterm results in kidney transplant recipients, only projections exist regarding its potential impact on long-term outcome. Therefore, we performed a retrospective case-match analysis of the 14 belatacept patients originally enrolled in the phase II multicenter trial at our center. Fifty six cyclosporine (CyA)-treated patients were matched according to age at transplantation, first/retransplant, and donor type. Ten years after kidney transplantation, kidney function remained superior in belatacept-treated patients compared with the CyA control group. Moreover, none of the belatacept-treated patients had donor-specific antibodies ≥10 years post-transplantation compared with 38.5% of tested CyA-treated subject (0/10 vs. 5/13; P = 0.045). Notably, however, patient and graft survival was virtually identical in both groups (71.4% vs. 71.3%; P = 0.976). In the present single-center study population, patients treated with belatacept demonstrated a patient and graft survival at 10 years post-transplant which was comparable to that of similarly selected CNI-treated patients. Larger studies with sufficient statistical power are necessary to definitively determine long-term graft survival with belatacept.

Recent studies have shown a decline in glomerular filtration rate and increased renal vasoconstriction after administration of normal saline when compared with IV solutions with less chloride. In this study, we investigated the impact of normal saline versus a chloride-reduced, acetate-buffered crystalloid on the incidence of hyperkalemia during cadaveric renal transplantation. The incidence of metabolic acidosis and kidney function were secondary aims.In this prospective randomized controlled trial, 150 patients received normal saline or an acetate-buffered balanced crystalloid during and after cadaveric renal transplantation. Venous blood gases were obtained at the start of anesthesia and every 30 minutes until discharge from the postoperative surveillance unit. Serum creatinine and 24-hour urine output were obtained on postoperative days 1, 3, and 7.Patients received a similar amount of fluid (median: 2625mL [interquartile range: 2000 to 3100] vs 2500 mL [2000 to 3050], P = 0.83). Hyperkalemia, defined as serum potassium5.9 mmol/L, occurred in 13 patients (17%) in the saline and 15 (21%) in the balanced group (P = 0.56; difference between proportions -0.037 [-16.5% to 8.9%]). Minimum base excess was lower in the saline group compared with the balanced regimen (-4.5 mmol/L [-6 to -2.4] vs -2.6 mmol/L [-4 to -1], P0.001) and maximum chloride was significantly higher in the saline group (109 mmol/L [107 to 111] vs 107 mmol/L [105 to 109], P0.001). No difference in creatinine or urine output was seen postoperatively. Significantly more patients needed catecholamines in the saline group (30% vs 15%, P = 0.03).The incidence of hyperkalemia differed by less than 17% between groups. Use of balanced crystalloid resulted in less hyperchloremia and metabolic acidosis. Significantly more patients in the saline group required administration of catecholamines for circulatory support.

BACKGROUND The development of metabolic alkalosis was described recently in patients with hypernatremia. However, the causes for this remain unknown. The current study serves to clarify whether metabolic alkalosis develops in vitro after removal of free water from plasma and whether this can be predicted by a mathematical model. MATERIALS AND METHODS Ten serum samples of healthy humans were dehydrated by 29 % by vacuum centrifugation corresponding to an increase of the contained concentrations by 41 %. Constant partial pressure of carbon dioxide at 40 mmHg was simulated by mathematical correction of pH [pH(40)]. Metabolic acid-base state was assessed by Gilfix' base excess subsets. Changes of acid-base state were predicted by the physical-chemical model according to Watson. RESULTS Evaporation increased serum sodium from 141 (140-142) to 200 (197-203) mmol/L, i.e., severe hypernatremia developed. Acid-base analyses before and after serum concentration showed metabolic alkalosis with alkalemia: pH(40): 7.43 (7.41 to 7.45) vs 7.53 (7.51 to 7.55), p = 0.0051; base excess: 1.9 (0.7 to 3.6) vs 10.0 (8.2 to 11.8), p = 0.0051; base excess of free water: 0.0 (- 0.2 to 0.3) vs 17.7 (16.8 to 18.6), p = 0.0051. The acidifying effects of evaporation, including hyperalbuminemic acidosis, were beneath the alkalinizing ones. Measured and predicted acid-base changes due to serum evaporation agreed well. CONCLUSIONS Evaporation of water from serum causes concentrational alkalosis in vitro, with good agreement between measured and predicted acid-base values. At least part of the metabolic alkalosis accompanying hypernatremia is independent of renal function.

OBJECTIVES To investigate the prevalence, etiology, and symptoms of severe hypokalemia in patients presenting to the emergency department. METHODS In this retrospective, cross-sectional analysis, we included all patients who received measurement of serum potassium between April 2008 and 31 March 2011 at the emergency department to calculate the prevalence rate for hypokalemia. Of all patients with a serum potassium below 2.6 mmol/l (severe hypokalemia), we performed a detailed review of the patients' charts from the emergency department and the chart of the subsequent hospitalization. We identified ECG changes attributable to hypokalemia from the ECGs performed in the emergency department. RESULTS During the study period, measurements of serum potassium for a total of 43 805 patients were performed. Of these patients, 4826 (11%) had hypokalemia (potassium

Peritonitis is a major complication of peritoneal dialysis (PD) being associated with hospitalization, catheter loss, technique failure, and increased mortality. Data on incidence rates and risk factors for peritonitis episodes vary between centers. In seven Austrian PD units clinical and laboratory data on each peritonitis episode were collected from all patients (n = 726) who performed PD between January 2000 and December 2009. The peritonitis incidence rate was 0.32 episodes/patient-year. In a multivariate analysis the risk of peritonitis was decreased by 57% in patients treated with oral active vitamin D (HR 0.43; 95% CI 0.28-0.64). Renal disease classified as "other or unknown" (HR 1.65; 95% CI 1.08-2.53) and serum albumin

Purpose Hyponatremia is frequently observed in intensive care unit (ICU) patients, but there is still lack information on the physiological mechanisms of development. Materials and Methods In this retrospective analysis we performed tonicity balances in 54 patients with ICU acquired hyponatremia. We calculated fluid and solute in and outputs during 24 hours in 106 patient days with decreasing serum-sodium levels. Results We could observe a positive fluid balance as a single reason for hyponatremia in 25% of patients and a negative solute balance in 57%. In 18% both factors contributed to the decrease in serum-sodium. Hyponatremic patients had renal water retention, measured by electrolyte free water clearance calculation in 79% and positive input of free water in 67% as reasons for decline of serum-sodium. The theoretical change of serum sodium during 24 hours according to the calculations of measured balances correlated well with the real change of serum sodium ( r = 0.78, P Conclusions Balance studies showed that renal water retention together with renal sodium loss and high electrolyte free water input are the major contributors to the development of hyponatremia. Control of renal water and sodium handling by urine analysis may contribute to a better fluid management in the ICU population.

Summary BACKGROUND: Thyroid hormone is a central regulator of body functions. Disorders of thyroid function are considered to be a cause of electrolyte disorders. Only few data on the association between thyroid function and electrolyte disorders exists. METHODS: In the present retrospective analysis data from all patients admitted to the Department of Emergency Medicine of a university hospital who had measurements of thyroid function (TSH, fT3, fT4) and electrolytes were included. RESULTS: 9,012 patients with measurement of TSH and electrolytes were available. 86% of patients had normal, 4% suppressed and 10% elevated TSH. Serum sodium was significantly lower in patients with high TSH levels (p

This study investigated Nrf2-activating properties of a coffee blend combining raw coffee bean constituents with 5-O-caffeoylquinic acid (CGA) as a lead component with typical roasting products such as N-methylpyridinium (NMP). In cell culture (HT29) the respective coffee extract (CN-CE) increased nuclear Nrf2 translocation and enhanced the transcription of ARE-dependent genes as exemplified for NAD(P)H:quinone oxidoreductase and glutathione-S-transferase (GST)A1, reflected in the protein level by an increase in GST enzyme activity. In a pilot human intervention study (29 healthy volunteers), daily consumption of 750 mL of CN-coffee for 4 weeks increased Nrf2 transcription in peripheral blood lymphocytes on average. However, the transcriptional response pattern of Nrf2/ARE-dependent genes showed substantial interindividual variations. The presence of SNPs in the Nrf2-promoter, reported recently, as well as the detection of GSTT1*0 (null) genotypes in the study collective strengthens the hypothesis that coffee acts as a modulator of Nrf2-dependent gene response in humans, but genetic polymorphisms play an important role in the individual response pattern.

Purpose of review Blockade of costimulatory signalling is a promising approach to inhibit T-cell responses and consequently allograft rejection. The last decade was marked by progress in understanding the details of various costimulatory pathways and by the development of biologicals targeting these pathways with the aim of selectively and efficiently modulating T-cell responses. Recent findings Here we focus on the clinically relevant costimulatory pathways CD28:CD80/86, CD40:CD154 (CD40L), CD2:LFA-3 and ICAM:LFA-1. We will give a short overview of the physiologic function of these pathways and discuss results from preclinical and clinical studies of costimulation blockers targeting these pathways. Summary The development of costimulation blockers for clinical application in the field of organ transplantation was delayed by several setbacks. However, belatacept has recently been approved as first in class for renal transplantation. Several additional costimulation blockers are under development with some having already entered into clinical trials. Costimulation blockers are a new class of rationally designed immunosuppressive drugs with considerable potential for improving outcome of organ transplantation.