Relationship between GFR, intact PTH, oxidized PTH, non-oxidized PTH as well as FGF23 in patients with CKD.

Fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) are regulators of renal phosphate excretion and vitamin D metabolism. In chronic kidney disease (CKD), circulating FGF23 and PTH concentrations progressively increase as renal function declines. Oxidation of PTH at two methionine residues (positions 8 and 18) causes a loss of function. The impact of n-oxPTH and oxPTH on FGF23 synthesis, however, and how n-oxPTH and oxPTH concentrations are affected by CKD, is yet unknown. The effects of oxidized and non-oxidized PTH 1-34 on Fgf23 gene expression were analyzed in UMR106 osteoblast-like cells. Furthermore, we investigated the relationship between n-oxPTH and oxPTH, respectively, with FGF23 in two independent patients' cohorts (620 children with CKD and 600 kidney transplant recipients). While n-oxPTH stimulated Fgf23 mRNA synthesis in vitro, oxidation of PTH in particular at Met8 led to a markedly weaker stimulation of Fgf23. The effect was even stronger when both Met8 and Met18 were oxidized. In both clinical cohorts, n-oxPTH-but not oxPTH-was significantly associated with FGF23 concentrations, independent of known confounding factors. Moreover, with progressive deterioration of kidney function, intact PTH (iPTH) and oxPTH increased substantially, whereas n-oxPTH increased only moderately. In conclusion, n-oxPTH, but not oxPTH, stimulates Fgf23 gene expression. The increase in PTH with decreasing GFR is mainly due to an increase in oxPTH in more advanced stages of CKD.

Sclerostin is an independent risk factor for all-cause mortality in kidney transplant recipients.

BACKGROUND: Sclerostin is a hormone contributing to the bone-vascular wall cross talk and has been implicated in cardiovascular events and mortality in patients with chronic kidney disease (CKD). We analyzed the relationship between sclerostin and mortality in renal transplant recipients. METHODS: 600 stable renal transplant recipients (367men, 233 women) were followed for all-cause mortality for 3 years. Blood and urine samples for analysis and clinical data were collected at study entry. We performed Kaplan-Meier survival analysis and Cox regression models considering confounding factors such as age, eGFR, cold ischemia time, HbA1c, phosphate, calcium, and albumin. Optimal cut-off values for the Cox regression model were calculated based on ROC analysis. RESULTS: Sixty-five patients died during the observation period. Nonsurvivors (n = 65; sclerostin 57.31 ± 30.28 pmol/L) had higher plasma sclerostin levels than survivors (n = 535; sclerostin 47.52 ± 24.87 pmol/L) (p = 0.0036). Kaplan-Meier curve showed that baseline plasma sclerostin concentrations were associated with all-cause mortality in stable kidney transplant recipients (p = 0.0085, log-rank test). After multiple Cox regression analysis, plasma levels of sclerostin remained an independent predictor of all-cause mortality (hazard ratio, 1.011; 95% CI 1.002-1.020; p = 0.0137). CONCLUSIONS: Baseline plasma sclerostin is an independent risk factor for all-cause mortality in patients after kidney transplantation.

Effect of Regional Citrate Anticoagulation vs Systemic Heparin Anticoagulation During Continuous Kidney Replacement Therapy on Dialysis Filter Life Span and Mortality Among Critically Ill Patients With Acute Kidney Injury: A Randomized Clinical Trial.

Importance: Although current guidelines suggest the use of regional citrate anticoagulation (which involves the addition of a citrate solution to the blood before the filter of the extracorporeal dialysis circuit) as first-line treatment for continuous kidney replacement therapy in critically ill patients, the evidence for this recommendation is based on few clinical trials and meta-analyses. Objective: To determine the effect of regional citrate anticoagulation, compared with systemic heparin anticoagulation, on filter life span and mortality. Design, Setting, and Participants: A parallel-group, randomized multicenter clinical trial in 26 centers across Germany was conducted between March 2016 and December 2018 (final date of follow-up, January 21, 2020). The trial was terminated early after 596 critically ill patients with severe acute kidney injury or clinical indications for initiation of kidney replacement therapy had been enrolled. Interventions: Patients were randomized to receive either regional citrate anticoagulation (n = 300), which consisted of a target ionized calcium level of 1.0 to 1.40 mg/dL, or systemic heparin anticoagulation (n = 296), which consisted of a target activated partial thromboplastin time of 45 to 60 seconds, for continuous kidney replacement therapy. Main Outcomes and Measures: Coprimary outcomes were filter life span and 90-day mortality. Secondary end points included bleeding complications and new infections. Results: Among 638 patients randomized, 596 (93.4%) (mean age, 67.5 years; 183 [30.7%] women) completed the trial. In the regional citrate group vs systemic heparin group, median filter life span was 47 hours (interquartile range [IQR], 19-70 hours) vs 26 hours (IQR, 12-51 hours) (difference, 15 hours [95% CI, 11 to 20 hours]; P < .001). Ninety-day all-cause mortality occurred in 150 of 300 patients vs 156 of 296 patients (Kaplan-Meier estimator percentages, 51.2% vs 53.6%; unadjusted difference, -2.4% [95% CI, -10.5% to 5.8%]; unadjusted hazard ratio, 0.91 [95% CI, 0.72 to 1.13]; unadjusted P = .38; adjusted difference, -6.1% [95% CI, -12.6% to 0.4%]; primary adjusted hazard ratio, 0.79 [95% CI, 0.63 to 1.004]; primary adjusted P = .054). Of 38 prespecified secondary end points, 34 showed no significant difference. Compared with the systemic heparin group, the regional citrate group had significantly fewer bleeding complications (15/300 [5.1%] vs 49/296 [16.9%]; difference, -11.8% [95% CI, -16.8% to -6.8%]; P < .001) and significantly more new infections (204/300 [68.0%] vs 164/296 [55.4%]; difference, 12.6% [95% CI, 4.9% to 20.3%]; P = .002). Conclusions and Relevance: Among critically ill patients with acute kidney injury receiving continuous kidney replacement therapy, anticoagulation with regional citrate, compared with systemic heparin anticoagulation, resulted in significantly longer filter life span. The trial was terminated early and was therefore underpowered to reach conclusions about the effect of anticoagulation strategy on mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT02669589.

Perioperative antibiotic prophylaxis in renal transplantation: a single-center comparison between two regimens and a brief survey among the Eurotransplant renal transplantation centers.

BACKGROUND: Perioperative antibiotic prophylaxis (PAP) is an integral part of kidney transplantation to prevent surgical site infections (SSI). In July 2015, we changed our standard from a multiple-dose to a single-dose (SD) prophylaxis. Here, we report on results with both regimens and a related survey among Eurotransplant renal transplantation centers. METHODS: From July 2015, all kidney graft recipients of our center were scheduled to receive SD i.v. cefazolin (group SD, n = 107). They were compared to patients, transplanted since January 2014, receiving our previous standard (i.v. piperacillin/flucloxacillin) until postoperative day (POD) 7, plus oral sultamicillin until POD 10 (group MD, n = 105). The primary endpoint was the number of SSIs during a 3-month observational period. RESULTS: The frequency of SSI episodes was generally low (group SD vs. MD: 2 vs. 4, p = 0.40). Of note, urinary tract infections occurred in 40 SD vs. 36 MD patients, respectively (p = 0.60). Urinary tract infections were caused by Escherichia coli in 36.8%. Female gender was the only independent risk factor on multivariate analysis (p = 0.002). In addition, 12 episodes of urosepsis in both groups occurred. All-cause infection with multi-resistant bacteria occurred less frequently in SD vs. MD patients (3.7% vs. 8.6%, p = 0.16). A majority of Eurotransplant centers used i.v. single-dose cephalosporins (36.9%), although substances and duration varied remarkably. CONCLUSION: Single-dose cefazolin was equally effective and less expensive compared to our previous MD regimen. Based on these findings, we conclude that future prospective studies should be designed to confirm the non-inferiority of single-dose antibiotic regimens.

Contrast-Enhanced Ultrasound (CEUS) and Quantitative Perfusion Analysis in Patients with Suspicion for Prostate Cancer.

PURPOSE: The aim of this study was to investigate contrast-enhanced ultrasound (CEUS) parameters acquired by software during magnetic resonance imaging (MRI) US fusion-guided biopsy for prostate cancer (PCa) detection and discrimination. MATERIALS AND METHODS: From 2012 to 2015, 158 out of 165 men with suspicion for PCa and with at least 1 negative biopsy of the prostate were included and underwent a multi-parametric 3 Tesla MRI and an MRI/US fusion-guided biopsy, consecutively. CEUS was conducted during biopsy with intravenous bolus application of 2.4 mL of SonoVue® (Bracco, Milan, Italy). In the latter CEUS clips were investigated using quantitative perfusion analysis software (VueBox, Bracco). The area of strongest enhancement within the MRI pre-located region was investigated and all available parameters from the quantification tool box were collected and analyzed for PCa and its further differentiation was based on the histopathological results. RESULTS: The overall detection rate was 74 (47 %) PCa cases in 158 included patients. From these 74 PCa cases, 49 (66 %) were graded Gleason ≥ 3 + 4 = 7 (ISUP ≥ 2) PCa. The best results for cancer detection over all quantitative perfusion parameters were rise time (p = 0.026) and time to peak (p = 0.037). Within the subgroup analysis (> vs ≤ 3 + 4 = 7a (ISUP 2)), peak enhancement (p = 0.012), wash-in rate (p = 0.011), wash-out rate (p = 0.007) and wash-in perfusion index (p = 0.014) also showed statistical significance. CONCLUSION: The quantification of CEUS parameters was able to discriminate PCa aggressiveness during MRI/US fusion-guided prostate biopsy.

Fetal Serum Metabolites Are Independently Associated with Gestational Diabetes Mellitus.

BACKGROUND/AIMS: Gestational diabetes (GDM) might be associated with alterations in the metabolomic profile of affected mothers and their offspring. Until now, there is a paucity of studies that investigated both, the maternal and the fetal serum metabolome in the setting of GDM. Mounting evidence suggests that the fetus is not just passively affected by gestational disease but might play an active role in it. Metabolomic studies performed in maternal blood and fetal cord blood could help to better discern distinct fetal from maternal disease interactions. METHODS: At the time of birth, serum samples from mothers and newborns (cord blood samples) were collected and screened for 163 metabolites utilizing tandem mass spectrometry. The cohort consisted of 412 mother/child pairs, including 31 cases of maternal GDM. RESULTS: An initial non-adjusted analysis showed that eight metabolites in the maternal blood and 54 metabolites in the cord blood were associated with GDM. After Benjamini-Hochberg (BH) procedure and adjustment for confounding factors for GDM, fetal phosphatidylcholine acyl-alkyl C 32: 1 and proline still showed an independent association with GDM. CONCLUSIONS: This study found metabolites in cord blood which were associated with GDM, even after adjustment for established risk factors of GDM. To the best of our knowledge, this is the first study demonstrating an independent association between fetal serum metabolites and maternal GDM. Our findings might suggest a potential effect of the fetal metabolome on maternal GDM.

Hyperlactatemia, Lactate Kinetics and Prediction of Citrate Accumulation in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy With Regional Citrate Anticoagulation.

OBJECTIVES: Citrate accumulation is a major complication of regional citrate anticoagulation during continuous renal replacement therapy. We studied the prediction of citrate accumulation during continuous veno-venous hemodialysis with regional citrate anticoagulation by initial lactate concentrations and lactate kinetics. DESIGN: A retrospective follow-up analysis from a cohort of critically ill patients. SETTING: Mixed medical-surgical ICUs at a university hospital. PATIENTS: All adult patients with acute kidney injury and treated with regional citrate anticoagulation-continuous veno-venous hemodialysis during a 3-year period (n = 1,070) were included in this retrospective study and screened for metabolic signs of citrate accumulation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The frequency of citrate accumulation during the first 48 hours of therapy was 2.26%. In patients with initial normal lactate (< 2.2 mmol/L), elevated lactate (≥ 2.2 to < 4 mmol/L), or severe hyperlactatemia (≥ 4 mmol/L), the frequency of citrate accumulation was 0.77%, 2.70%, and 6.33%, respectively. Receiver operating characteristics-area under the curve of initial lactate concentration was 0.789 for the prediction of citrate accumulation. Optimal cutoff from receiver operating characteristics (2.39 mmol/L) showed strong negative prediction (99.28%), but weak positive prediction (5.21%). The slope intercept of lactate kinetics over 48 hours was positive and significantly higher in patients with citrate accumulation compared to those without (+0.2 vs -0.006 mmol/L/hr; p < 0.001). In patients with initial severe hyperlactatemia (≥ 4 mmol/L), the median calculated lactate clearance at 6, 12, and 18 hours was 24.0%, 48.1%, and 59.4% in the nonaccumulation group. These clearance rates were significantly higher at each time-point compared to patients with citrate accumulation (-9.8%, -20.5%, and 2.3%, respectively; p < 0.001 for each time-point). The highest receiver operating characteristics-area under the curve for citrate accumulation was observed for 12-hour values of lactate clearance (area under the curve = 0.839; 95% CI, 0.751-0.927) with an optimal cut-off value of 24.3%. CONCLUSIONS: Risk of citrate accumulation during regional citrate anticoagulation in a well-selected cohort of patients is low even in case of initial severe hyperlactatemia. Lactate kinetics rather than initially elevated lactate concentration should be considered in assessing the risk of citrate accumulation.

A prospective study comparing tryptophan immunoadsorption with therapeutic plasma exchange for the treatment of chronic inflammatory demyelinating polyneuropathy.

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare paralyzing inflammatory neuropathy with probably autoimmune origin. While plasma exchange (PE) constitutes a first-line treatment option for CIDP, there is only little known about the efficacy and safety of immunoadsorption (IA), a more selective apheresis procedure with assumed better tolerability. METHODS: In this prospective-randomized pilot trial, patients were randomly assigned to receive 6 sessions of PE (n = 10) or IA (n = 10) treating equal plasma volumes. To evaluate efficacy, we calculated the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability score and the Medical Research Council (MRC) sum score at baseline (V1), after completion of 6 sessions (V2) as well as 4 weeks after completion (V3) in 9 patients per group (1 patient in each group did not complete follow-up). We additionally assessed safety and tolerability of treatments by monitoring adverse event and blood parameters. RESULTS: With IA, 6 out of 9 (66.7%) patients improved clinically, whereas with PE, 4 out of 9 (44.4%) patients improved, most of them immediately with completion of the apheresis treatment series. There was one adverse event (AE) out of 52 treatment sessions for the 9 patients in the IA group. In the PE group of 9 patients, there was 1 AE out of 51 sessions and a trend of greater fibrinogen reduction. No severe AE occurred in either group. CONCLUSION: The results of this pilot study suggest that IA is at least equally effective and safe compared to PE in CIDP patients.

Safety and efficacy of regional citrate anticoagulation in continuous venovenous hemodialysis in the presence of liver failure: the Liver Citrate Anticoagulation Threshold (L-CAT) observational study.

INTRODUCTION: Regional citrate anticoagulation (RCA) for continuous renal replacement therapy is widely used in intensive care units (ICUs). However, concern exists about the safety of citrate in patients with liver failure (LF). The aim of this study was to evaluate safety and efficacy of RCA in ICU patients with varying degrees of impaired liver function. METHODS: In a multicenter, prospective, observational study, 133 patients who were treated with RCA and continuous venovenous hemodialysis (RCA-CVVHD) were included. Endpoints for safety were severe acidosis or alkalosis (pH ≤7.2 or ≥7.55, respectively) and severe hypo- or hypercalcemia (ionized calcium ≤0.9 or ≥1.5 mmol/L, respectively) of any cause. The endpoint for efficacy was filter lifetime. For analysis, patients were stratified into three predefined liver function or LF groups according to their baseline serum bilirubin level (normal liver function ≤2 mg/dl, mild LF >2 to ≤7 mg/dl, severe LF >7 mg/dl). RESULTS: We included 48 patients with normal liver function, 43 with mild LF, and 42 with severe LF. LF was predominantly due to ischemia (39 %) or multiple organ dysfunction syndrome (27 %). The frequency of safety endpoints in the three patient strata did not differ: severe alkalosis (normal liver function 2 %, mild LF 0 %, severe LF 5 %; p = 0.41), severe acidosis (normal liver function 13 %, mild LF 16 %, severe LF 14 %; p = 0.95), severe hypocalcemia (normal liver function 8 %, mild LF 14 %, severe LF 12 %; p = 0.70), and severe hypercalcemia (0 % in all strata). Only three patients showed signs of impaired citrate metabolism. Overall filter patency was 49 % at 72 h. After censoring for stop of the treatment due to non-clotting causes, estimated 72-h filter survival was 96 %. CONCLUSIONS: RCA-CVVHD can be safely used in patients with LF. The technique yields excellent filter patency and thus can be recommended as first-line anticoagulation for the majority of ICU patients. TRIAL REGISTRATION: ISRCTN Registry identifier: ISRCTN92716512 . Date assigned: 4 December 2008.

Loss of insulin-induced activation of TRPM6 magnesium channels results in impaired glucose tolerance during pregnancy.

Hypomagnesemia affects insulin resistance and is a risk factor for diabetes mellitus type 2 (DM2) and gestational diabetes mellitus (GDM). Two single nucleotide polymorphisms (SNPs) in the epithelial magnesium channel TRPM6 (V(1393)I, K(1584)E) were predicted to confer susceptibility for DM2. Here, we show using patch clamp analysis and total internal reflection fluorescence microscopy, that insulin stimulates TRPM6 activity via a phosphoinositide 3-kinase and Rac1-mediated elevation of cell surface expression of TRPM6. Interestingly, insulin failed to activate the genetic variants TRPM6(V(1393)I) and TRPM6(K(1584)E), which is likely due to the inability of the insulin signaling pathway to phosphorylate TRPM6(T(1391)) and TRPM6(S(1583)). Moreover, by measuring total glycosylated hemoglobin (TGH) in 997 pregnant women as a measure of glucose control, we demonstrate that TRPM6(V(1393)I) and TRPM6(K(1584)E) are associated with higher TGH and confer a higher likelihood of developing GDM. The impaired response of TRPM6(V(1393)I) and TRPM6(K(1584)E) to insulin represents a unique molecular pathway leading to GDM where the defect is located in TRPM6.

Cervical sonoelastography for improving prediction of preterm birth compared with cervical length measurement and fetal fibronectin test.

AIM: Accurate prediction of the risk of spontaneous preterm birth is crucial for the clinical management of patients with preterm labor. The aim of the study was to investigate whether cervical sonoelastography improves prediction of spontaneous preterm birth compared with cervical length measurement and a fetal fibronectin (fFN) test. METHODS: A prospective cohort study was conducted including 64 patients with preterm labor at 23-34 weeks of gestation. Patients had an fFN test and transvaginal cervical length measurement, followed by real-time cervical sonoelastography. The ratio of nondeformable tissue to the total area of a designed region of interest was analyzed and related to the gestational week of delivery. RESULTS: Cervical sonoelastography and fFN test show a significant correlation with spontaneous preterm delivery (P=0.007, P=0.001), resulting in 72.7%/36% sensitivity and 73%/95% specificity. The positive predictive value (PPV) was 61.5%/81.8% and the negative predictive value was 81.8%/70%. The cervical length was not different in cases with and without term delivery (P=0.165). CONCLUSIONS: Cervical sonoelastography is a promising technique that can complement routine diagnostic procedures to improve prediction of preterm birth. The PPV is improved by an fFN test.

Maternal vitamin D deficiency and fetal programming--lessons learned from humans and mice.

BACKGROUND/AIMS: Cardiovascular disease partially originates from poor environmental and nutritional conditions in early life. Lack of micronutrients like 25 hydroxy vitamin D3 (25OHD) during pregnancy may be an important treatable causal factor. The present study explored the effect of maternal 25OHD deficiency on the offspring. METHODS: We performed a prospective observational study analyzing the association of maternal 25OHD deficiency during pregnancy with birth outcomes considering confounding. To show that vitamin D deficiency may be causally involved in the observed associations, mice were set on either 25OHD sufficient or insufficient diets before and during pregnancy. Growth, glucose tolerance and mortality was analyzed in the F1 generation. RESULTS: The clinical study showed that severe 25OHD deficiency was associated with low birth weight and low gestational age. ANCOVA models indicated that established confounding factors such as offspring sex, smoking during pregnancy and maternal BMI did not influence the impact of 25OHD on birth weight. However, there was a significant interaction between 25OHD and gestational age. Maternal 25OHD deficiency was also independently associated with low APGAR scores 5 minutes postpartum. The offspring of 25OHD deficient mice grew slower after birth, had an impaired glucose tolerance shortly after birth and an increased mortality during follow-up. CONCLUSIONS: Our study demonstrates an association between maternal 25OHD and offspring birth weight. The effect of 25OHD on birth weight seems to be mediated by vitamin D controlling gestational age. Results from an animal experiment suggest that gestational 25OHD insufficiency is causally linked to adverse pregnancy outcomes. Since birth weight and prematurity are associated with an adverse cardiovascular outcome in later life, this study emphasizes the need for novel monitoring and treatment guidelines of vitamin D deficiency during pregnancy.

Evaluation of acid-base control, electrolyte balance, and filter patency of a Prismaflex-based regional citrate anticoagulation protocol for pre-dilution continuous veno-venous hemodiafiltration.

BACKGROUND: Regional citrate anticoagulation (RCA) is increasingly used in patients requiring continuous renal replacement therapy (CRRT). This study evaluated a new RCA protocol based on the Prismaflex® dialysis device and an isotonic citrate solution (prismocitrate) for pre-dilution continous veno-venous hemodiafiltration. METHODS: The Prismaflex®/Prismocitrate-based protocol involved an AN69ST® membrane (Prisma Flex ST100), a blood flow of 120 mL/min, 1.8 L/h Prismocitrate (10 mmol/L citrate/2 mmol/L citric acid) substitution fluid in pre-dilution mode, and 0.8 L/h dialysate flow (PrismOcal) at the start. In parallel, infusions of potassium, calcium, and magnesium were initiated. Blood pH, bicarbonate, base excess, and ionized calcium levels were measured in 6 hours intervals and magnesium levels every 24 hours. Scheduled hemofilter run time was 72 hours. RESULTS: A consecutive series of 25 continuous renal replacement treatments was analyzed in 15 patients. After at least 6h of RRT, 69.9% of bicarbonate concentrations and 84.6% base excess (BE) calculations were below normal range. During CRRT, mean bicarbonate decreased from 22.9 to 20.2 mmol/L and mean BE from -1.5 to -4.2 mmol/L. In addition, 66.3% of ionized systemic calcium concentrations were out of the normal range, while 54.1% of the magnesium readings were above normal range. Five filters reached the scheduled run time of 72 hours, 19 treatments stopped prematurely because of RRT related reasons (5 filter clottings, 2 severe metabolic disarrangements, 12 major Prismaflex® hardware or software handling problems). One patient was switched to intermittent hemodialysis. CONCLUSIONS: The evaluated Prismaflex®/ Prismocitrate-based citrate anticoagulation protocol provides insufficient control of blood acid-base and electrolyte balance.

Severe renal impairment is associated with symptomatic intracerebral hemorrhage after thrombolysis for ischemic stroke.

BACKGROUND AND PURPOSE: Patients with renal impairment (RI) have an increased risk of both thrombotic and hemorrhagic events. We aimed to clarify whether RI increases the risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis with recombinant tissue plasminogen activator. METHODS: Patients who received intravenous thrombolysis with recombinant tissue plasminogen activator within 4.5 hours of symptom onset were retrospectively analyzed. Creatinine levels on admission served to calculate glomerular filtration rate (GFR) to estimate RI according to International Classification of Diseases criteria. Effect of RI on symptomatic ICH (sICH) was assessed using dichotomized (GFR <90 and <30 mL/min) and continuous GFR (centered data to test for linear and centered and squared data to test for curvilinear association). RESULTS: Of the 740 patients included, 83% had any RI (GFR <90 mL/min) and 5% had severe RI (GFR <30 mL/mL); 4.6% experienced sICH. Univariate comparisons revealed higher prevalence of sICH in patients with severe RI (P<0.01) but not with any RI. GFR as a continuous variable (centered and squared) was also associated with sICH (P=0.02), but GFR on its own was not. Severe RI and GFR (centered and squared) remained independently associated with sICH in multiple regression analyses. CONCLUSIONS: Severe RI (GFR <30 mL/min) is associated with sICH after intravenous thrombolysis with recombinant tissue plasminogen activator. The association is curvilinear. Severe RI must be taken into account when balancing the risk-benefit ratio of intravenous thrombolysis with recombinant tissue plasminogen activator.

Volume matters: CT-based renal cortex volume measurement in the evaluation of living kidney donors.

Currently, no international standard for the pre-transplant evaluation of living donor renal function exists. Following a standardized questionnaire on current practice in all Eurotransplant (ET) centers, we compared a new CT-based technique to measure renal cortex volume with our standard of DTPA-clearance combined with MAG3-scintigraphy (DTPA × MAG3) and with creatinine-based methods in 167 consecutive living kidney donors. Most ET centers use creatinine-clearance (64%) to measure total renal function and radioistopic methods (82%) to assess split renal function. Before transplantation, CT-measured total cortex volume (r = 0.67; P < 0.001) and estimated GFR using the Cockcroft-Gault formula [eGFR(CG)] (r = 0.55; P < 0.001) showed the strongest correlation with DTPA-clearance. In contrast, the correlation between DTPA-clearance and creatinine clearance was weak (r = 0.21; P = 0.02). A strong correlation was observed between CT-measured split cortex volume and MAG3-measured split renal function (r = 0.93; P < 0.001). A strong correlation was also found between pre-transplant split renal function assessed by eGFR(CG) together with cortex volume measurement and post-transplant eGFR(CG) of both, the donor (r = 0.83; P < 0.001) and the recipient (r = 0.75; P < 0.001). In conclusion CT-based assessment of renal cortex volume bears the potential to substitute existing methods to assess pre-transplant living donor split renal function.

Modeling of oxidized PTH (oxPTH) and non-oxidized PTH (n-oxPTH) receptor binding and relationship of oxidized to non-oxidized PTH in children with chronic renal failure, adult patients on hemodialysis and kidney transplant recipients.

BACKGROUND: The biological properties of oxidized and non-oxidized PTH are substantially different. Oxidized PTH (oxPTH) loses its PTH receptor-stimulating properties, whereas non-oxidized PTH (n-oxPTH) is a full agonist of the receptor. This was described in more than 20 well published studies in the 1970(s) and 80(s). However, PTH oxidation has been ignored during the development of PTH assays for clinical use so far. Even the nowadays used third generation assay systems do not consider oxidation of PTH We recently developed an assay to differentiate between oxPTH and n-oxPTH. In the current study we established normal values for this assay system. Furthermore, we compare the ratio of oxPTH to n-oxPTH in different population with chronic renal failure: 620 children with renal failure stage 2-4 of the 4C study, 342 adult patients on dialysis, and 602 kidney transplant recipients. In addition, we performed modeling of the interaction of either oxPTH or n-oxPTH with the PTH receptor using biophysical structure approaches. RESULTS: The children had the highest mean as well as maximum n-oxPTH concentrations as compared to adult patients (both patients on dialysis as well as kidney transplant recipients). The relationship between oxPTH and n-oxPTH of individual patients varied substantially in all three populations with renal impairment. The analysis of n-oxPTH in 89 healthy control subjects revealed that n-oxPTH concentrations in patient with renal failure were higher as compared to healthy adult controls (2.25-fold in children with renal failure, 1.53-fold in adult patients on dialysis, and 1.56-fold in kidney transplant recipients, respectively). Computer assisted biophysical structure modeling demonstrated, however, minor sterical- and/or electrostatic changes in oxPTH and n-oxPTH. This indicated that PTH oxidation may induce refolding of PTH and hence alters PTH-PTH receptor interaction via oxidation induced three-dimensional structure alteration of PTH. CONCLUSION: A huge proportion of circulating PTH measured by current state-of-the-art assay systems is oxidized and thus not biologically active. The relationship between oxPTH and n-oxPTH of individual patients varied substantially. Non-oxidized PTH concentrations are 1.5 - 2.25 fold higher in patients with renal failure as compared to health controls. Measurements of n-oxPTH may reflect the hormone status more precise. The iPTH measures describes most likely oxidative stress in patients with renal failure rather than the PTH hormone status. This, however, needs to be demonstrated in further clinical studies. © 2013 S. Karger AG, Basel.

Value of Doppler sonography near term: can umbilical and uterine artery indices in low-risk pregnancies predict perinatal outcome?

AIM: The goal of this study was to evaluate the umbilical and uterine Doppler velocimetry waveforms for predicting the perinatal outcome of low-risk pregnancies at term. METHODS: We prospectively recruited 514 women with low risk pregnancies and performed umbilical and uterine artery Doppler assessments between 37 and 41 weeks of gestation. Ultrasound measurements (completed in 365 patients) were correlated with the perinatal outcome. RESULTS: The velocimetry waveforms of the umbilical artery were significantly associated with birthweight, placental weight, and postpartal umbilical artery pH. Low pH, placental weight, and birthweight were correlated with increasing pulsatility index (PI) and resistance index (RI). An umbilical artery PI > 1.2 and a uterine artery RI > 0.5 were associated with statistically higher rates of infants that were small for gestational age (SGA). Also, high cesarean delivery rates were correlated with an umbilical artery PI > 1.2. CONCLUSIONS: In our low-risk pregnancies population, the elevated umbilical artery indices at term appeared to be associated with the higher rates of infants that were SGA and cesarean deliveries. The Doppler waveforms at term had low prognostic value for predicting neonatal acidosis or decreased Apgar scores.

Angle of progression measurements of fetal head at term: a systematic comparison between open magnetic resonance imaging and transperineal ultrasound.

OBJECTIVE: During labor, transperineal sonography is increasingly used to evaluate fetal head descent. The aim of this study was to compare the angle of progression assessed by open magnetic resonance imaging (MRI) vs transperineal ultrasound. STUDY DESIGN: A total of 31 pregnant women at term (>37 weeks), who were not in labor, underwent MRI in an open 1.0-T system. A midsagittal plane of the maternal pelvis was stored. Immediately after, without changing the supine position, a transperineal ultrasound was performed. The angle of progression was measured offline by transperineal ultrasound and MRI. RESULTS: The angles of progression measured by transperineal ultrasound (mean, 79.05 degrees; SD 11.44) and MRI (mean, 80.48 degrees; SD 11.06) correlated significantly (P < .001). The intraclass correlation coefficient between the 2 methods was 0.89 (95% confidence interval, 0.78-0.94). CONCLUSION: The angle of progression measurements obtained by transperineal ultrasound and open MRI showed very good agreement.

Impact of surgeon experience on complication rates and functional outcomes of 484 deceased donor renal transplants: a single-centre retrospective study.

OBJECTIVE: To determine how postoperative and functional outcomes after deceased donor renal transplantation (DDRT) are related to surgeon experience. PATIENTS AND METHODS: The outcomes of 484 adult DDRT performed by 13 urological surgeons were retrospectively reviewed. After completion of a staged renal transplant training programme under supervision of an attending urological transplant surgeon, the 13 surgeons were either assigned to the inexperienced group (n = 8) or the experienced group (n = 5). Surgeons in the experienced group had performed more than 30 unsupervised DDRT in a standard fashion with routine ureteric stenting. Between 1988 and 2005, inexperienced surgeons performed 152 DDRT, whereas experienced surgeons performed 332 DDRT. RESULTS: Patient and graft survival at 2 hyears were 98% and 94.7%, respectively. Early graft loss in five recipients was unrelated to surgeon experience. Delayed graft function occurred in 29% of cases and median 1-year serum-creatinine was 1.48 mg/dL, with no difference between surgeon groups. Postoperative bleeding and lymphocele formation were the most frequent surgical complications, with an equal distribution between groups. Ureteric complications had a significantly higher incidence among inexperienced surgeons (6.6% versus 2.7%; P = 0.04). CONCLUSION: We conclude that DDRT as performed by inexperienced urological renal transplant surgeons has both acceptable short- and long-term outcomes.

Extended daily on-line high-volume haemodiafiltration in septic multiple organ failure: a well-tolerated and feasible procedure.

BACKGROUND: The outcome of patients with septic multiple organ failure (MOF) remains poor. There are experimental and clinical data indicating a beneficial effect of high-volume haemofiltration. Delivering high-volume therapy is only cost effective using on-line devices because of high costs for additional solution bags in conventional continuous renal replacement therapy (CRRT). We investigated feasibility and effectiveness of extended daily on-line high-volume haemodiafiltration (HDF) with technically maximum convective volume in patients with septic MOF in a pilot study. METHODS: We included 21 consecutive critically ill patients with septic MOF having a mortality risk >50% (SAPS II >50, APACHE II >25). Renal replacement therapy (RRT) was applied with extended daily HDF for 6-23 h using the AK 200 Ultra S dialysis machine in the ultracontrol pre-dilution mode. Dialysate and substitution fluid were prepared on-line. Patients underwent 289 treatments. RESULTS: The mean convective volume was 17.8 ± 3.7 L/h and 208 ± 66 mL/kg/h, respectively, median treatment time was 10:15 h/day. Seventeen of 21 patients survived 28 days (81%). The 90-day survival rate was 52% (11/21) versus 19% compared to the survival rate predicted by APACHE II (33.6 mean) and SAPS II (68.6 mean) scores. Haemodynamics improved significantly during the treatment procedures. Material costs per treatment amounted to 35 €. CONCLUSIONS: Extended daily on-line HDF using maximum convective volume seems to improve the outcome of septic MOF, especially in the early phase. The investigated mode of treatment proved to be feasible, well tolerated and highly cost effective compared to conventional CRRT. At present, this procedure would be applicable at every ICU facility with nephrological support.