We and others have previously described signatures of tolerance in kidney transplantation showing the differential expression of B cell–related genes and the relative expansions of B cell subsets. ...However, in all of these studies, the index group—namely, the tolerant recipients—were not receiving immunosuppression (IS) treatment, unlike the rest of the comparator groups. We aimed to assess the confounding effect of these regimens and develop a novel IS‐independent signature of tolerance. Analyzing gene expression in three independent kidney transplant patient cohorts (232 recipients and 14 tolerant patients), we have established that the expression of the previously reported signature was biased by IS regimens, which also influenced transitional B cells. We have defined and validated a new gene expression signature that is independent of drug effects and also differentiates tolerant patients from healthy controls (cross‐validated area under the receiver operating characteristic curve AUC = 0.81). In a prospective cohort, we have demonstrated that the new signature remained stable before and after steroid withdrawal. In addition, we report on a validated and highly accurate gene expression signature that can be reliably used to identify patients suitable for IS reduction (approximately 12% of stable patients), irrespective of the IS drugs they are receiving. Only a similar approach will make the conduct of pilot clinical trials for IS minimization safe and hence allow critical improvements in kidney posttransplant management.
The relationship between B cell gene expression and transplantation tolerance is confounded by the effects of immunosuppressive drugs, and correcting for this effect on gene expression is possible, exposing an equally accurate signature of tolerance. See page 3320 for Markmann's editorial.
Many patients taking statins often complain of muscle pain and weakness. The extent to which muscle pain reflects muscle injury is unknown.
We obtained biopsy samples from the vastus lateralis muscle ...of 83 patients. Of the 44 patients with clinically diagnosed statin-associated myopathy, 29 were currently taking a statin, and 15 had discontinued statin therapy before the biopsy (minimal duration of discontinuation 3 weeks). We also included 19 patients who were taking statins and had no myopathy, and 20 patients who had never taken statins and had no myopathy. We classified the muscles as injured if 2% or more of the muscle fibres in a biopsy sample showed damage. Using reverse transcriptase polymerase chain reaction, we evaluated the expression levels of candidate genes potentially related to myocyte injury.
Muscle injury was observed in 25 (of 44) patients with myopathy and in 1 patient without myopathy. Only 1 patient with structural injury had a circulating level of creatine phosphokinase that was elevated more than 1950 U/L (10x the upper limit of normal). Expression of ryanodine receptor 3 was significantly upregulated in patients with biopsy evidence of structural damage (1.7, standard error of the mean 0.3).
Persistent myopathy in patients taking statins reflects structural muscle damage. A lack of elevated levels of circulating creatine phosphokinase does not rule out structural muscle injury. Upregulation of the expression of ryanodine receptor 3 is suggestive of an intracellular calcium leak.
Abstract
Objective:
Lipids and steroid hormones are closely linked. While cholesterol is the substrate for (placental) steroid hormone synthesis, steroid hormones regulate hepatic lipid production. ...The aim of this study was to quantify circulating steroid hormones and lipid metabolites, and to characterize their interactions in normal and pathological pregnancies with a focus on hepatic and placental pathologies.
Methods:
A total of 216 serum samples were analyzed. Group A consisted of 32 patients with uncomplicated pregnancies who were analyzed at three different time-points in pregnancy (from the first through the third trimester) and once post partum. Group B consisted of 36 patients (24th to 42nd week of gestation) with pregnancy pathologies (IUGR n = 10, preeclampsia n = 13, HELLP n = 6, intrahepatic cholestasis n = 7) and 31 controls with uncomplicated pregnancies. Steroid profiles including estradiol, progesterone, and dehydroepiandrosterone were measured by GC-MS and compared with lipid concentrations.
Results:
In Group A, cholesterol and triglycerides correlated positively with estradiol (cholesterol ρ = 0.50, triglycerides ρ = 0.57) and progesterone (ρ = 0.49, ρ = 0.53) and negatively with dehydroepiandrosterone (ρ = − 0.47, ρ = − 0.38). Smoking during pregnancy affected estradiol concentrations, leading to lower levels in the third trimester compared to non-smoking patients (p < 0.05). In Group B, cholesterol levels were found to be lower in IUGR pregnancies and in patients with HELLP syndrome compared to controls (p < 0.05). Steroid hormone concentrations of estradiol (p < 0.05) and progesterone (p < 0.01) were lower in pregnancies with IUGR.
Discussion:
Lipid and steroid levels were affected most in IUGR pregnancies, while only minor changes in concentrations were observed for other pregnancy-related disorders. Each of the analyzed entities displayed specific changes. However, since the changes were most obvious in pregnancies complicated by IUGR and only minor changes were observed in pregnancies where patients had impaired liver function, our data suggests that placental rather than maternal hepatic function strongly determines lipid and steroid levels in pregnancy.
Background. Mortality rates of critically ill patients with acute renal failure (ARF) requiring renal replacement therapy (RRT) are high. Intermittent and continuous RRT are available for these ...patients on the intensive care units (ICUs). It is unknown which technique is superior with respect to patient outcome. Methods. We randomized 125 patients to treatment with either continuous venovenous haemodiafiltration (CVVHDF) or intermittent haemodialysis (IHD) from a total of 191 patients with ARF in a tertiary-care university hospital ICU. The primary end-point was ICU and in-hospital mortality, while recovery of renal function and hospital length of stay were secondary end-points. Results. During 30 months, no patient escaped randomization for medical reasons. Sixty-six patients were not randomized for non-medical reasons. Of the 125 randomized patients, 70 were treated with CVVHDF and 55 with IHD. The two groups were comparable at the start of RRT with respect to age (62±15 vs 62±15 years, CVVHDF vs IHD), gender (66 vs 73% male sex), number of failed organ systems (2.4±1.5 vs 2.5±1.6), Simplified Acute Physiology Scores (57±17 vs 58±23), septicaemia (43 vs 51%), shock (59 vs 58%) or previous surgery (53 vs 45%). Mortality rates in the hospital (47 vs 51%, CVVHDF vs IHD, P = 0.72) or in the ICU (34 vs 38%, P = 0.71) were independent of the technique of RRT applied. Hospital length of stay in the survivors was comparable in patients on CVVHDF median (range) 20 (6–71) days, n = 36 and in those on IHD 30 (2–89) days, n = 27, P = 0.25. The duration of RRT required was the same in both groups. Conclusion. The present investigation provides no evidence for a survival benefit of continuous vs intermittent RRT in ICU patients with ARF.
Summary
Background
To date, the use of proton pump inhibitors (PPIs) has been associated with a low risk of hypomagnesaemia and associated adverse outcomes. We hypothesised that a better risk ...estimate could be derived from a large cohort of outpatients admitted to a tertiary emergency department (ED).
Methods
A cross‐sectional study was performed in 5118 patients who had measurements of serum magnesium taken on admission to a large tertiary care ED between January 2009 and December 2010. Hypomagnesaemia was defined as a serum magnesium concentration < 0.75 mmol/l. Demographical data, serum electrolyte values, data on medication, comorbidities and outcome with regard to length of hospital stay and mortality were analysed.
Results
Serum magnesium was normally distributed where upon 1246 patients (24%) were hypomagnesaemic. These patients had a higher prevalence of out‐of‐hospital PPI use and diuretic use when compared with patients with magnesium levels > 0.75 mmol/l (both p < 0.0001). In multivariable regression analyses adjusted for PPIs, diuretics, renal function and the Charlson comorbidity index score, the association between use of PPIs and risk for hypomagnesaemia remained significant (OR = 2.1; 95% CI: 1.54–2.85). While mortality was not directly related to low magnesium levels (p = 0.67), the length of hospitalisation was prolonged in these patients even after adjustment for underlying comorbid conditions (p < 0.0001).
Conclusion
Use of PPIs predisposes patients to hypomagnesaemia and such to prolonged hospitalisation irrespective of the underlying morbidity, posing a critical concern.
Background. Increased aldosterone concentrations and volume expansion of normal pregnancies are hallmarks of normal pregnancies and blunted in pre-eclampsia. Accordingly, we hypothesized an active ...mineralocorticoid system to protect from pre-eclampsia. Methods. In pregnant women (normotensive n = 44; pre-eclamptic n = 48), blood pressure, urinary tetrahydro-aldosterone excretion and activating polymorphisms (SF-1 site and intron 2) of the aldosterone synthase gene (CYP11B2) were determined; 185 non-pregnant normotensive individuals served as control. Amino acid-changing polymorphisms of the DNA- and agonist-binding regions of the mineralocorticoid receptor were evaluated by RT-PCR, SSCP and sequencing. Results. Urinary tetrahydro-aldosterone excretion was reduced in pre-eclampsia as compared to normal pregnancy (P < 0.05). It inversely correlated with blood pressure (r = 0.99, P < 0.04). Homozygosity for activating CYP11B2 polymorphisms was preferably present in normotensive as compared to pre-eclamptic pregnancies, identified (intron 2, P = 0.005; SF-1 site, P = 0.016). Two mutant haplotypes decreased the risk of developing pre-eclampsia (RR 0.16; CI 0.05–0.54; P < 0.001). In contrast, intron 2 wild type predisposed to pre-eclampsia (P < 0.0015). No functional mineralocorticoid receptor mutant has been observed. Conclusions. High aldosterone availability is associated with lower maternal blood pressure. In line with this observation, gain-of-function variants of the CYP11B2 reduce the risk of developing pre-eclampsia. Mutants of the mineralocorticoid receptor cannot explain the frequent syndrome of pre-eclampsia.
Delay of dialysis in end-stage renal failure: Prospective study on percutaneous renal artery interventions.
Renal artery stenosis (RAS) is a cause of end-stage renal failure. We studied the effect of ...percutaneous renal artery intervention (PRI) in patients with advanced, progressive disease at risk for renal failure, hypothesizing a beneficial effect.
Thirty-nine primary and 14 secondary PRIs were performed on 28 patients with atherosclerotic RAS, serum creatinine >300 μmol/L, and progressive loss of renal function ≥1year before PRI. Renal function and RA patency were prospectively followed for 12months after primary and secondary PRI. The intervention's effect on the progressive loss of renal function was calculated by comparing reciprocal slopes of serum creatinine against time before and after PRI.
Progression of renal failure slowed significantly following PRI. Mean (±SE) slopes of reciprocal serum creatinine values were: 6.69 ± 0.97L μmol−1 day−1 (×10−6) before and 6.76 ± 3.03L μmol−1 day−1 (×10−6) after PRI (P = 0.0007). Fifteen patients (53.5%) showed improvement or stabilization of progressive renal dysfunction. Out of 11 patients expected to become dialysis dependent within one year, 8 (72.7%) experienced an improvement in renal function sufficient to remain dialysis-free. Favorable outcome correlated with a lower creatinine level (P = 0.0137) and a more negative slope of progression (r = 0.49, P = 0.020) at entry. Mortality was 10.7%, and rate of local complications was 7.1%. Deterioration of renal function following PRI was suspected in 17.9% of patients.
PRI may improve renal function and ultimately delay dialysis in patients with advanced renal failure. Possible advantages must be weighed against the risk of renal failure advancement and high procedure-related complication rate.
•Exaggerated 11β-hydroxysteroiddehydrogenase in preeclampsia.•High cortisol turnover in preeclampsia.•Missing maternal response at intrauterine growth restriction.•Dissimilar pathophysiology of ...preeclampsia and intrauterine growth restriction.
The enzyme 11ß-dehydroxysteroid dehydrogenase 2 (11ß-HSD2) converts active cortisol (F) to inactive cortisone (E). A reduced 11ß-HSD2 activity in the placenta has been demonstrated for prematurity, low birth weight, and preeclampsia. We hypothesized that disturbed placental function rather than a maternal response contributes to decreased 11ßHSD2 activity as reflected by a diminished conversion of F to E. Hence, the aim of the present study was to estimate the systemic activity of 11ß-HSD2 throughout gestation and in pregnancies complicated by preeclampsia (PE) and intrauterine growth restriction (IUGR) by calculating maternal serum F/E ratios.
A total of 188 maternal serum samples were analyzed for nine glucocorticoid metabolites by gas chromatography–mass spectrometry (GC–MS) and F/E ratios were calculated. Study Group A: In a longitudinal set 33 healthy pregnant women were analyzed at three different time points throughout gestation and one postpartum. Study Group B: Cross-sectionally additional 56 patients were enrolled. We compared patients with PE (N = 14) and IUGR (N = 14) with gestational age matched healthy controls (CTRL = 28).
Group A: The apparent 11β-HSD2 activity dropped in the second trimester being restored to first trimester levels (P value = 0.016). Group B: The 11β-HSD2 activity was high in PE (P value < 0.05) but not in the IUGR group as compared to CTRL.
The increased apparent serum 11β-HSD2 activity observed with advancing gestation in normal pregnancy may reflect an elevated general increase in enzyme activity due to a higher placental mass. The high systemic 11β-HSD2 activity in PE but not in IUGR however suggests an increased F deactivation in maternal tissue in PE rather than in the placenta since placental insufficiency in the absence of PE does not significantly alter F/E ratio.
Background. Treatment of persistent hyperparathyroidism in renal transplant patients resistant to calcium and vitamin D sterols is limited and often requires parathyroidectomy. Given the potential ...hazards linked to surgery, an alternative approach to manage excess parathyroid hormone (PTH) secretion is needed. Calcimimetics inhibit PTH secretion by modulating the calcium-sensing receptor in the parathyroid. Lowering of the serum calcium concentration with the calcimimetic cinacalcet has previously been demonstrated in patients with primary hyperparathyroidism or with secondary hyperparathyroidism on dialysis. Here we present the first clinical observations of a calcimimetic in patients with persistent hyperparathyroidism. Methods. A 30 mg dose of cinacalcet was prescribed once daily for 3 months to seven female and seven male stable renal transplant patients, aged 23–65 years, 7 months to 14 years after transplantation, with a serum creatinine ranging from 89 to 229 µmol/l and persistent hyperparathyroidism. Concomitant medication included cyclosporin and low-dose prednisone in all patients. Results. On cinacalcet, serum calcium decreased and normalized in all but two patients (baseline 2.72±0.03 mmol/l; 1 month 2.42±0.04 mmol/l, P<0.001), whereas serum PTH and phosphate levels did not change significantly. A slight reduction in renal function, as assessed by serum creatinine concentration, was observed at months 2 and 3 (P<0.05). An immunoglobulin-deficient patient developed colitis after 1 week of treatment and cinacalcet was withdrawn. No patient stopped cinacalcet because of other presumed side effects. Conclusion. Calcimimetics are a promising therapy in renal transplant patients with persistent hyperparathyroidism. Prospective controlled studies must now be designed focusing on functionally relevant musculo-skeletal end-points and allowing the exclusion of negative effects on long-term renal and general outcome of such patients.
Objective The aim of this investigation was to assess soluble endoglin (sEng) and soluble fms-like tyrosine kinase-1 (sFlt1) as first-trimester serum markers to predict preeclampsia. Study Design ...First-trimester sera were obtained from 46 women with subsequent late-onset preeclampsia and from 92 controls. sEng and sFlt1 concentrations were determined immunoanalytically. Correlation analysis with inhibin A and placental growth factor levels was performed. Results sEng and sFlt1 serum concentrations were higher in women with subsequent preeclampsia than in controls (mean ± SD, sEng: 5.57 ± 1.18 ng/mL vs 5.02 ± 1.01 ng/mL, P = .009; sFlt1: 1764 ± 757 pg/mL vs 1537 ± 812 pg/mL, P = .036). Sensitivities and specificities for predicting preeclampsia were 63% and 57% for sEng and 64% and 56% for sFlt1, respectively. When sEng and inhibin A were combined, the sensitivity increased to 68%, whereas the specificity was 61%. Conclusion sEng and sFlt1 are increased in the first trimester in women with subsequent late-onset preeclampsia and might therefore prove useful to predict preeclampsia.
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