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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.

This is the second part of the series on interventional ultrasound guidelines of the Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB). It deals with the diagnostic interventional procedure. General points are discussed which are pertinent to all patients, followed by organ-specific imaging that will allow the correct pathway and planning for the interventional procedure. This will allow for the appropriate imaging workup for each individual interventional procedure (Long version).

Hypertension and chronic kidney disease (CKD) are complex traits representing major global health problems. Multiple genome-wide association studies have identified common variants in the promoter of the UMOD gene, which encodes uromodulin, the major protein secreted in normal urine, that cause independent susceptibility to CKD and hypertension. Despite compelling genetic evidence for the association between UMOD risk variants and disease susceptibility in the general population, the underlying biological mechanism is not understood. Here, we demonstrate that UMOD risk variants increased UMOD expression in vitro and in vivo. Uromodulin overexpression in transgenic mice led to salt-sensitive hypertension and to the presence of age-dependent renal lesions similar to those observed in elderly individuals homozygous for UMOD promoter risk variants. The link between uromodulin and hypertension is due to activation of the renal sodium cotransporter NKCC2. We demonstrated the relevance of this mechanism in humans by showing that pharmacological inhibition of NKCC2 was more effective in lowering blood pressure in hypertensive patients who are homozygous for UMOD promoter risk variants than in other hypertensive patients. Our findings link genetic susceptibility to hypertension and CKD to the level of uromodulin expression and uromodulin's effect on salt reabsorption in the kidney. These findings point to uromodulin as a therapeutic target for lowering blood pressure and preserving renal function.

Electrolytes handling by the kidney is essential for volume and blood pressure (BP) homeostasis but their distribution and heritability are not well described. We estimated the heritability of kidney function as well as of serum and urine concentrations, renal clearances and fractional excretions for sodium, chloride, potassium, calcium, phosphate and magnesium in a Swiss population-based study.

Introduction: The quality of Blood Pressure (BP) control remains poor among patients with Chronic Kidney Diseases (CKD). It is therefore crucial to develop therapeutic strategies enabling improvement in BP control in order to retard the progression of the underlying renal diseases. The cornerstones of therapy include the use of effective and well tolerated drugs and a good drug adherence. In this pilot study conducted in ambulant routine care we evaluated the potential clinical benefits of implementing a Telemonitoring System (TMS) in parallel to an anticipated change of treatment in hypertensive CKD patients with uncontrolled hypertension and/or adverse reactions due to the current antihypertensive treatment. Methods: This is an observational study conducted by 13 Swiss nephrologists in patients with CKD stage III-IV and a BP >130/80 mmHg under treatment with an antihypertensive drug. A validated, automated TMS for home BP and Heart Rate (HR) monitoring and an electronic scale to measure Body Weight (BW) and a modem to transfer the measured parameters to a central database were provided to each patient. The protocol included a run-in phase and a drug titration phase of 1 month each and a 2 month maintenance phase. During the titration phase, the calcium antagonist lercanidipine could be introduced and up titrated in case of uncontrolled BP. Results: The use of a TMS in conjunction with the introduction of lercanidipine resulted in a significant reduction of office systolic and diastolic BP of respectively -10 ± 21 mmHg (p=0.028) and -5.0 ± 11 mmHg (p=0.049). Home BP revealed a parallel significant reduction of -3 ± 1.4 mmHg systolic (p=0.043) and -3 ± 1.2 mmHg (p=0.021) diastolic, respectively. The fall in BP was associated with a slight but significant increase in serum creatinine and decrease in Estimated Glomerular Filtration Rate (eGFR). Conclusion: The results of this observational pilot study suggest that a telemonitoring system enabling to follow home BP may be useful to improve BP control in hypertensive patients with CKD. However, a prospective randomized control study would be needed to assess the real added benefits of this strategy. Administration of lercanidipine in CKD patients was effective and well tolerated.

Im Fachbeitrag wird eine kleinserientaugliche Fertigungstechnik zum Fügen von Glaschips, als Träger optischer Mikrobauelemente, wie Mikrofilter oder Mikrolinsen, und Fotoempfängerstrukturen, wie Fotodioden, -transistoren, CCD-Matrizen u. ä., im Waferstadium vorgestellt. Das Verfahren ist vor allem durch einen relativ geringen apparativen Aufwand und eine gute Kompatibilität zu eingefahrenen Optikfertigungsprozessen und zu Techniken des Wafer- und Chip-Handlings gekennzeichnet. Seine Besonderheit besteht darin, dass durch eine zweistufige mechanische Strukturierung des Optikwafers vor und nach dem justierten Kleben ein sehr einfaches Freisetzen der vorhandenen elektrischen Kontaktpads der optoelektronischen Bauelemente möglich wird. Die in einer längeren Testphase hergestellten Verbundbauelemente sind ohne besondere Umstellungen der Packagingtechnologie in Multi-Chip-Module integrierbar und erfüllen in Musteraufbauten alle Stabilitätsanforderungen. Mit dem vorgestellten Verfahren lassen sich beispielhaft Kombination von Farbfiltern unterschiedlicher spektraler Charakteristik mit Sensorarrays gleichen Typs realisieren, wodurch eine effektive Herstellung auch kleiner Stückzahlen spezieller Farbsensorbaureihen möglich ist. In einem Ausblick werden technische Möglichkeiten angerissen, das Hybrid-Montage-Verfahren für die Realisierung optoelektronischer System-in-Package-Aufbauten weiterzuentwickeln.

Toll-like receptors (TLRs) have been found to be key elements in pathogen recognition by the host immune system. Dendritic cells (DCs) are crucial for both innate immune responses and initiation of acquired immunity. Here we focus on the potential involvement of TLR ligand interaction in DC maturation. TLR2 knockout mice and mice carrying a TLR4 mutation (C3H/HeJ) were investigated for DC maturation induced by peptidoglycan (PGN), lipopolysaccharide (LPS), or lipoteichoic acids (LTAs). All stimuli induced maturation of murine bone marrow-derived DCs in control mice. TLR2− /− mice lacked maturation upon stimulation with PGN, as assessed by expression of major histocompatibility complex class II, CD86, cytokine, and chemokine production, fluorescein isothiocyanate-dextran uptake, and mixed lymphocyte reactions, while being completely responsive to LPS. A similar lack of maturation was observed in C3H/HeJ mice upon stimulation with LPS. DC maturation induced by LTAs from two different types of bacteria was severely impaired in TLR2− /−, whereas C3H/HeJ mice responded to LTAs in a manner similar to wild-type mice. We demonstrate that DC maturation is induced by stimuli from Gram-positive microorganisms, such as PGN and LTA, with similar efficiency as by LPS. Finally, we provide evidence that TLR2 and TLR4 interaction with the appropriate ligand is essential for bacteria-induced maturation of DCs.