Marcus Hiss

Neutrophilic Granulocytes Modulate Invariant NKT Cell Function in Mice and Humans

Invariant NKT (iNKT) cells are a conserved αβTCR+ T cell population that can swiftly produce large amounts of cytokines, thereby activating other leukocytes, including neutrophilic granulocytes (neutrophils). In this study, we investigated the reverse relationship, showing that high neutrophil concentrations suppress the iNKT cell response in mice and humans. Peripheral Vα14 iNKT cells from spontaneously neutrophilic mice produced reduced cytokines in response to the model iNKT cell Ag α-galactosyl ceramide and expressed lower amounts of the T-box transcription factor 21 and GATA3 transcription factor than did wild-type controls. This influence was extrinsic, as iNKT cell transcription factor expression in mixed chimeric mice depended on neutrophil count, not iNKT cell genotype. Transcription factor expression was also decreased in primary iNKT cells from the neutrophil-rich bone marrow compared with spleen in wild-type mice. In vitro, the function of both mouse and human iNKT cells was inhibited by coincubation with neutrophils. This required cell–cell contact with live neutrophils. Neutrophilic inflammation in experimental peritonitis in mice decreased iNKT cell T-box transcription factor 21 and GATA3 expression and α-galactosyl ceramide-induced cytokine production in vivo. This was reverted by blockade of neutrophil mobilization. Similarly, iNKT cells from the human peritoneal cavity expressed lower transcription factor levels during neutrophilic peritonitis. Our data reveal a novel regulatory axis whereby neutrophils reduce iNKT cell responses, which may be important in shaping the extent of inflammation.

Pharmacokinetics and dialysate levels of daptomycin given intravenously in a peritoneal dialysis patient

In this report we present pharmacokinetic (Pk) data of daptomycin given intravenously in a peritoneal dialysis patient. Daptomycin plasma levels were within therapeutic range; however, half-life of the drug was prolonged compared to haemodialysis. Both plasma and dialysate levels were found to be consistently above the minimal inhibitory concentration for daptomycin sensitive strains.

Effect of a single dialysis session on cognitive function in CKD5D patients: a prospective clinical study

BACKGROUND Cognitive function declines in parallel to the decrease in glomerular filtration rate, best epitomized by the markedly reduced cerebral performance in patients undergoing maintenance haemodialysis [chronic kidney disease stage 5 dialysis (CKD5D)]. Aside from structural permanent damage, there seems to be a reversible part of low cognitive performance. The potential effect of a single dialysis session on cognitive function remains still elusive. The aim of the study was to assess cognitive function using a widespread test battery and avoiding excluding effects of circadian variations. METHODS Twenty-eight medically stable CKD5D patients (age: 54.9 ± 13.2 years, dialysis vintage: 46.2 ± 51.0 month) at two tertiary care centres with outpatient dialysis units were enrolled. Cognitive testing was always performed twice within 24 h, 1 h prior to haemodialysis (T1pre-dialysis) as well as 19 h after the end of dialysis (T2post-dialysis) including assessment of memory, attention and concentration, executive functioning, word fluency and psychomotor speed by using a well-validated neuropsychological test battery. Patients were randomized into two groups. One group was examined before (T1pre-dialysis) and after (T2post-dialysis) Dialysis Session 1. The other group was first examined the day after Dialysis Session 1 (T2post-dialysis) and then before Dialysis Session 2 (T1pre-dialysis) in order to exclude potential learning effects. Twenty age-matched subjects with normal excretory renal function were used for comparison. RESULTS Neuropsychological testing found that the CKD5D performed significantly worse on measures of alertness, attention, working memory, logical and visual memory, word fluency and executive functions compared with non-CKD subjects. No differences in short-term memory, selective attention, as well as problem-solving and planning were found between CKD5D patients and non-CKD subjects. A single haemodialysis session led to a significant improvement in logical (Rivermead Behaviour Memory Test story: P < 0.001) and visual memories [Rey-Osterrieth Complex Figure Test (RCFT) memory quotient: P < 0.001], psychomotor speed [Trail Making Test (TMT) B: P = 0.020], activity planning (executive functions) (RCFT copy/points deduction: P < 0.001) and concentration (TMT A: P < 0.001). CONCLUSION Our data demonstrate improvements in memory functions, executive functions and psychomotor abilities after a single dialysis session, pointing to a reversible component of low cognitive performance in CKD5D.

Imaging in anatomy: a comparison of imaging techniques in embalmed human cadavers

BackgroundA large variety of imaging techniques is an integral part of modern medicine. Introducing radiological imaging techniques into the dissection course serves as a basis for improved learning of anatomy and multidisciplinary learning in pre-clinical medical education.MethodsFour different imaging techniques (ultrasound, radiography, computed tomography, and magnetic resonance imaging) were performed in embalmed human body donors to analyse possibilities and limitations of the respective techniques in this peculiar setting.ResultsThe quality of ultrasound and radiography images was poor, images of computed tomography and magnetic resonance imaging were of good quality.ConclusionComputed tomography and magnetic resonance imaging have a superior image quality in comparison to ultrasound and radiography and offer suitable methods for imaging embalmed human cadavers as a valuable addition to the dissection course.

Arteriolar Lesions in Renal Transplant Biopsies: Prevalence, Progression, and Clinical Significance

Arteriolar hyalinosis in kidney transplants is considered the histopathologic hallmark of chronic calcineurin inhibitor (CNI) toxicity. However, the lesion is not specific. We assessed prevalence, progression, and clinical significance of arteriolar lesions in 1239 renal transplant sequential protocol biopsy samples and 408 biopsy for cause samples in 526 patients. Associations between arteriolar lesions and presumed risk factors, concomitant histopathologic lesions, demographic factors, and graft function were evaluated. The frequency of arteriolar lesions was stable during the first 2 years after transplantation, and increased thereafter (14.8% at 6 months versus 48.6% at >2 years; P < 0.0001). We were unable to find associations with diabetes, hypertension, or CNI therapy. However, patients with early arteriolar lesions received grafts from older donors (mean ± SD age, 54.4 ± 13.4 years versus 43.1 ± 16.6 years; P < 0.0001), and had inferior graft function (estimated glomerular filtration rate 55 ± 21 mL/min versus 63 ± 24 mL/min at 6 weeks, 53 ± 19 mL/min versus 60 ± 23 mL/min at 1 year, and 49 ± 19 mL/min versus 59 ± 22 mL/min at 2 years; P < 0.05). Evaluation of late biopsy samples from patients not receiving CNI therapy revealed a high prevalence of AH without clear-cut identifiable underlying cause. Reproducibility of arteriolar lesions was at best moderate (κ ≤ 0.62). Sampling error in sequential biopsy samples was frequent. In conclusion, in samples from sequential protocol biopsies and biopsies for cause in individual patients, arteriolar lesions in renal transplants not only increase over time without being specific for CNI toxicity but are affected by sampling error and limited reproducibility.

A new rescue regimen with plasma exchange and rituximab in high-risk membranous glomerulonephritis

Even though current treatment guidelines for idiopathic membranous glomerulonephritis (iMGN) exist, many questions regarding an optimal therapy remain unanswered. Complete remission cannot be achieved in all patients; relapses occur, in some cases frequently, and side effects from the immunosuppressive therapy are common. Therapeutic options in high‐risk patients not responding to standard immunosuppressive therapies are limited. Recent research reveals that the human M‐type phospholipase A2 receptor (PLA2R) is a causative factor in iMGN that parallels clinical disease activity. However, in some patients, this correlation is not evident and additional undetermined factors seem to play a role.

Combination of everolimus with calcineurin inhibitor medication resulted in post-transplant haemolytic uraemic syndrome in lung transplant recipients—a case series

BACKGROUND Post-transplant haemolytic uraemic syndrome (HUS) is a rare but serious disease with a high mortality rate, when left untreated. Immunosuppressive drugs like calcineurin inhibitors as well as mammalian target of rapamycin inhibitors have been reported as causative agents for post-transplant HUS. METHODS A retrospective observational study was performed in lung transplant recipients, who took part in an interventional study, in two centres. Haemoglobin, platelets, creatinine and lactate dehydrogenase levels were monitored during routine follow-up and patients with deteriorating kidney function were screened for post-transplant HUS. All cases of post-transplant HUS were identified by clinical and laboratory findings. Outcome was recorded until 6 months after diagnosis. RESULTS A total of 2188 visits in 512 lung transplant recipients (outpatients) were analysed. Out of those, 126 patients took part in an interventional study. In this study, 67 were switched to everolimus in combination with calcineurin inhibitors 4 weeks after transplantation, 59 patients remained on standard immunosuppression (calcineurin inhibitors, mycophenolate mofetil and prednisolone). Five cases of post-transplant HUS were identified in the everolimus group. None of the patients had evidence of gastrointestinal infection or preexisting renal disease. Post-transplant HUS was treated with therapeutic plasma exchange and methylprednisolone pulse therapy. Everolimus was discontinued in all five patients. This treatment regimen led to normalization of haemoglobin, platelets and improved renal function. Two patients developed end-stage renal failure and were maintained on haemodialysis. One patient died due to multiorgan failure. Improvement of renal function was seen in two patients. No further cases were recorded in patients without everolimus during the study period. CONCLUSIONS Our data should raise the awareness of post-transplant HUS in lung transplant recipients. Post-transplant HUS is a rare disease, but it is a serious cause of acute renal failure in lung transplant recipients treated with a combination of everolimus and calcineurin inhibitors.

Surface receptor CD177/NB1 does not confer a recruitment advantage to neutrophilic granulocytes during human peritonitis.

To the Editor: Human neutrophilic granulocytes (PMN), the most abundant human leukocytes, are divided into two subpopulations by the GPI-linked NB1/CD177 surface receptor (1). Surface NB1 PMN lack NB1 protein in all cellular compartments. The proportion of NB1PMN varies between 0% and 100% in the human population, but is generally stable in an individual (1). Recent reports suggested a migration advantage of NB1 neutrophils using in vitro systems, possibly due to surface Proteinase 3 activity (2–4). To test whether or not NB1PMN are preferentially recruited in inflammation in vivo, we here investigated NB1 versus NB1PMN recruitment in human peritonitis.

Transgastrically placed endoscopic vacuum-assisted closure system as an addition to transgastric necrosectomy in necrotizing pancreatitis (with video)

BACKGROUND Endoscopic transluminal débridement of infected pancreatic necrosis has been proved to be an important alternative to surgical débridement. Recently, endoscopic vacuum-assisted closure (EVAC) has been described as a new effective treatment option in upper intestinal anastomotic leaks. OBJECTIVE To test whether the EVAC can be applied to transgastrically accessible infected cavities. DESIGN Single-center case study. SETTING Academic medical center. PATIENTS Two patients with necrotizing pancreatitis. MAIN OUTCOME MEASUREMENT Successful closure of leak. RESULTS We successfully applied EVAC to treat transgastrically accessible necrotic cavities. LIMITATIONS Small case number. CONCLUSIONS EVAC might be an important additional endoscopic treatment option for infected pancreatic necrosis, especially if established endoscopic treatment options fail.

Integrating MRI and chemokine receptor CXCR4-targeted PET for detection of leukocyte infiltration in complicated urinary tract infections after kidney transplantation

Complicated urinary tract infections (UTIs) are frequent in immunosuppressed patients after kidney transplantation and may lead to allograft failure or urosepsis. Noninvasive detection of allograft involvement as well as localization of the primary site of infection are challenging. Therefore, we sought to determine whether molecularly targeted PET, combined with diffusion-weighted MRI, enables detection of leukocytes in renal allografts. Methods: Thirteen kidney transplant recipients with complicated UTIs underwent both PET with a specific CXCR4 ligand, 68Ga-pentixafor, and diffusion-weighted MRI. The spatial distribution and intensity of CXCR4 upregulation in renal allografts as determined by SUVs on PET and diffusion restriction as determined by apparent diffusion coefficients (ADCs) on MRI were analyzed and compared with urinalysis, clinical chemistry and bacteriology, and biopsy, if available. Results: Combined PET/MRI detected acute allograft infection in 9 patients and lower UTI/nonurologic infections in the remaining 4 patients. Leukocyte infiltration was identified by areas of CXCR4 upregulation compared with unaffected parenchyma in PET (SUVmean, 4.6 vs. 3.7; P < 0.01), corresponding to areas with increased cell density in MRI (ADCmin, 0.89 vs. 1.59 × 10−3 mm2/s, P < 0.01). Allograft CXCR4 signal was paralleled by CXCR4 upregulation in lymphoid organs. Histopathologic evaluation supported a correlation between CXCR4 signal and presence of leukocytes. Conclusion: Combined CXCR4-targeted PET/MRI with 68Ga-pentixafor may enable the noninvasive detection of leukocytes in renal allografts. This novel methodology may refine the characterization of infectious and inflammatory kidney diseases and may serve as a platform for future clinical studies targeting allograft infection.