[Kidney function in contrast media-enhanced imaging]. / Nierenfunktion bei kontrastmittelverstärkter Bildgebung.

BACKGROUND: The potential adverse reactions to contrast media-enhanced imaging regularly offer challenges in decision-making for nephrologists and radiologists. OBJECTIVE: The clinical pictures of contrast media-induced acute kidney injury (CI-AKI) and nephrogenic systemic fibrosis (NSF) were evaluated, which are both caused by contrast media and closely linked to the kidney function. MATERIAL AND METHODS: The literature in PubMed and Medline was searched for the terms "kidney function" and "contrast media" and complemented by our own experiences. RESULTS: While there is an ongoing re-evaluation of the clinical relevance of CI-AKI, no new cases of NSF have recently been reported under consideration of certain preventive interventions and very restricted use of gadolinium-based contrast agents. CONCLUSION: Considering the results of the latest clinical research, the potential risk of CI-AKI has been overestimated for a long time and should no longer outweigh the diagnostic benefit of contrast media-enhanced imaging. Nevertheless, the most effective prophylaxis for CI-AKI is the avoidance of unnecessary administration of contrast media.

Autophagy activation in circulating proangiogenic cells aggravates AKI in type I diabetes mellitus.

Acute kidney injury (AKI) occurs frequently in hospitals worldwide, but the therapeutic options are limited. Diabetes mellitus (DM) affects more and more people around the globe. The disease worsens the prognosis of AKI even further. In recent years, cell-based therapies have increasingly been applied in experimental AKI. The aim of the study was to utilize two established autophagy inducers for pharmacological preconditioning of so-called proangiogenic cells (PACs) in PAC treatment of diabetic AKI. Insulin-dependent DM was induced in male C57/Bl6N mice by intraperitoneal injections of streptozotocine. Six weeks later, animals underwent bilateral renal ischemia for 45 min, followed by intravenous injections of either native or zVAD (benzyloxycarbonyl-Val-Ala-Asp-fluoro-methylketone)- or Z-Leu-Leu-Leu-al (MG132)-pretreated syngeneic murine PACs. Mice were analyzed 48 h (short term) and 6 wk (long term) later, respectively. DM worsened postischemic AKI, and PAC preconditioning with zVAD and MG132 resulted in a further decline of excretory kidney function. Injection of native PACs reduced fibrosis in nondiabetic mice, but cell preconditioning promoted interstitial matrix accumulation significantly. Both substances aggravated endothelial-to-mesenchymal transition (EndoMT) under diabetic conditions; these effects occurred either exclusively in the short (zVAD) or in the short and long term (MG132). Preconditioned cells stimulated the autophagocytic flux in intrarenal endothelial cells, and all experimental groups displayed increased endothelial abundances of senescence-associated ß-galactosidase, a marker of premature cell senescence. Pharmacological autophagy activation may not serve as an effective strategy for improving PAC competence in diabetic AKI in general. On the contrary, several outcome parameters (excretory function, fibrosis, EndoMT) may even be worsened.

Effect of ABO incompatibility on T-cell flow cytometry cross-match results prior to living donor kidney transplantation.

BACKGROUND: Due to its high sensitivity, the flow cytometry cross-match (FCXM) has been described as valuable tool for identifying an optimal donor. We here focused on the impact of ABO incompatibility on FCXM results. METHODS: We analyzed 29 ABO incompatible and 89 ABO compatible donor-recipient pairs (73 and 175 datasets, respectively) prior to living donor kidney transplantation. In all patients, lymphocytotoxic cross-matches for B and T cells were negative. RESULTS: Recipients with blood group O (A to O and B to O) displayed significantly (P < 0.05) higher T-FCXM results than those with blood group A and B (A to B, B to A and AB to A), respectively. Donor-specific T-FCXM responses (ΔMFI values) were significantly higher (P < 0.05) in ABO incompatible vs. compatible pairs (ABO incompatible recipients with blood group O: 32 ± 6; with blood group A: 19 ± 7; with blood group B: 7 ± 4; recipients with ABO compatibility: 3 ± 2, respectively, data represent mean ± SEM). Consistent with the T-FCXM results donor-specific isohemagglutinins (IgG titers) were significantly higher in recipients with blood group O vs. A, both prior to rituximab treatment and plasmapheresis/immune adsorption (P = 0.004) and immediately prior to transplantation, i.e., after rituximab and antibody-depleting therapies (P = 0.04). CONCLUSIONS: ABO incompatibility was associated with higher T-FCXM responses, especially in recipients with blood group O. This finding has major impact on the interpretation of flow cross-match results. Current cut-off values need to be reassessed in the ABO incompatible setting. © 2016 International Clinical Cytometry Society.

[Acute kidney injury : A clinical syndrome]. / Akutes Nierenversagen : Ein klinisches Syndrom.

Acute kidney injury (AKI) is a clinical syndrome occurring in the context of multiple and diverse disease entities. Although the term AKI implies renal damage as well as functional impairment or a combination of both, diagnosis is solely based on the functional parameters serum creatinine and urine output. Independent of the underlying disease and even assuming full recovery of renal function, AKI is associated with increased morbidity and mortality not only during the acute situation, but also long term. Awareness of the individual risk profile of each patient and the variety of causes and clinical manifestations of AKI is pivotal for prophylaxis, diagnosis, and therapy. The complexity of the clinical syndrome in the context of sepsis, solid organ transplantation, malignancy, and autoimmune diseases requires differentiated diagnostic and therapeutic approaches and interdisciplinary care.

Postischemic microvasculopathy and endothelial progenitor cell-based therapy in ischemic AKI: update and perspectives.

Acute kidney injury (AKI) dramatically increases mortality of hospitalized patients. Incidences have been increased in recent years. The most frequent cause is transient renal hypoperfusion or ischemia which induces significant tubular cell dysfunction/damage. In addition, two further events take place: interstitial inflammation and microvasculopathy (MV). The latter evolves within minutes to hours postischemia and may result in permanent deterioration of the peritubular capillary network, ultimately increasing the risk for chronic kidney disease (CKD) in the long term. In recent years, our understanding of the molecular/cellular processes responsible for acute and sustained microvasculopathy has increasingly been expanded. The methodical approaches for visualizing impaired peritubular blood flow and increased vascular permeability have been optimized, even allowing the depiction of tissue abnormalities in a three-dimensional manner. In addition, endothelial dysfunction, a hallmark of MV, has increasingly been recognized as an inductor of both vascular malfunction and interstitial inflammation. In this regard, so-called regulated necrosis of the endothelium could potentially play a role in postischemic inflammation. Endothelial progenitor cells (EPCs), represented by at least two major subpopulations, have been shown to promote vascular repair in experimental AKI, not only in the short but also in the long term. The discussion about the true biology of the cells continues. It has been proposed that early EPCs are most likely myelomonocytic in nature, and thus they may simply be termed proangiogenic cells (PACs). Nevertheless, they reliably protect certain types of tissues/organs from ischemia-induced damage, mostly by modulating the perivascular microenvironment in an indirect manner. The aim of the present review is to summarize the current knowledge on postischemic MV and EPC-mediated renal repair.

Decreased IL-10(+) regulatory B cells (Bregs) in lupus nephritis patients.

OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell-dependent autoantibody production. Recently, a new B-cell subset was discovered that has a regulatory capacity. The aim of this study was to analyse regulatory B cells (Bregs) in SLE patients. METHOD: Peripheral mononuclear blood cells (PBMCs) of 34 SLE patients fulfilling the American College of Rheumatology (ACR) criteria for SLE and 21 healthy controls (HC) were included. PBMCs were stained for CD19, CD24, and CD38 and analysed by flow cytometry. In vitro stimulated PBMCs with CpG and restimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin were investigated for IL-10(+) Bregs . RESULTS: The percentages of circulating CD19(+)CD24(hi)CD38(hi) cells in HC were not different those in from SLE patients. The percentages of IL-10(+) Bregs were significantly decreased in SLE patients, in particular those with lupus nephritis (LN), compared to HC. The proportion was independent of disease activity. CONCLUSIONS: This is the first study to demonstrate a decrease in IL-10-producing B cells in LN patients compared to HC, reflecting an impaired regulatory function.

Increased percentages of PD-1 on CD4+ T cells is associated with higher INF-γ production and altered IL-17 production in patients with systemic lupus erythematosus.

OBJECTIVES: Programmed death (PD)-1 is a cell death receptor that, upon stimulation, leads to apoptosis. Previous studies have shown alteration of PD-1 expression on T cells and PD-1 genes in patients with systemic lupus erythematosus (SLE). The aim of this study was to assess the expression of this receptor on effector T cells in patients with SLE. METHOD: In this study we enrolled 32 SLE patients and 31 healthy controls. T cells from peripheral blood were analysed by flow cytometry for the expression of PD-1. Interferon (IFN)-γ and interleukin (IL)-17-producing cells were investigated for the expression of this co-stimulatory marker. RESULTS: Percentages of CD4(+) T cells expressing PD-1 were significantly increased in patients with SLE compared to healthy controls. The percentage of PD-1 expression was correlated with the production of INF-γ (r = 0.83, p < 0.0001). We also investigated the production of IL-17 by PD-1(+) CD3(+) T cells. Inactive patients (3.2 ± 1.2% vs. 5.9 ± 3.5%, p = 0.002) and patients without lupus nephritis (LN) (3.2 ± 1.5% vs. 5.9 ± 3.5%, p = 0.005) showed lower levels of IL-17 compared to healthy controls. CONCLUSION: We have demonstrated increased expression of PD-1 on CD4(+) T cells in SLE patients and an association between PD-1 expression on CD4(+) T cells and IFN-γ expression on CD3(+) T cells. We have also shown that there is an altered subset of PD-1(+) T cells in inactive patients and patients without LN producing lower amounts of IL-17.

Treatment of severe psoriasis with etanercept in a pancreas-kidney transplant recipient.

Severe psoriasis is a rare condition under immunosuppressive therapy. We describe a 42-years-old man with psoriasis since the age of 22 years. The patient underwent a combined pancreas-kidney transplantation at the age of 32 because of Goodpasture syndrome with renal and pulmonary involvments and type 1 diabetes mellitus. Seven years later a pancreas retransplantation was performed due to nonfunction of the original pancreas allograft. Despite intensive systemic immunosuppression, consisting of prednisone, tacrolimus, and mycofenolate mofetil, and topical treatment with dithranol and steroids, there was significant worsening of psoriasis. In October 2009 we initiated therapy with etanercept (25 mg s.c.) twice weekly under close clinical and laboratory monitoring. Improvement was rapid with a decrease in Psoriasis Area and Severity Index (PASI) from 25.2 to <5 during the first months of treatment without a severe infection or other adverse reaction. Graft functions were not affected by the treatment. The patient remains till now on the same regimen and is almost free of skin manifestations. To our knowledge so far only 2 cases of etanercept therapy in psoriasis have been reported in liver transplant recipients. In both cases the treatment was well tolerated and effective. Psoriasis therapy in organ transplant recipients represents a major challenge. Biological agents such as etanercept may provide an effective option for refractory cases.

[Mobile applications and management of hypertension: possibilities, problems and perspectives]. / Mobilapplikationen und Management der Hypertonie: Möglichkeiten, Probleme und Perspektiven.

Via the internet smartphones allow the download of applications ("Apps") that can address various requirements of daily life. These technical advances create new opportunities to better meet needs of patients suffering from hypertension. This may apply particularly for medication adherence, blood pressure control and lifestyle-changing activities. At the moment younger users in particular are interested in such technology. From other clinical contexts it is known that text messages via cell phones improve medication adherence. A combination of a smartphone and a blood pressure measurement device with the possibility to electronically collect data is promising as the quality of data may improve. Technology interventions by mobile applications that are supported by education or an additional intervention demonstrate a beneficial impact for the reduction of physical inactivity and/or overweight and obesity. However, it is not clear what parts of the technology or interventions are effective. For future developments it will be important to reduce costs and better meet hardware and software requirements of elderly users.

Peripherally circulating CD4⁺ FOXP3⁺ CXCR3⁺ T regulatory cells correlate with renal allograft function.

Peripheral immunoregulation depends on T regulatory cell trafficking into the allograft to modulate the local alloresponse. Little is known about the relevance of trafficking receptors for Tregs after solid organ transplantation in humans. In this study, expression of the peripheral chemokine receptors CXCR3 and CCR5 on CD4⁺ FOXP3⁺ Treg cells was analysed and correlated with allograft function in renal transplant recipients. Flow cytometry analysis of peripheral blood mononuclear cells of 54 renal transplant recipients receiving a calcineurin inhibitor-based immunosuppression was performed for CD4, CD25, FOXP3, CXCR3 and CCR5 within the first 18 months post-transplantation. Correlation analysis of chemokine receptor expression and glomerular filtration rate as calculated by MDRD (eGFR) was performed. Expression of the peripheral homing receptors CXCR3 (r = 0.44, P < 0.05) and CCR5 (r = 0.45, P < 0.05) on FOXP3⁺ Tregs correlated with renal allograft function (eGFR) in patients receiving tacrolimus (n = 28), but not cyclosporine A (CsA) (n = 26). CsA but not tacrolimus reduced surface expression of CXCR3 on FOXP3⁺ Tregs in renal transplant recipients as correlated to trough levels (r = -0.42, P < 0.05). In contrast to CD4⁺ CXCR3⁺ CD25(lo) T cells, flow-sorted CD4⁺ CXCR3⁺ CD25(hi) Tregs isolated from healthy individuals did not produce IFNγ or IL-17 ex vivo and expressed high levels of GARP mRNA both at baseline as well as after TCR activation indicating functional regulatory activity. Expression of the peripheral trafficking receptors CXCR3 and CCR5 on FOXP3⁺ Tregs is associated with renal allograft function. These results suggest that Treg trafficking may also depend on the interaction of CXCR3 or CCR5 and their respective ligands.

[Managing EHEC in hospital routine]. / Krankenhaushygiene: Umgang mit einem EHEC-Ausbruch.

BACKGROUND: During May and June 2011 an outbreak of enterohemorrhagic Escherichia coli (EHEC) occurred in Germany. More than 4000 patients were infected of which 800 developed hemolytic uremic syndrome (HUS) as a severe complication. Reports in the press led to great concern in the general population. Many people with diarrhea reported to hospitals in order to exclude EHEC infections. METHODS: We describe the management of patients with suspected infectious diarrhea at the university hospital of Essen. A hospital with a significant number of immunocompromised patients. RESULTS: One important measure to handle the surge of contagious patients was to establish a multidisciplinary coordination team under leadership and guidance of the Department of Nephrology and the Department of Hospital Hygiene. Suspected infectious patients were separated in a modified emergency room. A new ward for infectious diseases was established to isolate in-patients. CONCLUSION: In our hospital the management of EHEC outbreak enabled us to treat these additional infectious patients without hampering the treatment of the other patients. As a result we plan the implementation of a coordination team for future epidemics.

Cyclosporin but not everolimus inhibits chemokine receptor expression on CD4+ T cell subsets circulating in the peripheral blood of renal transplant recipients.

The peripheral chemokine receptors chemokine receptor 3 (CXCR3) and CC chemokine receptor 5 (CCR5) have been reported to be associated with allograft rejection. The impact of the expression of immunosuppressive drugs on peripherally circulating CD4(+) T cell subsets after renal transplantation is unknown. Expression of CXCR3 and CCR5 was investigated by flow cytometry in 20 renal allograft recipients participating in a prospective, randomized trial (NCT00514514). Initial immunosuppression consisted of basiliximab, cyclosporin A (CsA), mycophenolate sodium and corticosteroids. After 3 months, patients were treated either with CsA, mycophenolate sodium (MPA) plus corticosteroids (n = 6), CsA and everolimus plus corticosteroids (n =8) or CsA-free (CsA(free)) receiving everolimus, MPA and corticosteroids (n = 6). After initial reduction of CD4(+) forkhead box protein 3 (FoxP3)(+) and CD4(+) CD25(hi) FoxP3(+) regulatory T cells (T(regs)) (P < 0.05; P < 0.01), 3-month post-transplant percentages of T(regs) were reconstituted in CsA(free) and CsA(lo) arms compared to CsA(reg) 12 months post transplant. Expression of CCR5 and CXCR3 on CD4(+) FoxP3(+) and CD4(+) FoxP3(-) T cells 12 months post transplant was increased in CsA(free) versus CsA(reg). Increase in CCR5(+) CXCR3(+) co-expressing CD4(+) FoxP3(-) cells between 3 and 12 months correlated negatively with the glomerular filtration rate (GFR) slope/year [modification of diet in renal disease (MDRD); r = -0.59, P < 0.01]. CsA, but not everolimus, inhibits both T(reg) development and expression of CXCR3 and CCR5 on CD4(+) T cell subsets. Increase in CCR5(+) CXCR3(+) co-expressing CD4(+) FoxP3(-) T cells is associated with early loss in allograft function.

Plasma noradrenaline and state anxiety levels predict placebo response in learned immunosuppression.

Large interindividual differences exist in the presence and extent of placebo responses in both experimental and clinical studies, but little is known about possible predictors of these responses. We employed a behaviorally conditioned immunosuppression paradigm in healthy men to analyze predictors of learned placebo responses. During acquisition, the subjects received either the immunosuppressant cyclosporin A (n = 32) or a placebo (n = 14) (unconditioned stimuli (US)) together with a novel-tasting drink (conditioned stimulus (CS)). During evocation, the subjects were reexposed to the CS alone. In responders (n = 15), the CS alone caused a significant inhibition of interleukin (IL)-2 production by anti-CD3-stimulated peripheral blood T cells, closely mimicking the drug effect. Nonresponders (n = 17) did not show responses different from those of the controls. Multiple-regression analyses showed that baseline IL-2, plasma noradrenaline, and state anxiety predicted nearly 60% of the variance in the conditioned IL-2 response. These data provide first evidence for putative biological and psychological predictors of learned placebo responses.

Impact of renal failure on metabolic bone parameters in a vitamin D-deficient patient cohort.

INTRODUCTION: Chronic renal failure is associated with major changes in bone metabolism, but studies evaluating bone metabolism with mild or moderate renal failure are rare. Moreover, the study populations were often heterogenous and/or patients were pretreated with calcium and vitamin-D preparations. Therefore, we prospectively evaluated metabolic bone parameters in patients with renal insufficiency (Stage 1 - 4) on their first visit to outpatient nephrologists. PATIENTS AND METHODS: 285 patients were prospectively evaluated regarding renal function, serum phosphorous, plasma parathyroid hormone (PTH), serum 25-OH-vitamin-D and serum bone specific alkaline phosphatase (BAP) concentrations. Patients were subdivided according to the stages of chronic kidney disease. RESULTS: Hypocalcemia occurred in only 10% of patients in Stage 4, whereas serum phosphorous was elevated at the same stage in 40% of the patients. PTH increased from Stage 1 to 4 continually with a high prevalence of elevated PTH levels (> 65 pg/ml) in Stage 1: 44%; Stage 4: 84%. Serum 25-OH-vitamin-D levels were very low irrespective of renal function: < 15 ng/dl, i.e., 37.5 nmol/l in 70% of all patients. 25-OH-D was negatively correlated with PTH (r = 0.3, p < 0.0002). BAP was within the normal range in all stages but with a high prevalence of BAP values < 7.5 ng/ml in up to 25% in Stage 4. Only 6.5% of patients had features of classical renal hyperparathyroidism. Nearly 20% had low BAP levels in the presence of normal (9.5%) or increased (9.6%) PTH levels. CONCLUSION: This study demonstrates a high prevalence of hyperphosphatemia in patients with moderate renal failure. Hyperparathyroidism was present even in earlier stages and was aggravated by a high prevalence of vitamin D deficiency. However, also in the presence of elevated PTH levels, there is indication of low bone turnover as evidenced by low BAP levels, suggesting adynamic bone disease.

[Acute kidney injury]. / Akutes Nierenversagen.

New guidelines of the "Kidney Disease: Improving Global Outcome" (KDIGO) working group standardize the definition of acute kidney injury (AKI) and acute kidney disease (AKD) allowing the assessment of prognosis and efficacy of prophylactic and therapeutic measures in different patient cohorts. The degree of severity and the duration of acute kidney injury are critical factors for the development of chronic kidney disease and mortality. The achievement of optimal fluid volumes is a cornerstone in the treatment during the early phase of AKI, while volume overload should be avoided in the late phase of established AKI. Recently employed biomarkers are promising for the early detection and prognosis of AKI, but cannot yet be used as routine tests. Microscopic urinalysis, a very old and cost-effective diagnostic measure, provides valuable informations about the severity and the course of AKI.

[Urinary tract infections after kidney transplantation: Essen algorithm for calculated antibiotic treatment]. / Harnwegsinfektionen nach Nierentransplantation : Essener Algorithmus zur kalkulierten Antibiotikatherapie.

Urinary tract infections are the most common infection early after transplantation and can affect long-term graft function. Any urinary tract infection in renal transplant recipients should be seen as "complex" with regard to consequences for diagnosis and therapy. The increase in resistance to anti-infective agents seen among uropathogens is one of the central therapeutic problems. This means for routine clinical practice that contact isolation precautions should be consistently implemented for affected patients and the duration of introducing urinary tract instruments should be minimized. Detection of pyuria and urine cultures are required to confirm infection, to identify the corresponding pathogen, and to review the antibiotic therapy.The "Essen algorithm for calculated antibiotic treatment of urinary tract infections in renal transplant patients" takes into consideration the high incidence of Gram-negative pathogens in general and the increased incidence of enterococci in the early phase after transplantation. Within the first 2 months after transplantation quinolones should be used and later cephalosporins. In case of urosepsis, calculated antibiotic therapy should cover problematic Gram-negative pathogens such as pseudomonades. The calculated antibiotic therapy should be administered intravenously in severe infections. In any case the local and regional antibiotic susceptibility should be taken into account when deciding on the calculated antibiotic therapy.