[Diagnosis and treatment of interstitial cystitis (IC/PBS) : S2k guideline of the German Society of Urology]. / Diagnostik und Therapie der interstitiellen Zystitis (IC/BPS) : S2k-Leitlinie der Deutschen Gesellschaft für Urologie.

In this review article, the authors describe all relevant aspects of the new S2k guideline from the German Society of Urology (Deutschen Gesellschaft für Urologie, DGU) for the diagnosis and treatment of IC/PBS (interstitial cystitis/painful bladder syndrome). A list of necessary and optional examinations and the necessity of diagnosis of exclusion are summarized and evaluated. The treatment options listed (ranging from conservative, oral drug, and complementary medicine to interventional surgical procedures) also give the reader a good overview of the contents of the guideline and possible therapeutic approaches. Finally, the recommendations including consensus of the guideline group are also summarized in various information boxes.

[Reasons for the low organ donation rate in Germany]. / Ursachen der niedrigen Organspenderate in Deutschland.

BACKGROUND: The number of organ donations in Germany decreased by 32.3% between 2010 and 2017. For this reason, more than 1500 fewer organ transplantations were performed in 2017 than in 2010. QUESTION: What are the causes of this development? METHODS: Analysis of available statistics and scientific publications. RESULTS: A decline of the organ donation potential can be ruled out as the cause of the declining organ donation figures, since the number of patients who were eligible for organ donation from a medical point of view increased during the period under consideration. Similarly, there is no indication that a change in the population's attitude towards organ donation can be held responsible for this development. The decline is rather due to a recognition and reporting deficit of potential organ donors. The extent of this deficit differs considerably between different hospitals and is not only responsible for the decline in the donor rate in recent years, but also for the low donor numbers in Germany by international standards. CONCLUSION: The low organ donation figures in Germany are due to a recognition and reporting deficit. The number of organ donations could be considerably increased by improving the internal processes in hospitals.

Analysis of the Eurotransplant Kidney Allocation Algorithm: How Should We Balance Utility and Equity?

BACKGROUND: Since 2014, expected graft and recipient survival are matched by the U.S. kidney allocation system to improve organ utility. This mechanism is based on the kidney donor profile index (KDPI) and the estimated posttransplant survival score (EPTS). Here we analyzed 1. the transferability of these scores into the Eurotransplant (ET) region and 2. the extent to which the ET kidney allocation algorithm promotes utility. METHODS: We studied data of 262 kidney transplantations performed at the University Hospital Kiel between 2000 and 2009 (median follow-up, 9.94 years). RESULTS: Multivariable Cox regression analysis revealed that only the variables donor age of the KDPI and recipient's age of the EPTS have a significant value as predictors of posttransplant graft and recipient survival. The other variables showed no additional predictive value. Analyzing all kidneys allocated in the ET kidney allocation system and the European Senior Program, we found that donor and recipient's age and KDPI and EPTS were weakly correlated (rage-age = 0.5, P < .001; rKDPI-EPTS = 0.4, P < .01). If both programs were analyzed separately, no correlation between donor and recipient's age and between KDPI and EPTS was detected. CONCLUSION: The ET kidney allocation algorithm poorly matched predicted graft and recipient survival at our center. A better age-matching may improve organ utility.

Necroptosis in immunity and ischemia-reperfusion injury.

Transplantation is invariably associated with ischemia-reperfusion injury (IRI), inflammation and rejection. Resultant cell death has morphological features of necrosis but programmed cell death has been synonymous with apoptosis until pathways of regulated necrosis (RN) have been described. The best-studied RN pathway, necroptosis, is triggered by perturbation of caspase-8-mediated apoptosis and depends on receptor-interacting protein kinases 1 and 3 (RIPK1/RIPK3) as well as mixed linage kinase domain like to form the necroptosome. The release of cytosolic content and cell death-associated molecular patterns (CDAMPs) can trigger innate and promote adaptive immune responses. Thus, the form of cell death can substantially influence alloimmunity and graft survival. Necroptosis is a key element of IRI, and RIPK1 interference by RN-specific inhibitors such as necrostatin-1 protects from IRI in kidney, heart and brain. Necroptosis may be a general mechanism in response to other forms of inflammatory organ injury, and will likely emerge as a promising target in solid organ transplantation. As second-generation RIPK1 and RIPK3 inhibitors become available, clinical trials for the prevention of delayed graft function and attenuation of allograft rejection-mediated injury will emerge. These efforts will accelerate upon further identification of critical necroptosis-triggering receptor(s).

Increased mycophenolic acid exposure in stable kidney transplant recipients on tacrolimus as compared with those on sirolimus: implications for pharmacokinetics.

The pharmacokinetics of mycophenolic acid (MPA) was studied in 23 kidney transplant recipients with stable, long-term graft function who were receiving mycophenolate mofetil (MMF) in combination with either tacrolimus or sirolimus therapy. After 500 mg MMF, the mean MPA area under the curve (AUC) was significantly lower in sirolimus-treated patients than in those treated with tacrolimus (35.4 +/- 32.3 vs. 77.1 +/- 67.5 mg/l). MPA peak plasma concentration (C(max)) and MPA trough plasma concentration (C(min)) were significantly higher in patients who received tacrolimus than in those who received sirolimus. There were no significant differences between the two groups with respect to MPA time to maximum concentration (T(max)), MPA-glucuronide (MPAG) AUC, MPAG C(max), MPAG C(min), MPAG T(max), MPA-acyl-glucuronide (AcMPAG) AUC, AcMPAG C(max), AcMPAG C(min), and AcMPAG T(max). In conclusion, MPA exposure is greater in tacrolimus-treated patients than in those treated with sirolimus during maintenance immunosuppression after kidney transplant. It is suggested that the influence of tacrolimus on the pharmacokinetics of MPA reflects an interaction of the two agents at the level of their intestinal absorption.

[Chronic renal failure and transplantation]. / Chronische Niereninsuffizienz und Transplantation.

Kidney transplantation is the best option for all patients with terminal renal failure. Kidney transplantation is not only associated with an improved quality of life in comparison to all other renal replacement therapies, this method also offers a significantly extended lifespan. Therefore, the option for transplantation has to be verified for every patient with renal failure. Graft and patient survival is best when transplantation is carried out just before starting dialysis treatment. Realistically, only living donor transplantation offers the option of sparing the recipient a long waiting period on dialysis. Although transplantation from living donors is superior to cadaveric kidney transplantation, a small risk remains for the donor. Kidney transplantation and the immunosuppressive therapy are associated with an increased risk for certain types of infection, an increased tumour risk and an increased risk for cardiovascular complications. To address these problems, specific recommendations for patient surveillance have been provided by different transplantation societies.

CYP3A5 genotype markedly influences the pharmacokinetics of tacrolimus and sirolimus in kidney transplant recipients.

It is currently not clear whether the concentration-time curves of the immunosuppressants differ with respect to the CYP3A5, MDR1, or MRP2 genotype in dose-adapted stable kidney transplant patients. Dose/trough concentration ratios were obtained in 134 tacrolimus and 20 sirolimus-treated patients, and plasma concentration-time profiles were obtained from 16 (tacrolimus) and 10 (sirolimus) patients. Genotyping was carried out for CYP3A5 6986A>G; ABCB1 2677G>T/A, 3435C>T and ABCC2 -24C>T; 1249G>A; 3972C>T. Dose/trough concentration ratios were 0.67+/-0.3 and 1.36+/-0.73 x 10(3) l (P<0.00001) for tacrolimus and 0.42+/-0.17 and 0.84+/-0.46 x 10(3) l (P=0.18) for sirolimus in CYP3A5 non-expressors and expressors. The unadjusted tacrolimus area under curve (AUC)(0-12) was 106.8+/-17.5 ng/ml x h compared with 133.3+/-42.2 ng/ml x h (P=0.37) without affecting serum creatinine. Mean unadjusted AUC(0-24) of sirolimus did not differ significantly either. Therefore, CYP3A5 expressor status and not transporter variants is a main determinant of oral clearance, particularly for tacrolimus. Dose adaptation according to trough levels, however, appears to be sufficient to maintain similar concentration-time profiles.

FTY720/cyclosporine regimens in de novo renal transplantation: a 1-year dose-finding study.

FTY720 is a novel immunomodulator being investigated for rejection prophylaxis in renal transplantation when combined with full-dose cyclosporine (CsA; FDC). This 1-year phase II study compared FTY720 plus FDC (Neoral) with FTY720 plus reduced-dose CsA (RDC) and mycophenolate mofetil (MMF) plus FDC in de novo renal transplant patients. Patients were randomized 2:2:2:1 to FTY720 5 mg plus RDC (n = 72); FTY720 2.5 mg plus RDC (n = 74); FTY720 2.5 mg plus FDC (n = 76); or MMF plus FDC (n = 39) for 12 months. CsA exposure in the RDC group was reduced on average by 50% as assessed by C(2) monitoring. The primary efficacy endpoint was the composite incidence of biopsy-proven acute rejection (BPAR), graft loss, death or premature study discontinuation. The incidences for this composite endpoint were 24% and 22%, respectively, for FTY720 5 mg plus RDC and FTY720 2.5 mg plus FDC versus 39% for MMF plus FDC. Patients receiving FTY720 2.5 mg plus RDC were discontinued from treatment due to risk of under-immunosuppression. FTY720 2.5 mg plus FDC and FTY720 5 mg plus RDC were safe and effective in de novo renal transplant patients over 12 months.

"Very delayed" graft function in a patient after living related kidney transplantation: a case report.

We report the case of a patient who experienced anuric renal transplant failure for 44 days after living related kidney transplantation. Immunosuppressive and other therapies were carefully adapted to the findings of frequent renal transplant biopsies, which ultimately led to excellent graft function.

[Infections under immunosuppressive therapy following organ transplantation]. / Infektionen unter immunsuppressiver Therapie nach Organtransplantation.

The risk to acquire opportunistic infections is clearly increased in patients receiving immunosuppressive therapeutic regimens following organ transplantation or during treatment of autoimmune disorders. The modulation of the immune system can alter the clinical symptoms and the course of infectious diseases, including diagnostic signs such as fever or pathological changes in radiographs or blood cell counts. However, a rapid diagnosis and start of treatment is essential in these patients. Thus, a correct interpretation of even mild symptoms in the initial phase of an infectious disease is essential for establishing a diagnosis and initiation of a therapy at an early stage. Therefore, it is necessary that the clinical hallmarks of these diseases are widely known and that physicians treating these patients cooperate closely with transplant centers.

Determination of the pharmacokinetics of cerivastatin when administered in combination with sirolimus and cyclosporin A in patients with kidney transplant, and review of the relevant literature.

OBJECTIVE: Therapy of elevated cholesterol serum concentrations is often necessary in patients with kidney transplants. However, the pharmacokinetics of HMG-CoA reductase inhibitors when administered in combination with sirolimus and cyclosporin A (CsA) have not been determined. The aim of this study was to investigate the pharmacokinetics of cerivastatin when administered in combination with sirolimus in patients with kidney transplants, and to review the literature with regard to the differences in pharmacological behavior between sirolimus, CsA and tacrolimus. METHODS: Patients (n = 7) with a stable and functioning kidney transplant and elevated LDL cholesterol serum concentrations were included in the study. After an observation period of 3 months, and whilst receiving sirolimus and CsA, cerivastatin (0.2 mg daily) was administered for a period of 3 months. Pharmacokinetic parameters were calculated on Day 1 and 3 months after initiation of cerivastatin therapy. Routine laboratory parameters and clinical adverse events were monitored throughout the study period. RESULTS: Single-dose cerivastatin AUC was 2 to 3-fold higher in comparison to published values obtained in healthy subjects. The accumulation ratio of cerivastatin (after 3 months/ Day 1) was 1.6. Sirolimus and CsA trough levels, and the sirolimus AUC did not differ after single dose and multiple doses of cerivastatin. CONCLUSIONS: The combination therapy of cerivastatin with sirolimus and CsA leads to a significant increase in cerivastatin exposure. Additional drug monitoring of sirolimus and CsA is not necessary.

Simultaneous hemodialysis during coronary angiography fails to prevent radiocontrast-induced nephropathy in chronic renal failure.

BACKGROUND: Radiocontrast medium- (RM) associated nephrotoxicity continues to be a common cause of acute renal failure and may lead in patients with pre-existing chronic renal insufficiency even to end-stage renal failure requiring chronic dialysis. Since extracorporeal removal of RM after RM administration has been shown to be effective but does not prevent radiocontrast-induced nephropathy, the effect of a simultaneous dialysis during RM administration on renal function is not clear. METHODS: In a prospective, randomized and controlled trial, we studied the effect of a 4-hour online dialysis during RM (iomeprol) application in patients with advanced chronic renal failure (serum creatinine > or = 3 mg/dl) undergoing coronary angiography. All patients received hydration with saline before and after standardized coronary angiography and were randomized to receive a simultaneous high-flux hemodialysis (7 patients, HD group) or to control group (10 patients). 24-hour creatinine clearance (CrCl) was measured in all patients before, 1 week and 8 weeks after coronary angiography. The clinical follow-up comprised 8 weeks after RM application. RM plasma levels were measured in both groups 15, 30, 60 minutes, 2, 4, 12, 24, 48 and 72 hours after application by high-pressure liquid chromatography. RESULTS: At baseline, CrCl (19 +/- 10 vs 17 +/- 7 ml/min), percentage of diabetics (57 vs 70%) and dose of RM (77 +/- 27 vs 86 +/- 21 ml) were similar in both groups. Pharmacokinetics: Total clearance of iomeprol was significantly higher (54 +/- 15 vs 20 +/- 12 ml/min, p < 0.001) and the area under curve (AUC) was significantly lower (23 +/- 10 g x h/l vs 94 +/- 57 g x h/l, p < 0.001) in the HD group compared to control group. RM peak plasma levels 15 min after application were not different in both groups (3.0 +/- 1.1 vs 4.2 +/- 1.7 mmol/l, NS), however, significantly lower 60 min (1.6 +/- 0.4 vs 3.7 +/- 1.5 mmol/l, p < 0.01) and 240 min (0.7 +/- 0.3 vs 2.3 +/- 0.7 p < 0.001) after angiography. CLINICAL RESULTS: CrCl showed no difference 1 week (24 +/- 11 vs 19 +/- 9 ml/min, ns) and 8 weeks (24 +/- 5 vs 20 +/- 9 ml/min, NS) after angiography from baseline or between the groups. In each group, 2 patients developed end-stage renal disease and requested permanent dialysis during the 8-week follow-up. CONCLUSION: Simultaneous dialysis reduces AUC of iomeprol significantly, however, does not influence plasma peak concentration after angiography. Renal function and incidence of end-stage renal failure were not influenced by online-dialysis.

Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients.

BACKGROUND: Supplementation of immunosuppressive therapy with mycophenolate mofetil (MMF) has been found to reduce the rate of acute rejection in renal transplantation. We report a dose-finding study for MMF when administered in combination with low-dose tacrolimus and corticosteroid prophylaxis in cadaveric renal transplant recipients. METHODS: Two hundred thirty-two patients at 16 centers were enrolled in this randomized, parallel-group study. The three treatment groups were tacrolimus and corticosteroids (MMF-0 group, n=82); tacrolimus, corticosteroids, and 1 g of MMF daily (MMF-1 g group, n=79); and tacrolimus, corticosteroids, and 2 g of MMF daily (MMF-2 g group, n=71). Study duration was 6 months, and patients were followed up for patient and graft survival for 12 months. RESULTS: At 6 months posttransplantation, daily doses of 1 g and 2 g of MMF were associated with significantly lower rates of acute rejection compared with tacrolimus alone. The Kaplan-Meier rates were 48.5%, 24.9%, and 22.9%, respectively, for the three treatment groups when acute rejection was determined by clinical criteria (P=0.007). At month 12, patient survival rates were 100%, 97.5%, and 97.2% and graft survival rates were 90.2%, 92.4%, and 93.0% for the MMF-0 group, MMF-1 g group, and the MMF-2 g group, respectively. Gastrointestinal adverse events and leukopenia were higher in the MMF groups, especially in the MMF-2 g group (P<0.05). CONCLUSIONS: Low-dose tacrolimus combined with a MMF dose of 1 g daily and corticosteroids provided an optimized efficacy and safety profile. A higher dose of MMF (2 g) was associated with greater toxicity without a significant improvement in efficacy.

The immune dysregulatory compound mercuric chloride induces integrin-mediated T-lymphocyte adhesion.

Exposure of Brown Norway rats to mercuric chloride induces systemic autoimmunity, involving T- and B-lymphocyte activation, (auto-)antibody production and multiorgan inflammation. Several divalent metal ions, such as Mg2+ and Mn2+, can activate binding of integrins to their ligands, thus causing lymphocyte adhesion. To test the hypothesis that Hg2+ acts in a similar way, we studied the effect of HgCl2 on integrin-mediated T-cell adhesion. HgCl2 induced cell-cell aggregation of human T lymphoblasts. Exposure of a human T-cell clone to HgCl2 for 1 hr enhanced, in a dose-dependent way, cell binding to fibronectin (FN) and to intercellular adhesion molecules (ICAM) -1, -2 and -3. Furthermore, HgCl2 induced strong binding of Jurkat T cells to FN. These effects of HgCl2 were of similar magnitude as the effects of phorbol 12-myristate 13-acetate (PMA) or MnCl2. Studies using blocking antibodies indicated the involvement of CD11a in binding to ICAMs, and of CD49d, CD49e, and CD29 in binding to FN. Adhesion to FN induced by HgCl2 or by PMA, but not by MnCl2, was dependent on temperature and on extracellular Ca2+ or Mg2+. Addition of cytochalasin B enhanced synergistically the FN adhesion induced by MnCl2, whereas the effects of PMA and HgCl2 were not modified. These results indicate that Hg2+ is a potent activator of T-cell adhesion, mediated by several integrins and ligands. In contrast to the effect of MnCl2, HgCl2-induced cell adhesion probably involves an intracellular pathway. Activation of integrins by HgCl2 may play an important role in activation and migration of leucocytes involved in HgCl2-induced immune dysregulation in vivo.

The outcome of acute interstitial nephritis: risk factors for the transition from acute to chronic interstitial nephritis.

BACKGROUND: Acute interstitial nephritis has been known as a complication of mainly streptococcal infection for nearly a century. With the advent of infection control, it became a complication caused by antibiotics and later by other drugs, which might have changed the outcome. To determine risk factors for the development of chronic renal insufficiency, and thus, the transition from acute to chronic interstitial nephritis, we performed a retrospective study of all cases of acute interstitial nephritis found by reviewing 1,068 renal biopsies from 1968 to 1997. METHODS: Patients with permanent and reversible renal insufficiency after acute interstitial nephritis were compared with respect to the causative event, the symptoms, and the clinical and histological findings. Differences between the groups were calculated by applying bi- and multivariate analysis. RESULTS: Acute interstitial nephritis was found in 6.5% of all biopsies (64 patients with 68 episodes of acute interstitial nephritis); it was infection-induced in 10%, idiopathic in 4%, and drug-induced in 85% of the cases (antibiotics in 13 cases, analgesics in 17, non-steroidal anti-inflammatory drugs (NSAIDs) in 16, diuretics in 5, and various other drugs in 7). Renal insufficiency was reversible in 69% and permanent in 31% (12% partially reversible, 19% irreversible). The infection-induced and idiopathic types of acute interstitial nephritis were always reversible. Drug-related acute interstitial nephritis caused permanent renal insufficiency in 36% with a maximum of 56% in NSAID-induced cases. In drug-induced cases, intake of the suspected drug for more than a month prior to diagnosis caused permanent renal insufficiency in 88% and interstitial granuloma in 31%. Multivariate analysis disclosed the following significant features separating the permanent from the reversible renal insufficiency group: patients in the first group had more tubular atrophy in their histology, more chronic use of mixed analgesics and/or NSAIDs, less oliguria or anuria as an acute symptom, fewer antibiotics as causative agents, more interstitial granuloma, more pronounced interstitial cell infiltration in their histology, and more imaging of renal shrinkage. Renal histology had the highest predictive value. CONCLUSION: Today, acute interstitial nephritis is mainly drug-induced. NSAIDs are the most frequent cause of permanent renal insufficiency after acute interstitial nephritis. Clinically, subacute symptoms, a prolonged intake of the suspect drug, and chronic analgesic or NSAID use are related to a more chronic course of interstitial nephritis. In histology, tubular atrophy, interstitial granuloma, and pronounced interstitial cell infiltration indicate chronicity.

The HTLV-I tax protein transcriptionally modulates OX40 antigen expression.

OX40 is a member of the TNF receptor family, expressed on activated T cells. It is the only costimulatory T cell molecule known to be specifically up-regulated in human T cell leukemia virus type-I (HTLV-I)-producing cells. In a T cell line, OX40 surface expression was shown to be induced by HTLV-I Tax alone. To understand molecular mechanisms of OX40 gene regulation and modulation by HTLV-I Tax, we have cloned the human OX40 gene and analyzed its 5'-flanking region. By reporter gene analysis with progressive 5' deletions from nucleotides -1259 to -64, we have defined a 157-bp DNA fragment as a minimal promoter for constitutive expression. In addition, we show that in the OX40+ cell line, Co, Tax is able to further increase OX40 surface expression. Up-regulation of OX40 promoter activity by Tax requires two upstream NF-kappaB sites, which are not active in the constitutive OX40 expression. Their deletion abrogates Tax responsiveness in reporter gene analysis. The site-directed mutagenesis of each NF-kappaB site demonstrates that cooperative NF-kappaB binding is a prerequisite for Tax-directed activity as neither site alone is sufficient for a full Tax responsiveness of the OX40 promoter. Upon Tax expression, both sites bind p65 and c-Rel. These data provide new insight into the direct regulation of OX40 by Tax and add to our understanding of the possible role of the OX40/OX40 ligand system in the proliferation of HTLV-I+ T cells.

An interleukin-2-IgG-Fas ligand fusion protein suppresses delayed-type hypersensitivity in mice by triggering apoptosis in activated T cells as a novel strategy for immunosuppression.

BACKGROUND: Cell-mediated immune responses can be down-regulated by induction of apoptosis of immunoreactive lymphocytes. In the present study, we have tested the feasibility of a strategy for immunosuppression by the selective induction of apoptosis in activated, interleukin (IL)-2 receptor-positive lymphocytes, using a triple IL-2-IgG-FasL fusion protein. The IL-2-IgG-FasL fusion protein combines IL-2 for the selection of activated T cells, with the extracellular domain of the FasL molecule for inducing T-cell apoptosis. These components were separated by the Fc part of IgG1 serving as a spacer as well as for half-life prolongation. METHODS: The gene for the chimeric protein was created by fusing DNA sequences encoding for the three functional components: human IL-2, the Fc part of human IgG1, and the extracellular domain of murine FasL. When the fusion gene was expressed in murine J558L cells, we obtained soluble dimeric immunoglobulin-like proteins in the supernatant. After analyzing the function of the IL-2 and FasL portions individually in vitro, a delayed-type hypersensitivity (DTH) reaction to sheep red blood cells as model for cell-mediated immune responses was investigated to evaluate the IL-2-IgG-FasL-mediated immunosuppression in vivo. RESULTS: In vitro, the IL-2-IgG-FasL fusion protein supported IL-2-dependent proliferation of Fas-resistant CTLL-2 cells, whereas concanavalin A-T blasts were induced to undergo apoptosis by the FasL portion. In vivo, this fusion protein potently inhibited a murine DTH. This was associated with an increased rate of apoptosis in activated lymphocytes in the spleen, even at very low doses of the fusion protein. Furthermore, a second antigen challenge 10 days after IL-2-IgG-FasL treatment still failed to elicit a DTH response. CONCLUSION: The abrogation of a standard T cell-dependent immune response in vivo demonstrates that IL-2-IgG-FasL can be successfully exploited to trigger the death of deleterious T cells, presenting a potentially useful strategy in the management of autoimmune diseases and allotransplant rejections.