A multimodal aftercare intervention improves the outcome after kidney transplantation - results of the KTx360° aftercare program using claims data.

Background: The after-care treatment project KTx360° aimed to reduce graft failure and mortality after kidney transplantation (KTx). Methods: The study was conducted in the study centers Hannover, Erlangen and Hannoversch Muenden from May 2017 to October 2020 under the trial registration ISRCTN29416382. The program provided a multimodal aftercare program including specialized case management, telemedicine support, psychological and exercise assessments, and interventions. For the analysis of graft failure, which was defined as death, re-transplantation or start of long-term dialysis, we used longitudinal claims data from participating statutory health insurances (SHI) which enabled us to compare participants with controls. To balance covariate distributions between these nonrandomized groups we used propensity score methodology, in particular the inverse probability of treatment weighting (IPTW) approach. Findings: In total, 930 adult participants were recruited at three different transplant centres in Germany, of whom 320 were incident (enrolled within the first year after KTx) and 610 prevalent (enrolled >1 year after KTx) patients. Due to differences in the availability of the claims data, the claims data of 411 participants and 418 controls could be used for the analyses. In the prevalent group we detected a significantly lower risk for graft failure in the study participants compared to the matched controls (HR = 0.13, 95% CI = 0.04-0.39, p = 0.005, n = 389 observations), whereas this difference could not be detected in the incident group (HR = 0.92, 95% CI = 0.54-1.56, p = 0.837, n = 440 observations). Interpretation: Our findings suggest that a multimodal and multidisciplinary aftercare intervention can significantly improve outcome after KTx, specifically in patients later after KTx. For evaluation of effects on these outcome parameters in patients enrolled within the first year after transplantation longer observation times are necessary. Funding: The study was funded by the Global Innovation fund of the Joint Federal Committee of the Federal Republic of Germany, grant number 01NVF16009.

Prevalence of Mental Disorders in a German Kidney Transplant Population: Results of a KTx360°-Substudy.

In patients after kidney transplantation (KTx) an increased rate of affective and anxiety disorders has been observed. Repeatedly, a relationship between mental health issues and increased morbidity and mortality in KTx recipients has been reported. However, information on the prevalence of mental disorders in KTx patients is scarce. As part of the structured multimodal follow-up program (KTx360°), mental disorders were examined in 726 patients after KTx through structured diagnostic interviews using the Mini-DIPS Open Access. Overall, 27.5% had a current and 49.2% a lifetime mental disorder. Only 14.5% with a current mental disorder reported to be in treatment. Affected patients were younger, more often female, reported more symptoms of anxiety and depression and less perceived social support. While comparable to the rate in general population samples, the prevalence of mental disorders should attract attention. The low treatment rate requires an improved identification of afflicted patients and provision of specialist treatment.ISRCTN registry, https://doi.org/10.1186/ISRCTN29416382 , date of registry: 03.05.2017.

Chemokine/Cytokine Levels Correlate with Organ Involvement in PR3-ANCA-Associated Vasculitis.

BACKGROUND: ANCA-associated vasculitis (AAV) is a rare small vessel disease characterized by multi-organ involvement. Biomarkers that can measure specific organ involvement are missing. Here, we ask whether certain circulating cytokines and chemokines correlate with renal involvement and if distinct cytokine/chemokine patterns can differentiate between renal, ear/nose/throat, joints, and lung involvement of AAV. METHODS: Thirty-two sets of Birmingham vasculitis activity score (BVAS), PR3-ANCA titers, laboratory marker, and different cytokines were obtained from 17 different patients with AAV. BVAS, PR3-ANCA titers, laboratory marker, and cytokine concentrations were correlated to different organ involvements in active AAV. RESULTS: Among patients with active PR3-AAV (BVAS > 0) and kidney involvement we found significant higher concentrations of chemokine ligand (CCL)-1, interleukin (IL)-6, IL21, IL23, IL-28A, IL33, monocyte chemoattractant protein 2 (MCP2), stem cell factor (SCF), thymic stromal lymphopoietin (TSLP), and thrombopoietin (TPO) compared to patients without PR3-ANCA-associated glomerulonephritis. Patients with ear, nose, and throat involvement expressed higher concentrations of MCP2 and of the (C-X-C motif) ligand-12 (CXCL-12) compared to patients with active AAV and no involvement of these organs. CONCLUSION: We identified distinct cytokine patterns for renal manifestation and for ear, nose and throat involvement of PR3-AAV. Distinct plasma cytokines might be used as non-invasive biomarkers of organ involvement in AAV.

Organ integration in kidney transplant patients - Results of a KTx360° substudy.

OBJECTIVE: Organ transplantation is the treatment of choice for patients with end-stage organ disease. From early on, the psychological perspective on integrating the organ has been of interest. As quantitative studies on organ integration are scarce, we aimed at evaluating this aspect in a large sample of kidney transplant (KTx) recipients. METHODS: For this cross-sectional study, 684 patients after KTx were recruited within the structured post-transplant care program KTx360°. To measure organ integration and donor relationship, a previously developed and published questionnaire (FOSP), generated explicitly for this purpose, was used. Associations with sociodemographic, medical, donation-specific, and psychological variables were investigated. RESULTS: Overall, more than 90% of the patients perceived the transplant as part of themselves; however, a small minority reported perceiving it as a foreign object. Frequent thoughts about the donor and the belief of having adopted some of the donor's traits were common (52% and 14%, respectively), specifically in living donor recipients. Higher anxiety and depression scores and reduced kidney functioning were associated with less ideal organ integration, while a more extended period since KTx and more perceived social support correlated with better organ integration. No association between organ integration and adherence, as well as organ integration and cognitive functioning, could be found. CONCLUSION: Organ integration and donor relationship were unproblematic in most KTx patients. However, offering psychosocial support to those struggling with organ integration and donor relationship is crucial from a clinical perspective.

Use and preferences regarding internet-based health care delivery in patients with chronic kidney disease.

BACKGROUND AND OBJECTIVES: Internet-based technologies play an increasingly important role in the management and outcome of patients with chronic kidney disease (CKD). The healthcare system is currently flooded with digital innovations and internet-based technologies as a consequence of the coronavirus disease 2019 (COVID-19) pandemic. However, information about the attitude of German CKD-patients with access to online tools towards the use of remote, internet-based interactions such as video conferencing, email, electronic medical records and apps in general and for health issues in particular, are missing. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: To address the use, habits and willingness of CKD patients in handling internet-based technologies we conducted a nationwide cross-sectional questionnaire survey in adults with CKD. RESULTS: We used 380 questionnaires from adult CKD patients (47.6% on dialysis, 43.7% transplanted and 8.7% CKD before renal replacement therapy) for analysis. Of these 18.9% denied using the internet at all (nonusers). Nonusers were significantly older (74.4 years, SD 11.4) than users (54.5 years, SD 14.5, p < 0.001), had a lower educational level than users (≥ 12 years: 6.9% versus 47.1%, p < 0.001) and were more often on dialysis. Within the group of internet users only a minority (2.6%) was using video conferencing with their physician, only 11.7% stated that they were using email to report symptoms and 26.6% were using the internet to schedule appointments. Slightly more than one-third of internet users (35.1%) are concerned that their personal medical data are not safe when submitted via the internet. CONCLUSIONS: Within our group of German CKD-patients we found that almost one out of five patients, especially older patients and patients with a lower educational level, did not use the internet at all. The majority of internet users reported in our survey that they have not used internet-based technologies within a medical context so far, but are willing to consider it. Therefore, it seems to be important to introduce and teach motivated CKD-patients the use and benefits of simple and safe internet-based health care technologies.

Knowledge About Immunosuppressant Medication and Its Correlates in a German Kidney Transplant Population - Results of a KTx360° Substudy.

PURPOSE: After organ transplantation, adherence to immunosuppressive medication (ISM) is crucial to prevent organ rejection. To enable adherence, patients need to be well informed about the different aspects associated with their ISM. However, literature suggests that knowledge regarding ISM is often inadequate. PATIENTS AND METHODS: In a cross-sectional study, 702 patients after kidney transplantation participating in a structured multimodal follow-up program (KTx360°) were evaluated. We utilized a self-developed questionnaire which has been successfully used before to measure patients' knowledge about the ISM. Above that we aimed to evaluate potential associations between sociodemographic, medical, donation-specific, and psychosocial variables including adherence, levels of depression and anxiety, perceived social support, and cognitive functioning with the knowledge level. RESULTS: The mean age of the patients was 52.4 years, 58.1% were men, and 66.6% were living in a partnership. The mean time since transplantation was 65.1 months. On average, patients answered 70.9% of the questions correctly. The percentage of correct answers per question differed considerably (54%-92%). In univariate analyses, knowledge levels were positively associated with female gender, current partnership, German as first language and better cognitive functioning. However, the effect sizes were small. CONCLUSION: Taking into account that the patients after KTx can be expected to answer all questions correctly as they aim at basic knowledge, an average result of 70.9% corresponds to a moderate knowledge level. Consequently, the current educational approaches do not seem to be sufficient to inform all patients adequately. Further research is necessary on how to improve health knowledge in the long term.

Ischemia Reperfusion Injury Triggers CXCL13 Release and B-Cell Recruitment After Allogenic Kidney Transplantation.

Ischemia reperfusion injury (IRI) is linked with inflammation in kidney transplantation (ktx). The chemokine CXCL13, also known as B lymphocyte chemoattractant, mediates recruitment of B cells within follicles of lymphoid tissues and has recently been identified as a biomarker for acute kidney allograft rejection. The goal of this study was to explore whether IRI contributes to the up-regulation of CXCL13 levels in ktx. It is demonstrated that systemic levels of CXCL13 were increased in mouse models of uni- and bilateral renal IRI, which correlated with the duration of IRI. Moreover, in unilateral renal IRI CXCL13 expression in ischemic kidneys was up-regulated. Immunohistochemical studies revealed infiltration of CD22+ B-cells and, single-cell RNA sequencing analysis a higher number of cells expressing the CXCL13 receptor CXCR5, in ischemic kidneys 7 days post IRI, respectively. The potential relevance of these findings was also evaluated in a mouse model of ktx. Increased levels of serum CXCL13 correlated with the lengths of cold ischemia times and were further enhanced in allogenic compared to isogenic kidney transplants. Taken together, these findings indicate that IRI is associated with increased systemic levels of CXCL13 in renal IRI and ktx.

Obesity After Kidney Transplantation-Results of a KTx360°Substudy.

OBJECTIVE: There is solid evidence that kidney transplant (KTx) patients are susceptible to weight gain after transplantation. Post-transplantation obesity [body mass index (BMI) ≥ 30 kg/m2] seems to be associated with higher risks of hypertension, dyslipidemia, diabetes mellitus, and cardiovascular events, while there are contradicting findings regarding the association between obesity and mortality, graft failure after transplantation as well as other variables. We aimed to evaluate the course of weight after KTx and to assess the prevalence of post-transplant obesity in a large sample of German KTx patients. Further, we focused on potential associations between weight gain, obesity, and BMI after transplantation with sociodemographic, medical, psychological [levels of anxiety and depression measured with the Hospital Anxiety and Depression Scale (HADS)], and donation-specific variables. METHODS: In a structured post-transplant care program 433 KTx patients were evaluated at Hannover Medical School. Information on the pre-transplant body weight/dry weight of dialysis patients was taken from the electronic patient charts. At post-transplant assessment body weight was measured in the transplant center. For statistical analyses, descriptive statistics, analyses of variance, tests for correlations, and regression analyses were used. RESULTS: Mean age was 51.3 years, 59% were male and 26.3% had ≥12 years of school attendance. Regarding somatic conditions 6.0% were suffering from type 2 diabetes mellitus, 6.9% were affected by new-onset diabetes after transplantation (NODAT), and the mean estimated glomerular filtration rate (eGFR) was 47.7 ml/min/1.73m2. The prevalence rates of obesity before and after kidney transplantation were 14.8 and 19.9%, respectively. This represents an increase of 34%. Obesity after transplantation was associated with higher rates of type 2 diabetes mellitus and of NODAT. Additionally, there was an association between increasing pre-transplant as well as post-transplant BMI and decreasing eGFR. Higher age and female sex were associated with higher rates of post-transplant obesity. CONCLUSIONS: Our results suggest that obesity represents a serious problem in KTx patients, especially regarding the association between increasing BMI and decreasing graft functioning (eGFR). However, this aspect is often overlooked and information on effective treatment options for these patients are scarce making further research on this topic necessary.

Beliefs about immunosuppressant medication and correlates in a German kidney transplant population.

OBJECTIVE: A common reason for organ rejection after transplantation is the lack of adherence regarding immunosuppressive medication (ISM). A variety of different aspects can promote non-adherent behavior, including the relationship between perceived benefits and concerns regarding ISM ("necessity-concerns-framework"). Little is known about the variables associated with this framework. METHODS: As part of this cross-sectional study, 570 patients after kidney transplantation who participated in a structured multimodal follow-up program (KTx360°) were examined in two transplant centers in Lower Saxony. We used the Beliefs about Medicines Questionnaire (BMQ) to evaluate the patients' believes and concerns regarding their ISM. RESULTS: The mean age of the participants was 51.9 (SD 14.17) years, 58.4% were men, and 25.8% had ≥12 years of school attendance. The mean time since transplantation was 65.9 months. In patients undergoing kidney transplantation, the perceived benefit of ISM mostly exceeded the concerns. We found an association between lower perceived benefits and greater concerns and lower adherence. Also, a higher perceived necessity was significantly associated with higher age and lower levels of depression and anxiety. Greater concerns were significantly associated with more symptoms of depression and anxiety, lower perceived social support, and lower kidney functioning (eGFR). CONCLUSION: Even though patients after kidney transplantation usually acknowledge the importance of their ISM, they still have considerable concerns that are associated with less adherence and various psychosocial risk factors. Further longitudinal studies are needed to assess the extent to which beliefs about medication are variable and can be individually addressed to improve adherence.

[Challenges in Long-Term Follow-Up Care of Patients After Kidney Transplantation in Specialized Transplant Centers]. / Herausforderungen der ambulanten Nachsorge von nierentransplantierten Patienten in spezialisierten Transplantationszentren.

Medical care after kidney transplantation requires a close follow-up in specialized transplant centers to minimize complications. Especially in bigger territorial states, the distance the patients have to cover is an underestimated problem for the patients. We performed a survey of 498 patients who underwent kidney transplantation at the transplant center of Hannover Medical School in Lower Saxony in order to find out the burden imposed by having to travel to one of the outpatient clinics affiliated with it for follow-ups. We found that 72% of the patients had to travel more than 100 km to reach the outpatient clinic and the costs for the trip were € 36.30 (standard deviation € 34.15). A distance between home and transplant center of more than 100 km reduced the motivation to attend the outpatient clinic significantly (p=0.023), whereas reimbursement of travel costs improved the motivation to attend the outpatient clinic only partially (p=0.012). We conclude that novel modern media-based care models like televisits could reduce patient burdens and optimize post-transplant care.

Prevalence and Correlates of Cognitive Impairment in Kidney Transplant Patients Using the DemTect-Results of a KTx360 Substudy.

Cognitive impairment in kidney transplantation (KTx) patients is associated with allograft survival and mortality. However, the prevalence of cognitive impairment after KTx is still understudied. Thus, we aimed to assess the prevalence of cognitive impairment in KTx patients and to identify sociodemographic, medical, donation-specific, and psychological variables associated with cognitive impairment. In this cross-sectional two-center study, 583 KTx patients participated in a structured post-transplant care program. The DemTect was used to assess cognition, and cognitive impairment was defined as a score of < 13. Mean age was 52.11 years, 59% were male, 27.4% had ≥12 years of school attendance, and 85.9% had hypertension. The prevalence of cognitive impairment was 15.6%. Cognitive impairment was significantly associated with higher age, male sex, lower educational level, subjective perception of cognitive decline, higher rates of hypertension, lower kidney functioning, and obesity (BMI > 30 kg/m2). Using logistic regression analysis, all variables except age remained significant. Our results suggest that cognitive impairment affects a significant number of patients after KTx. Transplant centers may consider screening for cognitive impairment using objective tests, especially in patients with a high-risk profile. Furthermore, studies with longitudinal designs are required in order to assess moderators and mediators for cognitive trajectories.

Information Needs of Patients About Immunosuppressive Medication in a German Kidney Transplant Sample: Prevalence and Correlates.

Background: Worldwide clinical guidelines for the care of kidney transplant (KT) recipients recognize the importance of health care providers imparting appropriate immunosuppressive medication (ISM) information for the facilitation of safe medication self-management. The extent of medication information made available is, however, not necessarily what patients require to know about their prescribed medicines. A useful indicator for determining the quality of prescription practice is to what degree the provided information meets the personal needs of patients. No previous studies have focused on the ISM information needs of KT patients. This study aims to investigate how satisfied KT patients are with the provided ISM information and to examine the association between satisfaction levels and socio-demographic, psychosocial, and transplant-related variables. Materials and Methods: KT patients (n = 440) were asked to complete a series of self-report questionnaires to evaluate the variables adherence, ISM experience, perceived social support, symptoms of anxiety, and depression, and transplant-related information (e.g., donation type). ISM information needs were assessed with the Satisfaction with Information about Medicines Scale (SIMS-D). Results: On average, 35.9% of the answers to the SIMS-D items indicated dissatisfaction with the received information; dissatisfaction was more prevalent for the SIMS-D subscale "potential problems" (46.1%) than the SIMS-D subscale "action and usage" (26.7%). On an individual item level, the dissatisfaction with information concerning ISM side effects on drowsiness (57.1%) and sex life (56.3%) was most notable. Higher satisfaction with ISM information was correlated with higher age, better adherence, higher perceived social support, and lower anxiety levels. Multiple linear regression analyses revealed that adherence, perceived social support, and age were independently associated with ISM information satisfaction. No associations were found with sex, educational level, partnership status, symptoms of depression, experience of side effects, and transplant-related variables. Discussion: The data indicate that a substantial proportion of KT patients have unmet ISM information needs, especially with regard to potential problems of ISM. Dissatisfaction with ISM information is a potential amendable risk factor for KT patients engaging in non-adherent behavior, thus justifying further research in this area. ISM information should be tailored to meet the individual needs of KT patients in order to promote optimal medication self-management and adherence behavior.

Chemokine CXCL13 as a New Systemic Biomarker for B-Cell Involvement in Acute T Cell-Mediated Kidney Allograft Rejection.

The presence of B-cell clusters in allogenic T cell-mediated rejection (TCMR) of kidney allografts is linked to more severe disease entities. In this study we characterized B-cell infiltrates in patients with TCMR and examined the role of serum CXCL-13 in these patients and experimentally. CXCL-13 serum levels were analyzed in 73 kidney allograft recipients at the time of allograft biopsy. In addition, four patients were evaluated for CXCL13 levels during the first week after transplantation. ELISA was done to measure CXCL-13 serum levels. For further mechanistic understanding, a translational allogenic kidney transplant (ktx) mouse model for TCMR was studied in BalbC recipients of fully mismatched transplants with C57BL/6 donor kidneys. CXCL-13 serum levels were measured longitudinally, CD20 and CD3 composition and CXCL13 mRNA in tissue were examined by flow cytometry and kidneys were examined by histology and immunohistochemistry. We found significantly higher serum levels of the B-cell chemoattractant CXCL13 in patients with TCMR compared to controls and patients with borderline TCMR. Moreover, in patients with acute rejection within the first week after ktx, a >5-fold CXCL13 increase was measured and correlated with B-cell infiltrates in the biopsies. In line with the clinical findings, TCMR in mice correlated with increased systemic serum-CXCL13 levels. Moreover, renal allografts had significantly higher CXCL13 mRNA expression than isogenic controls and showed interstitial CD20+ B-cell clusters and CD3+ cell infiltrates accumulating in the vicinity of renal vessels. CXCL13 blood levels correlate with B-cell involvement in TCMR and might help to identify patients at risk of a more severe clinical course of rejection.

CXCL13 in idiopathic pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

BACKGROUND: Chemokine CXC ligand 13 (CXCL13) has been implicated in perivascular inflammation and pulmonary vascular remodeling in patients with idiopathic pulmonary artery hypertension (IPAH). We wondered whether CXCL13 may also play a role in chronic thromboembolic pulmonary hypertension (CTEPH) and whether serum levels of CXCL13 might serve as biomarkers in these conditions. METHODS: Lung tissue from patients with IPAH or CTEPH was immunostained for CXCL13. Serum samples were obtained from patients with IPAH (n = 42) or CTEPH (n = 50) and from healthy controls (n = 13). Serum CXCL13 concentrations were measured by enzyme-linked immunosorbent assay technology and were evaluated for associations with markers of disease severity and survival. RESULTS: CXCL13 was expressed in pulmonary vascular lesions and lymphocytes of patients with IPAH and inoperable CTEPH, respectively. Serum CXCL13 was elevated in patients compared to healthy controls [median, interquartile range, 83 (55,114) pg/ml versus 40 (28, 48) pg/ml; p < 0.001]. Serum CXCL13 showed only weak and inconsistent correlations with markers of inflammation or disease severity. In both populations, patients with serum CXCL13 above the median of the respective groups did not have a higher risk of death than patients with lower serum CXCL13. CONCLUSIONS: CXCL13 was overexpressed in pulmonary vascular lesions of patients with IPAH and CTEPH, and increased serum concentrations were found in patients with IPAH and CTEPH, suggesting a potential pathogenic role of CXCL13 in both diseases. However, given the weak associations between serum CXCL13 and markers of disease severity and outcome, CXCL13 is unlikely to become a promising biomarker in these patient populations.

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

BACKGROUND: 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 (PLA2 R) 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. DESIGN: We evaluated a new rescue protocol including plasma exchanges (PE) against albumin, intravenous immunoglobulins (IVIGs) and rituximab for 10 patients with a biopsy-proven diagnosis of iMGN who were therapy-resistant to all conventional regimens and had a urinary protein to creatinine ratio of more than 10 000 mg/g Crea. We compared this protocol with standard immunosuppressive protocols including monthly alternating prednisolone plus cyclophosphamide (18 patients), cyclosporine plus prednisolone (23 patients) and rituximab alone (eight patients) in a retrospective design. RESULTS: Our rescue regimen with PE, IVIGs and rituximab achieved partial remission in 90% of patients who had been otherwise refractory to therapy. The mean time to partial remission was 2·1 months. Furthermore, two anti-PLA2 R-antibody negative patients were also treated with this rescue regimen, achieving partial remission after 1 and 4 months. CONCLUSION: A combination of PE, IVIGs and rituximab is a treatment option to consider for high-risk patients with iMGN who are refractory to conventional therapy.

Serum with phospholipase A2 receptor autoantibodies interferes with podocyte adhesion to collagen.

BACKGROUND: The majority of sera from patients with primary membranous nephropathy have autoantibodies against the M-type phospholipase A2 receptor (PLA2R) which is expressed on human podocytes. The rabbit variant of PLA2R attaches to collagen type IV via the fibronectin type II domain, which is also present in the human variant of PLA2R. DESIGN: To assess whether the human PLA2R variant is also involved in attachment to collagen type IV, we conducted a cell adhesion assay on a collagen-coated surface using PLA2R-transfected and mock-transfected human embryonic kidney (HEK) cells. To test the hypothesis that sera from patients containing anti-PLA2R antibodies interfere with the adhesion of podocytes to collagen, we performed cell adhesion assays on a collagen type IV-coated surface using positive and negative serum samples from patients and cultured human podocytes in vitro expressing PLA2R. RESULTS: The HEK cell adhesion assay confirmed an enhanced attachment of PLA2R-transfected cells to collagen type IV. We confirmed diminished podocyte adhesion in the presence of serum with anti-PLA2R antibodies. The concentration of anti-PLA2R antibodies correlated with proteinuria and to the degree of diminished adhesion of podocytes. CONCLUSIONS: We demonstrated that serum of patients containing autoantibodies directed to PLA2R interferes with the ability of podocytes to attach to collagen type IV in vitro, providing evidence of a serum soluble pathogenic factor interfering with podocyte adhesion in membranous nephropathy.

Low-dose irinotecan improves advanced lupus nephritis in mice potentially by changing DNA relaxation and anti-double-stranded DNA binding.

OBJECTIVE: Despite clear advances in the treatment of systemic lupus erythematosus (SLE), many patients still present with refractory lupus nephritis, requiring new treatment strategies for this disease. This study was undertaken to determine whether reduced doses of the topoisomerase I (topo I) inhibitor irinotecan, which is known as a chemotherapeutic agent, suppress SLE in (NZB × NZW)F1 (NZB/NZW) mice, and to evaluate the potential mechanism by which irinotecan influences the course of SLE. METHODS: NZB/NZW mice were treated with low-dose irinotecan beginning at either 24 weeks of age or established glomerulonephritis, defined as proteinuria of grade ≥3+. Binding of anti-double-stranded DNA (anti-dsDNA) antibodies was measured by enzyme-linked immunosorbent assay (ELISA), and DNA relaxation was visualized by gel electrophoresis. RESULTS: Significantly reduced irinotecan doses improved lupus nephritis and prolonged survival in NZB/NZW mice. The lowest dose successfully used for the treatment of established murine lupus nephritis was >50 times lower than the dose usually used for chemotherapy in humans. As a mechanism, low-dose irinotecan reduced B cell activity. However, the levels of B cell activity in irinotecan-treated mice were similar to those in BALB/c mice of the same age, suggesting that irinotecan did not induce clear immunosuppression. In addition, incubation of dsDNA with topo I increased binding of murine and human anti-dsDNA antibodies, showing for the first time that relaxed DNA is more susceptible to anti-dsDNA antibody binding. This effect was reversed by addition of the topo I inhibitor camptothecin. CONCLUSION: Our findings indicate that topo I inhibition may be a novel and targeted therapy for SLE.

Rationale and design of the RIACT-study: a multi-center placebo controlled double blind study to test the efficacy of RItuximab in Acute Cellular tubulointerstitial rejection with B-cell infiltrates in renal Transplant patients: study protocol for a randomized controlled trial.

BACKGROUND: Acute kidney allograft rejection is a major cause for declining graft function and has a negative impact on the long-term graft survival. The majority (90%) of acute rejections are T-cell mediated and, therefore, the anti-rejection therapy targets T-cell-mediated mechanisms of the rejection process. However, there is increasing evidence that intragraft B-cells are also important in the T-cell-mediated rejections. First, a significant proportion of patients with acute T-cell-mediated rejection have B-cells present in the infiltrates. Second, the outcome of these patients is inferior, which has been related to an inferior response to the conventional anti-rejection therapy. Third, treatment of these patients with an anti-CD20 antibody (rituximab) improves the allograft outcome as reported in single case observations and in one small study. Despite the promise of these observations, solid evidence is required before incorporating this treatment option into a general treatment recommendation. METHODS/DESIGN: The RIACT study is designed as a randomized, double-blind, placebo-controlled, parallel group multicenter Phase III study. The study examines whether rituximab, in addition to the standard treatment with steroid-boli, leads to an improved one-year kidney allograft function, compared to the standard treatment alone in patients with acute T-cell mediated tubulointerstitial rejection and significant B-cell infiltrates in their biopsies. A total of 180 patients will be recruited. DISCUSSION: It is important to clarify the relevance of anti-B cell targeting in T-cell mediated rejection and answer the question whether this novel concept should be incorporated in the conventional anti-rejection therapy. TRIAL REGISTRATION: Clinical trials gov. number: NCT01117662.

B-cell-attracting chemokine CXCL13 as a marker of disease activity and renal involvement in systemic lupus erythematosus (SLE).

OBJECTIVES: The chemokine CXCL13, also known as BCA-1 (B-cell-attracting chemokine-1) or BLC (B-lymphocyte chemoattractant), is a major regulator of B-cell trafficking. We have recently shown that excessive expression of dendritic cell-derived CXCL13 is a distinctive early event for nephritis in a murine model of systemic lupus erythematosus (SLE). Furthermore, in kidney biopsies from SLE patients, CXCL13 protein and mRNA are strongly expressed in B-cell-containing inflammatory lesions. Here, we ask whether serum levels of CXCL13 correlate with disease activity and renal involvement in SLE patients. METHODS: CXCL13 was measured in sera obtained from 91 patients with SLE and 40 healthy controls by ELISA methodology. Disease activity was calculated according to the SLE Disease Activity Index (SLEDAI). RESULTS: Median (IQR) serum CXCL13 concentrations were increasingly higher across the following groups: healthy controls [31.6 (26.8-41.3) pg/ml], SLE patients with inactive disease (SLEDAI <6) [68.2 (27.8-133.0) pg/ml, P = 0.0006 versus controls] and active disease [196.0 (75.9-416.8) pg/ml, P = 0.0001 versus controls] (inactive versus active P < 0.0001). Concentrations of circulating CXCL13 correlated with SLEDAI (r = 0.56, P < 0.0001) and double-stranded DNA titres (r = 0.36, P < 0.0005). Moreover, median CXCL13 concentrations were higher in patients with renal involvement [175.5 (105.3-422.6) pg/ml] compared to those without renal involvement [82.1 (42.9-219.8) pg/ml]. CONCLUSIONS: Our data indicate that increased level of CXCL13 is a feature of SLE that correlates with disease activity. Furthermore, CXCL13 might be a readily available surrogate marker to monitor the extent of aberrant B-cell (dys-)function.

Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis.

Costimulatory blockade with CTLA4Ig and anti-CD40L along with a single dose of cyclophosphamide induces remission of systemic lupus erythematosus nephritis in NZB/W F(1) mice. To understand the mechanisms for remission and for impending relapse, we examined the expression profiles of 61 inflammatory molecules in the perfused kidneys of treated mice and untreated mice at different stages of disease. Further studies using flow cytometry and immunohistochemistry allowed us to determine the cellular origins of several key markers. We show that only a limited set of inflammatory mediators is expressed in the kidney following glomerular immune complex deposition but before the onset of proteinuria. Formation of a lymphoid aggregate in the renal pelvis precedes the invasion of the kidney by inflammatory cells. Regulatory molecules are expressed early in the disease process and during remission but do not prevent the inevitable progression of active inflammation. Onset of proliferative glomerulonephritis and proteinuria is associated with activation of the renal endothelium, expression of chemokines that mediate glomerular cell infiltration, and infiltration by activated dendritic cells and macrophages that migrate to different topographical areas of the kidney but express a similar profile of inflammatory cytokines. Increasing interstitial infiltration by macrophages and progressive tubular damage, manifested by production of lipocalin-2, occur later in the disease process. Studies of treated mice identify a type II (M2b)-activated macrophage as a marker of remission induction and impending relapse and suggest that therapy for systemic lupus erythematosus nephritis should include strategies that prevent both activation of monocytes and their migration to the kidney.