The humoral immune response more than one year after SARS-CoV-2 infection: low detection rate of anti-nucleocapsid antibodies via Euroimmun ELISA.

PURPOSE: Antibody assays against SARS-CoV-2 are used in sero-epidemiological studies to estimate the proportion of a population with past infection. IgG antibodies against the spike protein (S-IgG) allow no distinction between infection and vaccination. We evaluated the role of anti-nucleocapsid-IgG (N-IgG) to identify individuals with infection more than one year past infection. METHODS: S- and N-IgG were determined using the Euroimmun enzyme-linked immunosorbent assay (ELISA) in two groups: a randomly selected sample from the population of Stuttgart, Germany, and individuals with PCR-proven SARS-CoV-2 infection. Participants were five years or older. Demographics and comorbidities were registered from participants above 17 years. RESULTS: Between June 15, 2021 and July 14, 2021, 454 individuals from the random sample participated, as well as 217 individuals with past SARS-CoV-2 infection. Mean time from positive PCR test result to antibody testing was 458.7 days (standard deviation 14.6 days) in the past infection group. In unvaccinated individuals, the seroconversion rate for S-IgG was 25.5% in the random sample and 75% in the past infection group (P = < 0.001). In vaccinated individuals, the mean signal ratios for S-IgG were higher in individuals with prior infection (6.9 vs 11.2; P = < 0.001). N-IgG were only detectable in 17.1% of participants with past infection. Predictors for detectable N-IgG were older age, male sex, fever, wheezing and in-hospital treatment for COVID-19 and cardiovascular comorbidities. CONCLUSION: N-IgG is not a reliable marker for SARS-CoV-2 infection after more than one year. In future, other diagnostic tests are needed to identify individuals with past natural infection.

Proteinuria and sirolimus after renal transplantation: a retrospective analysis from a large German multicenter database.

The German Sirolimus Study Group has established a database among 10 transplant centers throughout Germany to study the outcomes in 726 renal transplant patients being converted to a sirolimus-containing therapy between 2000 and 2008 with a total of more than 1500 recorded patient years on therapy. In this study, we present a detailed description of the cohort, of characteristic changes over the observation period, proteinuria and graft survival, and new-onset proteinuria after conversion. Over the study period, age, graft function at the time of conversion, and the proportion of patients switched to sirolimus because of malignancy increased, whereas the proportion of patients with significant proteinuria at conversion decreased. Already modest proteinuria (151-268 mg/L) at conversion and new-onset proteinuria (>500 mg/L) after conversion were associated with inferior graft survival. Even mild proteinuria (>71 mg/L) at conversion was associated with new-onset proteinuria (>500 mg/L) post-conversion. Serum creatinine and urinary protein excretion at conversion together with age at transplantation had a significant impact on patient and graft survival. This large data set confirms and extends previous observations that proteinuria is an important indicator for graft outcome after conversion to sirolimus. We conclude that patients without any proteinuria have the greatest benefit from conversion to sirolimus.

SARS-CoV-2 infection is associated with physical but not mental fatigue - Findings from a longitudinal controlled population-based study.

OBJECTIVE: Fatigue has been identified as the core symptom of long-Covid, however, putative pandemic-related influences remain largely unclear. We investigated trajectories of total, physical and mental fatigue and the factors associated with it in previously infected and non-infected individuals up to one year post- infection. METHODS: We used data from a longitudinal cohort study of German adults with two samples: A representative probability sample and a sample of individuals with proven SARS-CoV-2 infection. Surveys were conducted in spring 2020(T1), autumn 2020(T2) and summer 2021(T3). Fatigue was assessed using the FAS, distinguishes between physical and mental fatigue. Depression, anxiety and stress were assessed using PHQ-4 and PSQ. RESULTS: 1990 participants [mean age 47.2 (SD = 17.0), 30.5% previously infected] were included in the survey at T1 (n = 1118 at T2, n = 692 at T3). Total and physical fatigue, but not mental fatigue were significantly higher in the previously infected compared to the non-infected sample at T2, but this group difference disappeared at T3. We identified Covid-infection as a factor associated with transient total and physical fatigue at T2. Depression, anxiety and stress at T1 were associated with total, physical and mental fatigue at both follow-ups. CONCLUSIONS: Our results highlight the importance of considering physical and mental fatigue as separate entities, while suggesting a greater relevance of the physical signs of fatigue in understanding long-Covid. The results further showed that baseline mental health symptoms were the most strongly associated with fatigue trajectories.

Stress and Depressive and Anxiety Symptoms in the General Population and in SARS-CoV-2-Infected Patients-Findings from a Population-Based Three-Wave Study.

Objective: Understanding factors that impaired mental health during the COVID-19 pandemic is extremely relevant in order to mitigate long-term consequences of the pandemic and to promote resilience in future crises. Method: Data were collected in southern Germany in a population-based survey study (CoKoS) with three times of measurement in May 2020, November 2020 and July 2021. Predictors of depressive and anxiety symptoms were measured with a short version of the Patient Health Questionnaire (PHQ-4) in the general population (N = 758) and individuals who were infected with SARS-CoV-2 in the beginning of the pandemic (N = 412). We investigated differences between both samples and how stress components (worry, tension, demands and joy) measured with the Perceived Stress Questionnaire (PSQ) varied with depressive and anxiety symptoms over time. Three linear mixed models (GLMMs) were fitted to predict the PHQ-4 stepwise, including sociodemographic variables and stress (PSQ). Results: Depressive and anxiety symptoms increased from May 2020 to November 2020 and remained stable until July 2021. There were no differences between people with SARS-CoV-2 infection and the general population. Those with a pre-existing disease and lower education reported higher levels of depressive and anxiety symptoms. Stress explained a substantial fraction of variance in depressive and anxiety symptoms. The stress component worry emerged as the strongest predictor of depressive and anxiety symptoms, whereas joy seemed to buffer these symptoms. Conclusions: The results suggest that mitigating people's worry and increasing joy may promote resilience in future crises. Future studies should assess mental health interventions targeted at vulnerable groups, such as those with lower socioeconomic status and poorer health.

Mycophenolate mofetil maintenance therapy in renal transplant patients: long-term results of the TranCept STAY study.

BACKGROUND: This prospective observational study documented long-term renal function in transplant recipients receiving mycophenolate mofetil (MMF). METHODS: Kidney allograft recipients>6 months post-transplantation, with a glomerular filtration rate (GFR)>20 mL/min, receiving MMF from time of transplantation were enrolled and followed for four yr. Subgroups were identified based on time between transplantation and enrollment: Y<1 (6 months-1 yr); Y1-2 (>1-2 yr); Y2-5 (>2-5 yr) and Y>5 (>5 yr). RESULTS: A total of 2040 patients were analyzed; 780, 410, 541 and 309 in subgroups Y<1, Y1-2, Y2-5 and Y>5. For all patients combined GFR decreased during the observational period by approximately 1 mL/min/yr (median GFR (mL/min) was 50.8, 50.5, 48.7, and 47.6 at one, two, three, and four yr). Survival estimates for decline in renal function (>20% GFR decline at one time point) were 78%, 66%, 57%, and 51% at one, two, three and four yr, with no significant differences between subgroups (p>0.05). In adult patients, higher doses of MMF (≥1 g/d) were associated with better GFR outcomes (median GFR (mL/min) 48.1 vs. 39.9 at four yr post-enrollment; p=0.0037). When comparing the effects of MMF combined with calcineurin inhibitors (CNIs), GFR was increased with lower doses of tacrolimus or cyclosporin. There were no major tolerability or acute rejection problems and graft survival was similar in all subgroups (graft survival estimates for all patients combined were 99%, 95%, 92%, and 90% at one, two, three, and four yr). CONCLUSIONS: Long-term MMF immunosuppression preserves renal function and higher MMF doses combined with lower CNI doses may provide better patient outcomes.

Longitudinal development of depression and anxiety during COVID-19 pandemic in Germany: Findings from a population-based probability sample survey.

The stress response to the COVID-19 pandemic might differ between early and later stages. Longitudinal data on the development of population mental health during COVID-19 pandemic is scarce. We have investigated mental health trajectories and predictors for change in a probability sample of the general population in Germany at the beginning and after 6 months of the pandemic. We conducted a longitudinal survey in a population-based probability sample of German adults. The current study analyzed data from a first assessment in May 2020 (T1; N = 1,412) and a second in November 2020 (T2; N = 743). Mental health was assessed in terms of anxiety and depression using the Patient Health Questionnaire-4 (PHQ-4). Mental health outcomes at T1 were compared with PHQ-4 norm data. Trajectories over time were investigated based on outcome classifications of PHQ-4 scores. Predictors of mental health outcomes and change were identified using multiple regression analysis. In spring 2020, participants showed significantly higher PHQ-4 scores as compared to the norm data, however, overall anxiety and depression remained low also 6 months later. 6.6% of respondents showed a mental health deterioration in autumn 2020, entering subclinical and clinical ranges, outweighing the proportion of people with improved outcomes. Sociodemographic variables associated with mental distress at T1 were mainly not predictive for change at T2. Even under prolonged pandemic-related stress, mental health remained mainly stable in the general population. Further development of the considerable subgroup experiencing deterioration of depression and anxiety should be monitored, in order to tailor prevention and intervention efforts.

Sirolimus in renal transplant recipients with malignancies in Germany.

BACKGROUND: Renal transplant recipients have an increased cancer risk. The mammalian target of rapamycin inhibitor sirolimus (SRL) has immunosuppressive and antitumour activities but knowledge about its use in recipients with cancer is limited. METHODS: We retrospectively analysed 726 renal allograft recipients converted to SRL from 10 German transplant centres. Patient and graft survival were analysed depending on malignancy status prior to conversion and tumour entity. RESULTS: Malignancy before conversion to SRL was reported in 230 patients, with 137 patients having skin cancers and 101 having solid cancers. Cancer occurred 4.6 ± 9.4 (median 3.0) years after transplantation. Basal cell carcinoma, squamous cell carcinoma and Bowen's disease were the most prevalent skin cancers, while carcinomas of the kidney, colon and breast were the most prevalent solid cancers before conversion. Patients with prior malignancy were older and had better renal function at conversion compared with patients without a history of cancer. After conversion to SRL, cancer incidence rates (IRs) of all tumours were lower compared with rates before conversion. Cancer IRs after conversion were higher in patients with malignancy before conversion compared with those without. Patient survival was worse in patients with solid cancers compared with patients with skin cancers or without malignancies. Biopsy-proven acute rejections in the first year after conversion were less frequent in patients with malignancy compared with those without. Graft survival and renal function in all cancer types were better than in patients converted to SRL without cancers. CONCLUSIONS: Conversion to SRL in patients with a history of cancer is safe regarding renal function and graft survival, while patient survival is largely dependent on tumour entity.

Determinants of Successful Use of Sirolimus in Renal Transplant Patients.

BACKGROUND: Sirolimus is an established immunosuppressant in renal transplantation with antineoplastic and antiviral features, but side effects like proteinuria limit its use. The aim of this retrospective multicenter observational study is to define predictors for determining which patients most likely benefit from a sirolimus-based therapy. METHODS: All patients from 10 German centers that were switched to a sirolimus-containing maintenance immunosuppression in 2000 to 2008 after 3 months or later post-transplantation were enrolled (n = 726). Observation times after switching to sirolimus ranged from 4 days to 9 years (median: 24.3 months). With multinomial logistic regression, risk factors for the endpoints terminal graft failure and withdrawal of sirolimus therapy compared to successful therapy were identified. RESULTS: Successful sirolimus therapy was observed in 304 patients. Forty patients died with functioning graft. Therapy failures included graft loss (n = 106) and sirolimus-discontinuation for various reasons (n = 276). Successful sirolimus-use was predicted in 83% and graft failure in 65%, whereas prediction of deliberate sirolimus-discontinuation was poor (48%). Most favorable results for sirolimus-use were observed in patients switched in 2006 to 2008. Using ROC analysis, an estimated glomerular filtration rate (eGFR) below 32 mL/min was shown to be the cut-off in patients withdrawing from therapy as a result of renal reasons, as well as in patients with graft loss. Proteinuria above 151 mg/L was shown to be predictive for patients with graft failure. CONCLUSIONS: eGFR and proteinuria are the major determinants for successful sirolimus-therapy. Our findings help stratifying patients who will benefit most from this therapy and avoid toxicities in patients without potential benefits for this therapy.

Erythropoietin gene expression in renal carcinoma is considerably more frequent than paraneoplastic polycythemia.

Signalling by erythropoietin (EPO) is increasingly recognised as a relevant mechanism in tumour biology, potentially leading to enhanced proliferation, angiogenesis and therapy resistance. Paraneoplastic polycythemia by cancerous overproduction of EPO is a rare event, but most frequently seen in patients with renal cell carcinoma (RCC). The majority of clear cell RCC displays a strong activation of the transcription factor regulating EPO, the Hypoxia-inducible Factor (HIF). Therefore, it is unclear why only a small minority of patients develop polycythemia. We studied 70 RCC for EPO gene and HIFalpha isoform expression. 34% of all RCC showed expression of EPO mRNA in RNase protection assays, which were almost exclusively of the clear cell type. Only 1 patient presented with polycythemia. In situ hybridisation revealed that expression of EPO was in the tumour cells. Expression of EPO mRNA was always associated with activation of HIF, which could involve HIF-1alpha and/or HIF-2alpha. The frequency of EPO gene expression in RCC is therefore much higher than the prevalence of polycythemia. Furthermore, activation of HIF appears necessary for EPO gene expression in RCC, but is clearly not the only determinant. Further to the reported expression of EPO receptors in tumour tissues, the finding of widespread expression of EPO in RCC supports the recent notion of an involvement of this system in paracrine or autocrine effects of tumour cells.

Risk stratification for renal transplantation after cardiac or lung transplantation: single-center experience and review of the literature.

BACKGROUND: Long-term survival after heart (HTx) or lung (LuTx) transplantation increases the risk for end-stage renal disease (ESRD). After HTx ESRD was reported to enhance mortality, and kidney transplantation (KTx) was shown to improve survival. However, prognostic factors in ESRD after HTx or LuTx are largely unknown. METHODS: Single-center observational study in HTx and LuTx patients who accessed the KTx waiting list; baseline characteristics were correlated with mortality. RESULTS: KTx was performed in 15 of 65 study patients. Survival was comparable on the KTx waiting list and in reference patients from the same center without ESRD. KTx significantly improved survival (5 years' survival 84.6% with KTx vs. 56.5% on the KTx waiting list, p = 0.030). None of the baseline parameters predicted mortality in the KTx group. Only on the KTx waiting list BMI (median 24.7 vs. 20.7; p < 0.05) and left ventricular ejection fraction (LVEF, median 63 vs. 53%, p < 0.008) significantly correlated with survival. CONCLUSIONS: The risk for mortality after HTx or LuTx is not increased by ESRD, provided that patients meet access criteria for the KTx waiting list. KTx improves survival in ESRD after HTx or LuTx. BMI and LVEF may predict outcome in HTx/LuTx patients on the KTx waiting list.

Stabilization of hypoxia inducible factor rather than modulation of collagen metabolism improves cardiac function after acute myocardial infarction in rats.

UNLABELLED: Prolyl hydroxylase domain-containing enzymes (PHD) hydroxylate a proline residue that controls the degradation of hypoxia inducible factor (HIF). Hypoxia inhibits this hydroxylation thus increasing HIF levels. HIF is upregulated in ischemic tissues, growing tumors and in nonischemic, mechanically stressed myocardium. Pharmacological inhibition of prolyl 4-hydroxylase (P4-H) stabilizes HIF-protein in vitro and may modulate collagen turnover. The aims of this study were to investigate whether inhibition of P4-H protects myocardium against ischemia, and whether the observed effects are related to modulation of collagen metabolism or due to the stabilization of HIF. METHODS: Rats were treated with a specific P4-H inhibitor (P4-HI) or vehicle starting 2 days before induction of myocardial infarction (MI). Rats were investigated 7 or 30 days after MI. Induction of HIF-1alpha and -2alpha was visualized by immunohistochemistry. Expression of growth factors (connective tissue growth factor, Osteopontin) and mRNA expression and protein levels of Collagen I and III as well as HIF-2alpha were measured. RESULTS: P4-HI augments HIF in the myocardium as early as 24 h after treatment. P4-HI did not alter the MI-induced enhanced expression of growth factors and collagen. Treatment with P4-HI significantly reduced heart and lung weight, improved left ventricular contractility, prevented left ventricular enlargement and improved left ventricular ejection fraction without affecting infarct size after 30 days. CONCLUSIONS: Specific inhibition of the P4-H improved cardiac function without affecting the infarct size after experimental myocardial infarction in rats. Stabilization of HIF rather than inhibition of collagen maturation by P4-HI may prevent cardiac remodeling after MI.

[Systematic pressure ulcer risk management.: Results of implementing multiple interventions at Charité-Universitätsmedizin Berlin]. / Systematisches Risikomanagement Dekubitus.: Ergebnisse der Umsetzung eines Maßnahmenbündels an der Charité-Universitätsmedizin Berlin.

Pressure ulcers impose a high burden of disease on both the affected individual and society. Demographic change and multimorbidity aggravate the problem. The present study describes the systematic implementation of a comprehensive approach to reduce the incidence of pressure ulcers in an inpatient setting. The introduction of systematic risk assessment and the subsequent risk-adjusted application of evidence-based prevention, combined with continuous feedback of outcomes as well as tailored training, were associated with a significant decline in the incidence of pressure ulcers. Especially the occurrence of high-grade ulcers could be minimized by this systems approach.

Activation of the hypoxia-inducible factor-pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors.

Hypoxia-inducible transcription factors (HIF) mediate complex adaptations to reduced oxygen supply, including neoangiogenesis. Regulation of HIF occurs mainly through oxygen-dependent destruction of its alpha subunit. In the presence of oxygen, two HIFalpha prolyl residues undergo enzymatic hydroxylation, which is required for its proteasomal degradation. We therefore tested whether pharmacological activation of HIFalpha by hydroxylase inhibitors may provide a novel therapeutic strategy for the treatment of ischemic diseases. Three distinct prolyl 4-hydroxylase inhibitors-l-mimosine (L-Mim), ethyl 3,4-dihydroxybenzoate (3,4-DHB), and 6-chlor-3-hydroxychinolin-2-carbonic acid-N-carboxymethylamid (S956711)-demonstrated similar effects to hypoxia (0.5% O2) by inducing HIFalpha protein in human and rodent cells. L-Mim, S956711, and, less effectively, 3,4-DHB also induced HIF target genes in cultured cells, including glucose transporter 1 and vascular endothelial growth factor, as well as HIF-dependent reporter gene expression. Systemic administration of L-Mim and S956711 in rats led to HIFalpha induction in the kidney. In a sponge model for angiogenesis, repeated local injection of the inhibitors strongly increased invasion of highly vascularized tissue into the sponge centers. In conclusion, structurally distinct inhibitors of prolyl hydroxylation are capable of inducing HIFalpha and HIF target genes in vitro and in vivo and induce adaptive responses to hypoxia, including angiogenesis.

Persistent induction of HIF-1alpha and -2alpha in cardiomyocytes and stromal cells of ischemic myocardium.

Hypoxia-inducible factor (HIF)-1alpha and -2alpha are key regulators of the transcriptional response to hypoxia and pivotal in mediating the consequences of many disease states. In the present work, we define their temporo-spatial accumulation after myocardial infarction and systemic hypoxia. Rats were exposed to hypoxia or underwent coronary artery ligation. Immunohistochemistry was used for detection of HIF-1alpha and -2alpha proteins and target genes, and mRNA levels were determined by RNase protection. Marked nuclear accumulation of HIF-1alpha and -2alpha occurred after both systemic hypoxia and coronary ligation in cardiomyocytes as well as interstitial and endothelial cells (EC) without pronounced changes in HIF mRNA levels. While systemic hypoxia led to widespread induction of HIF, expression after coronary occlusion occurred primarily at the border of infarcted tissue. This expression persisted for 4 wk, included infiltrating macrophages, and colocalized with target gene expression. Subsets of cells simultaneously expressed both HIF-alpha subunits, but EC more frequently induced HIF-2alpha. A progressive increase of HIF-2alpha but not HIF-1alpha occurred in areas remote from the infarct, including the interventricular septum. Cardiomyocytes and cardiac stromal cells exhibit a marked potential for a prolonged transcriptional response to ischemia mediated by HIF. The induction of HIF-1alpha and -2alpha appears to be complementary rather than solely redundant.

Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs.

Cellular responses to oxygen are increasingly recognized as critical in normal development and physiology, and are implicated in pathological processes. Many of these responses are mediated by the transcription factors HIF-1 and HIF-2. Their regulation occurs through oxygen-dependent proteolysis of the alpha subunits HIF-1alpha and HIF-2alpha, respectively. Both are stabilized in cell lines exposed to hypoxia, and recently HIF-1alpha was reported to be widely expressed in vivo. In contrast, regulation and sites of HIF-2alpha expression in vivo are unknown, although a specific role in endothelium was suggested. We therefore analyzed HIF-2alpha expression in control and hypoxic rats. Although HIF-2alpha was not detectable under baseline conditions, marked hypoxic induction occurred in all organs investigated, including brain, heart, lung, kidney, liver, pancreas, and intestine. Time course and amplitude of induction varied between organs. Immunohistochemistry revealed nuclear accumulation in distinct cell populations of each tissue, which were exclusively non-parenchymal in some organs (kidney, pancreas, and brain), predominantly parenchymal in others (liver and intestine) or equally distributed (myocardium). These data indicate that HIF-2 plays an important role in the transcriptional response to hypoxia in vivo, which is not confined to the vasculature and is complementary to rather than redundant with HIF-1.

Cost-effectiveness of modern mTOR inhibitor based immunosuppression compared to the standard of care after renal transplantation in Germany.

OBJECTIVES: Standards of immunosuppression in renal transplantation have changed dynamically in recent years. We here provide a refined advanced pharmacoeconomic model which uses state-of-the-art methods including a mixed treatment comparison (MTC) analysis. The aim was to assess the cost-effectiveness of current immunosuppressive therapy regimens (TR): "sirolimus + early withdrawal of cyclosporine + steroids" (TR1), "sirolimus-early transition" (TR2), "everolimus-early transition" (TR3) and "tacrolimus low dose + mycophenolate mofetil (MMF) + steroids" (TR4). METHODS: An up-to-date Markov model with current source data was employed to assess the cost-effectiveness of modern immunosuppressive regimens over 12-month and 10-year time periods. Transition probabilities for the occurrence of events for the first year were based on an MTC analysis. The robustness of the model was tested in extensive sensitivity analyses. RESULTS: Within the 12-month time period TR2 yields the highest life years (0.987 LY), generating costs of 17,500 . In terms of years with functioning graft (FG), TR4 yields the best efficacy over the 12-month model duration (0.970 years with FG). For the 10-year time period, TR2 yields the lowest costs (107,246 ) and dominates both TR3 and TR1, as it is simultaneously more effective. Within the 10-year model duration, TR4 reaches slightly higher effects compared with TR2 (6.493 vs. 6.474 LY) resulting in an incremental cost-effectiveness ratio of 387,684 per LY gained. CONCLUSIONS: The early transition to sirolimus provides long-term efficiency results comparable with a tacrolimus-based regimen, which represents a common treatment standard after kidney transplantation. Both are superior to other investigated immunosuppressive regimens.

Portable computed tomography performed on the intensive care unit.

OBJECTIVE: We report on the use of portable computed tomography (CT) in an ICU setting. The additional diagnostic gain and therapeutic consequences were assessed. PATIENTS: Ten ICU patients underwent 14 portable chest CT examinations. In 64% maximum intensive care was required, according to TISS28 (>40), and 42% were at a risk of mortality higher than 25% (MODS) on the day of portable CT examination. In three portable CT examinations the patients were considered not transportable and were examined directly in the patient room. All other examinations were performed in a special interventional suite directly on the ICU. RESULTS: Of 14 examinations 8 (57%) resulted in a change in patient management within 48 h. All patients profited from portable CT and no hazards occurred related to CT. CONCLUSIONS: To perform portable CT in the interventional suite on the ICU allows immediate minimally invasive therapeutic interventions and provides full ICU monitoring.

Bone morphogenic protein-4 expression in vascular lesions of calciphylaxis.

Calciphylaxis is characterized by an extensive media-calcification of cutaneous and subcutaneous arterioles and capillaries. Recent studies have provided evidence that vascular calcification is a process with similarities to bone metabolism. Bone morphogenic protein-4 (BMP-4) is physiologically involved in bone development and repair. The presence of BMP-4 in atherosclerosis and in sclerotic heart valves led us to suggest that BMP-4 is also involved in calciphylaxis. A 47-year-old male patient developed end-stage renal failure due to chronic glomerulonephritis. He has had two kidney transplants with an immunosuppressive regimen consisting of cyclosporine A and steroids. He was admitted to our hospital because of an increase in serum creatinine (Cr) and he subsequently developed progressive dermal ulcerations. A skin biopsy led to the diagnosis of calciphylaxis. Immunohistochemistry for BMP-4 of a skin specimen from our patient showed strong cytoplasmic immunoreactivity of intradermal cells with clear spatial association to arterioles and hair follicles. Whereas there are identified inhibitors and promoters of vascular calcification, the presence of BMP-4 has not been demonstrated in calcific uremic arteriolopathy. In contrast to atherosclerosis, BMP-4 in calciphylaxis cannot be found in vascular media, but in intradermal cells at the border of arterioles and hair follicles. Therefore, in calciphylaxis BMP-4 can play the role of a cytokine, a growth factor or a media-calcification promoter.

Cost-effectiveness of immunosuppressive regimens in renal transplant recipients in Germany: a model approach.

BACKGROUND: The choice of immunosuppression regimen is of paramount importance for outcomes and cost of renal transplantation. We compared the cost-effectiveness of triple immunosuppressive regimens in Germany. METHODS: A strong micro-simulation model was built comparing regimens based on cyclosporine, everolimus, sirolimus, and tacrolimus. Mean cost per patient, incremental cost per life year gained, and incremental cost per additional year with functioning graft were assessed from the perspective of the German statutory health insurance (SHI) after 2 and 10 years. RESULTS: Over the 2-year period, the model predicted mean total costs per patient of 26,732, 29,352, 33,415, and 49,978 euro for sirolimus, cyclosporine, everolimus, and tacrolimus, respectively. Focusing on the cost per life year gained, the sirolimus-based regimen compared favorably with those based on everolimus and tacrolimus. The incremental cost-effectiveness ratio (ICER) of cyclosporine versus sirolimus is 524,000 euro per life year gained. Regarding the cost per year with functioning graft gained, sirolimus dominated cyclosporine and everolimus, while the ICER for tacrolimus compared to sirolimus amounts to 1,788,154 euro. Over the 10-year time frame, mean total costs per patient were 100,758, 108,300, 120,316, and 183,802 euro for sirolimus, cyclosporine, everolimus, and tacrolimus, respectively. With regard to life years gained, sirolimus dominated both cyclosporine and everolimus. The ICER of tacrolimus versus sirolimus was 1,766,894 euro. Considering the years with functioning graft gained, sirolimus dominated cyclosporine and everolimus, while the ICER for tacrolimus compared to sirolimus amounted to 1,339,419 euro. CONCLUSIONS: Over both the 2-year and the 10-year time horizon, sirolimus-based immunosuppression represents a cost-effective option in renal transplantation in Germany.