Urinary free light chains may help to identify infection in patients with elevated systemic inflammation due to rheumatic disease.

The risk of infection in patients with rheumatic diseases is elevated, but a clear marker to differentiate the cause of the systemic inflammation is missing. We assessed the ability urinary immunoglobulin free light chains (FLCs) to indicate the presence of infection in patients with rheumatic disease. We performed a retrospective analysis of patients with rheumatic disease attending the Georg-August University Hospital in Goettingen, Germany, from January 2011 to December 2013. Subjects were included if they had urine levels of κ and λ FLCs available. A reference group of patients without autoimmune disease, but with documented infection, was constructed. A total of 1500 patients had their urinary FLCs quantified during the study period. Of the 382 patients with rheumatic disease, 172 (45%) displayed no systemic inflammation, 162 (42%) had inflammation due to the underlying disease activity, and 48 (13%) had inflammation due to a confirmed infection. Urinary FLC concentrations were much higher in patients with rheumatic diseases and infection (κ 68.8 ± 81.8 mg/L, λ 31.4 ± 53.5 mg/L) compared to those with inflammation due to rheumatic disease activity (κ 22.7 ± 26.3 mg/L, λ 8.1 ± 9.1 mg/L, κ p < 0.001, λ p = 0.004). Urinary κ FLCs demonstrated good ability to predict infection, with a sensitivity of 63% and specificity of 84%. Urinary λ FLCs gave similar values, with a sensitivity of 65% and specificity of 81%. FLCs may be useful for distinguishing inflammation due to rheumatic disease activity from that due to the additional presence of infection. The ability to quantify these proteins in urine provides a simple alternative to the use of blood.

New data shed light on Y-loss-related pathogenesis in myelodysplastic syndromes.

Loss of the Y-chromosome (LOY) is described as both a normal age-related event and a marker of a neoplastic clone in hematologic diseases. To assess the significance of LOY in myelodysplastic syndromes (MDS), we determined the percentage of LOY in clonal CD34+ peripheral blood cells in comparison to normal CD3+ T-cells of 27 MDS patients using fluorescence in situ hybridization (FISH) analysis. Results were compared with the percentage of LOY in CD34+ and CD3+ cells of 32 elderly men without hematologic diseases and in 25 young blood donors. While LOY could not be detected in CD3+ cells of young men, it was observed in CD3+ cells of elderly men without hematologic diseases (2.5% LOY) as well as in CD3+ cells of elderly MDS patients (5.8% LOY). The percentage of CD34+ cells affected by LOY was significantly higher in MDS patients compared to elderly men without hematologic diseases (43.3% vs. 13.2%, P = 0.005), indicating that LOY has an age-related basis but is also associated with MDS. Furthermore, we aimed to define a threshold between age- and disease-associated LOY in MDS. Statistical analysis revealed that a value of 21.5% LOY in CD34+ peripheral blood cells provided the best threshold to discriminate between these two conditions in MDS. We conclude that LOY is clonal in a substantial number of MDS based on an age-related predisposition.

Bone morphogenetic protein (BMP)-7 expression is decreased in human hypertensive nephrosclerosis.

BACKGROUND: Bone Morphogenetic Protein (BMP)-7 is protective in different animal models of acute and chronic kidney disease. Its role in human kidneys, and in particular hypertensive nephrosclerosis, has thus far not been described. METHODS: BMP-7 mRNA was quantified using real-time PCR and localised by immunostaining in tissue samples from normal and nephrosclerotic human kidneys. The impact of angiotensin (AT)-II and the AT-II receptor antagonist telmisartan on BMP-7 mRNA levels and phosphorylated Smad 1/5/8 (pSmad 1/5/8) expression was quantified in proximal tubular cells (HK-2). Functional characteristics of BMP-7 were evaluated by testing its influence on TGF-ß induced epithelial-to-mesenchymal transition (EMT), expression of TGF-ß receptor type I (TGF-ßRI) and phosphorylated Smad 2 (pSmad 2) as well as on TNF-α induced apoptosis of proximal tubular cells. RESULTS: BMP-7 was predominantly found in the epithelia of the distal tubule and the collecting duct and was less abundant in proximal tubular cells. In sclerotic kidneys, BMP-7 was significantly decreased as demonstrated by real-time PCR and immunostaining. AT-II stimulation in HK-2 cells led to a significant decrease of BMP-7 and pSmad 1/5/8, which was partially ameliorated upon co-incubation with telmisartan. Only high concentrations of BMP-7 (100 ng/ml) were able to reverse TNF-α-induced apoptosis and TGF-ß-induced EMT in human proximal tubule cells possibly due to a decreased expression of TGF-ßRI. In addition, BMP-7 was able to reverse TGF-ß-induced phosphorylation of Smad 2. CONCLUSIONS: The findings suggest a protective role for BMP-7 by counteracting the TGF-ß and TNF-α-induced negative effects. The reduced expression of BMP-7 in patients with hypertensive nephrosclerosis may imply loss of protection and regenerative potential necessary to counter the disease.

Predictors of complications in therapeutic plasma exchange.

Plasma exchange (PE) is used for blood purification to modulate proteins involved in pathological processes. As the number of patients receiving PE treatment and the heterogeneity of the underlying diseases is steadily increasing, we evaluated the most frequent complications and analyzed causes leading to adverse reactions. 883 PE procedures in 113 patients between the years 2000 to 2006 were retrospectively analyzed with respect to complications. Additionally, underlying diseases and settings of PE procedure were analyzed to identify high-risk patients and respective PE settings. A total of 226 adverse reactions were recorded (25.6% of all PE procedures). Most complications were mild (n = 121, 13.7%) or moderate (n = 98, 11.0%). In seven cases (n = 7, 0.7%), severe, life-threatening adverse events were induced by PE either due to severe allergic reactions (n = 4, 0.5%) or to sepsis (n = 3, 0.3%). Patients with neurologic diseases had a significantly higher risk to develop complications compared to those with internal diseases (P = 0.013). This was due to a higher rate of PE associated adverse events (in particular hypotension) and complications associated with vascular access. Among patients from internal medicine those with hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) had the highest risk to develop complications. Patients with neurological diseases compared to those with medical conditions and patients with HUS/TTP compared to those with other diseases had a higher risk to develop complications. However, severe adverse events are rare. Thus, PE seems to be a safe and recommendable procedure.

[Albuminuria: an indicator of cardiovascular risk]. / Albuminurie: ein kardiovaskulärer Risikoindikator.

BACKGROUND: The transition of albumin from the vascular lumen into the surrounding tissue always indicates a serious disturbance of the vascular wall. Clinically, this process can be recognized as "cotton-wool" spots of the retina or by testing the urine for the presence of albumin. The appearance of albumin in the urine is pathologic and should be evaluated within the context of the accompanying cardiovascular risk. PATHOPHYSIOLOGY AND DEFINITIONS: Albumin transition is indicative of a disturbance of the barrier function of endothelial cells. In the kidney, damage to podocytes, mesangial and endothelial cells, a loss of charge selectivity, and an altered expression of matrix proteins can be observed. However, vascular alterations are not confined to the kidney but can also be observed in the myocardium. Even though thresholds for microalbuminuria (> 30 mg/24 h) and proteinuria (> 300 mg/24 h) have been arbitrarily defined, an increase in risk starts at much lower levels of albumin excretion. PREVALENCE AND PROGNOSTIC IMPORTANCE: The prevalence of microalbuminuria in the general population is about 8%. However, prevalence rates of > 50% have been observed in high-risk groups, which are accompanied by an increased risk for cardiovascular morbidity and mortality. THERAPEUTIC OPTIONS: A number of therapeutic options (tight blood sugar control, blood pressure reduction, lipid lowering) lead to a reduction of albuminuria and an improvement in cardiovascular prognosis. This has particularly been described for renin-angiotensin-aldosterone system-(RAAS-)blocking agents. Their use is not only associated with a reduced risk of end-organ damage (heart failure, diabetic nephropathy, cerebrovascular events) but has been described to decrease mortality as well. RECOMMENDATION: A timely diagnosis, a consecutive cardiovascular diagnostic work-up and the subsequent use of RAAS-blocking agents is indicated in patients in whom albuminuria has been diagnosed.

Characterization and history of arterial hypertension leading to inpatient treatment.

BACKGROUND AND AIMS: Arterial hypertension is a major cause of death worldwide. For the most part, treatment for hypertension can be performed on an outpatient basis. However, some patients also require inpatient treatment, and the contributing factors for this remain unknown. Therefore, the primary objective of the present study was to determine which patient characteristics are associated with inpatient treatment for arterial hypertension. METHODS: Here, we conducted a mono-centric study of 103 hypertensive subjects, who were treated as inpatients in the Department of Nephrology and rheumatology of the university medical faculty of Göttingen. Therapies were not altered, and data collection was performed retrospectively. In addition to epidemiological information, the following data were recorded: patient symptoms, blood pressure (BP), anti-hypertensive therapy, and concomitant diseases (e.g., renal and cardiovascular conditions). RESULTS: Approximately half (53 %) of all subjects treated on an inpatient basis displayed elevated BP (>140/90 mmHg), while the remaining 47 % of patients showed normotensive readings (<140/90 mmHg) following admission. Moreover, 34 % of patients could be classified as therapy refractory. The main reasons for hospital admission were hypertension-related symptoms, including shortness of breath, dizziness, and headache (69 %). These patients were multi-morbid, with approximately 60 % displaying a secondary form of hypertension. Indeed, over half of the subjects showed renoparenchymatous forms of hypertension, and a large percentage of patients received hypertension-inducing drugs (32 %). Moreover, a high proportion of inpatients were treated with reserve antihypertensives, with the most commonly used drug being Moxonidin. CONCLUSION: The majority of hypertensive patients were hospitalized due to their clinical symptoms and not as a result of BP values alone. The high proportion of patients with secondary forms of hypertension or treated with BP-boosting medications was striking.

[Polycythemia vera and D-dimer-negative thromboembolism]. / D-Dimer-negative Thromboembolien bei Polycythaemia vera.

CASE REPORT: A 65-year-old patient with polycythemia vera (PV) was admitted with a painful edema of the right arm lasting for 24 h. The D-dimer assay was negative. By phlebography the patient was diagnosed with a fresh thrombosis of the right subclavian vein. 1 week later she developed a D-dimer-negative symptomatic pulmonary embolism. CONCLUSION: If clinical signs of a thromboembolic event are present, the negative predictive value of the D-dimer assay is not sufficient to abandon further definitive diagnosis. Since thromboembolic events are frequent in PV patients, a prophylactic treatment with low-dose acetylsalicylic acid is recommended.

Targeted therapies for treatment of renal cell carcinoma: recent advances and future perspectives.

PURPOSE: A wide variety of targeted therapies are available for the treatment of renal cancer that has progressed beyond the point at which surgery is a viable option. In addition, there are many more that are in the different stages of clinical trials. Here, we provide a methodical discussion of the efficacy and safety of targeted therapies for the treatment of advanced renal cell carcinoma. METHODS: We conducted a systematic literature employing the search terms: renal cell carcinoma targets, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and each of the drugs discussed within these papers. RESULTS: The identified targeted therapies work by disrupting specific signalling pathways involved in tumour progression, such as those responsible for angiogenesis and cell proliferation. Tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are now established classes of drugs used in the treatment of renal cancer, with a total of six having received regulatory approval to date (sorafenib, sunitinib, pazopanib, axitinib, temsirolimus, and everolimus). Ongoing trials are likely to result in addition to these in the near future, for example, tivozanib, dovitinib, and cediranib. Furthermore, in addition to these small molecule drugs, immunotherapies involving monoclonal antibodies against signalling molecules such as vascular endothelial growth factor (bevacizumab) or programmed death-1 (nivolumab) are receiving increasing attention. CONCLUSIONS: Targeted therapies have great potential for disrupting tumour progression by inhibiting certain signalling pathways. As our understanding of the biochemical pathways involved in cancer progresses, additional targets are certain to become apparent, expanding treatment options even further.

The role of bone morphogenetic protein-5 (BMP-5) in human nephrosclerosis.

BACKGROUND: Bone morphogenetic protein-5 (BMP-5) has been shown to be essential for nephrogenesis. Its role in adult kidney and in patients with hypertensive nephrosclerosis is still unknown. METHODS: BMP-5 expression was evaluated by immunostaining and real-time PCR in tissue samples from normal and nephrosclerotic human kidneys. The impact of transforming growth factor-ß (TGF-ß), tumor necrosis factor-α (TNF-α) and angiotensin-II (AT-II) on expression of BMP-5 and its receptors was quantified in proximal tubular cells (HK-2). Functional characteristics of BMP-5 were evaluated by testing its influence on TGF-ß-induced epithelial-to-mesenchymal transition (EMT), TNF-α-induced apoptosis of HK-2 cells and inflammatory cell infiltration. RESULTS: BMP-5 expression was localized in tubular epithelial cells and significantly decreased in nephrosclerotic kidneys. Stimulation of HK-2 cells with TGF-ß, TNF-α and AT-II resulted in a significant decreased expression of BMP-5 and its receptors. BMP-5 attenuated TGF-ß-induced EMT, TNF-α-induced apoptosis and migration of mononuclear cells. CONCLUSIONS: BMP-5 is expressed in the tubuli of adult kidneys. Its decreased expression in nephrosclerosis along with its regenerative capabilities in HK-2 cells may point to a protective role in hypertensive nephrosclerosis.

Low-density lipoprotein apheresis decreases ferritin, transferrin and vitamin B12, which may cause anemia in serially treated patients.

Clinical observations revealed an increased prevalence of iron deficiency anemia without chronic bleeding in patients treated with serial low-density lipoprotein (LDL) apheresis. Since several different proteins are adsorbed by LDL apheresis beside pro-atherogenic lipoproteins, we examined the modification of the full blood count, plasma iron, vitamin B12, folic acid, and hemolysis by LDL apheresis. Nineteen patients (55 (50-59) years, 4 female, 15 male) undergoing chronic LDL apheresis due to mixed dyslipidemia (N = 17), homozygous familiar hypercholesterolemia (N = 1) or isolated elevated lipoprotein(a) (N = 1) were included in this study. They were treated with direct adsorption of lipoproteins (DALI; N = 6), heparin-induced LDL-precipitation (HELP; N = 7) or double filtration plasmapheresis (DFPP; N = 6). The patients' full blood count, iron metabolism (plasma iron, ferritin, transferrin, transferrin saturation), vitamins involved in erythropoiesis (vitamin B12 and folic acid), and markers of hemolysis (haptoglobin and free hemoglobin) were analyzed directly before and after LDL apheresis. A single LDL apheresis session significantly decreased the levels (reduction in the median [25(th)-75(th) percentiles] of: ferritin 9.8 [1.3-18] %; P = 0.004), transferrin (12.1 [10.0-15.96] %; P = 0.0005), and vitamin B12 (17.8 [16.2-20.8] %; P = 0.0005). Thereby, transferrin and vitamin B12 were decreased in all (N = 19) and ferritin in 74% (N = 14) of the patients. Twelve out of 19 patients (63.2%) had mild anemia despite iron administration in 14 out of 19 patients (73.7%). LDL apheresis had no significant influence on full blood count, plasma iron, transferrin saturation, folic acid, or hemolysis. Similar changes were observed in all LDL apheresis methods used. LDL apheresis significantly decreases ferritin, transferrin, and vitamin B12, suggesting an influence of serial LDL apheresis on erythropoiesis.

[Prevention of cardiovascular disease by blocking the endocannabinoid system]. / Prävention kardiovaskulärer Erkrankungen durch Blockade des Endocannabinoidsystems.

Risk factors for the development of cardiovascular disease, in particular myocardial infarction, are smoking, high body weight, sedentary lifestyle, unfavorable diet, high blood pressure, elevated fasting glucose or diabetes, and dyslipidemia (Tables 1 and 2). If the risk for cardiovascular mortality of 5% (using the SCORE Score) or for nonfatal cardiovascular events of 20% (PROCAM Score) within the next 10 years is exceeded or overt atherosclerosis or type 2 diabetes mellitus is present, the use of (poly)pharmacotherapy is indicated and lifestyle intervention (diet, physical activity) alone is not sufficient at that point (Figure 1). A new therapeutic option, able to modify a number of cardiovascular risk factors at a time, is the blockade of the so-called endocannabinoid system (Figure 2). For rimonabant not only a reduction of body weight and waist circumference was shown in clinical trials, its use was also accompanied by an increase of HDL cholesterol, a decrease in triglycerides, and a reduction in HbA1c and fasting blood glucose (Table 4). Together with preliminary data on the efficacy in smoking cessation, rimonabant has a therapeutic impact on four out of eight relevant risk factors in order to prevent myocardial infarction as promoted by the American College of Cardiology/American Heart Association. Currently, a large clinical study program is ongoing to further investigate the role of rimonabant in managing cardiovascular risk (Table 3). Published clinical trial results have revealed, that rimonabant is generally well tolerated (most frequent side effect: nausea) and the data are promising with regard to the potential future role of rimonabant in managing cardiovascular risk.

Decrease in expression of bone morphogenetic proteins 4 and 5 in synovial tissue of patients with osteoarthritis and rheumatoid arthritis.

Bone morphogenetic proteins (BMPs) have been identified as important morphogens with pleiotropic functions in regulating the development, homeostasis and repair of various tissues. The aim of this study was to characterize the expression of BMPs in synovial tissues under normal and arthritic conditions. Synovial tissue from normal donors (ND) and from patients with osteoarthritis (OA) and rheumatoid arthritis (RA) were analyzed for BMP expression by using microarray hybridization. Differential expression of BMP-4 and BMP-5 was validated by semiquantitative RT-PCR, in situ hybridization and immunohistochemistry. Activity of arthritis was determined by routine parameters for systemic inflammation, by histological scoring of synovitis and by semiquantitative RT-PCR of IL-1beta, TNF-alpha, stromelysin and collagenase I in synovial tissue. Expression of BMP-4 and BMP-5 mRNA was found to be significantly decreased in synovial tissue of patients with RA in comparison with ND by microarray analysis (p < 0.0083 and p < 0.0091). Validation by PCR confirmed these data in RA (p < 0.002) and also revealed a significant decrease in BMP-4 and BMP-5 expression in OA compared with ND (p < 0.015). Furthermore, histomorphological distribution of both morphogens as determined by in situ hybridization and immunohistochemistry showed a dominance in the lining layer of normal tissues, whereas chronically inflamed tissue from patients with RA revealed BMP expression mainly scattered across deeper layers. In OA, these changes were less pronounced with variable distribution of BMPs in the lining and sublining layer. BMP-4 and BMP-5 are expressed in normal synovial tissue and were found decreased in OA and RA. This may suggest a role of distinct BMPs in joint homeostasis that is disturbed in inflammatory and degenerative joint diseases. In comparison with previous reports, these data underline the complex impact of these factors on homeostasis and remodeling in joint physiology and pathology.