[Insulin autoimmune syndrome : A rare, but important differential diagnosis of hypoglycemia]. / Insulinautoimmunsyndrom : Eine seltene, aber wichtige Differentialdiagnose der Hypoglykämie.

A 69-year-old female patient was referred to the Medical University of Hanover for further diagnostic evaluation of recurrent severe hypoglycemia. The patient had previously been started on clopidogrel after arterial stenting for peripheral arterial obstructive disease (PAOD). The presence of an insulinoma and paraneoplastic syndrome was excluded. Increased serum insulin and insulin autoantibodies levels were confirmed, despite normal to low blood sugar levels. An insulin autoimmune syndrome was diagnosed, most likely induced by the prior intake of clopidogrel. Treatment with immunoadsorption was initiated, achieving a significant reduction in hypoglycemic events and a lasting response to treatment over 3 months.

Lipid-lowering therapy with PCSK9-inhibitors in the management of cardiovascular high-risk patients: Effectiveness, therapy adherence and safety in a real world cohort.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9)-inhibitors have shown great po-tential in efficient lipid lowering to achieve low-density lipoprotein-cholesterol (LDL-C) treatment goals. The aim of the study was too describe the clinical use of PCSK9-inhibitors and to investigate therapy adherence and safety outside of clinical trials. METHODS: Thirty-eight patients were treated with PSCK9-inhibitors. Patients were eligible for this therapy based on their individual cardiovascular risk and when all other available lipid-lowering regi-men had failed. Every patient answered a questionnaire concerning medical history and relevant side effects and therapy adherence. RESULTS: Conventional therapy reduced patient LDL-C levels by about 38%. However, in 26 of the 38 patients, LDL-C treatment goals were not fulfilled because patients did not tolerate further dose es-calation due to side effects. Using a PCSK9 inhibitor, LDL-C levels were reduced by another 54% and 42% of patients reaching treatment goals. The results show that most patients still require concomitant therapy to reach LDL-C target levels. Three patients required dose reduction or change of the PCSK9 inhibitor. 16% did not inject the PCSK9 inhibitor regularly. CONCLUSIONS: Only a minority of patients reached the recommended LDL-C goals. PCSK9-inhibitors were generally well tolerated. Despite low rates of reported side effects, therapy adherence was incom-plete, with 6 patients not injecting PCSK9-inhibitors on a regular basis. In-depth information about the medication and close supervision is advisable. PCSK9 inhibitors have shown great potential in aggressive lipid lowering therapy, but basic therapy is still required in most cases. Close supervision is recommended to improve therapy adherence. (Cardiol J 2018; 25, 1: 32-41).

Fetuin, matrix-Gla protein and osteopontin in calcification of renal allografts.

BACKGROUND: Calcification of renal allografts is common in the first year after transplantation and is related to hyperparathyroidism. It is associated with an impaired long-term function of the graft (Am J Transplant 5∶1934-41, 2005). Aim of this study is to examine the role of the anti-calcifying/calcifying factors in the pathophysiology of renal allograft calcification. METHODS: We analyzed protocol allograft biopsies, blood and urine samples of 31 patients with and 27 patients without allograft calcification taken at 6 weeks, 3 and 6 months after transplantation. Patient demographical data, cold ischemia time, initial graft function and donor characteristics were comparable between the two groups. Biopsies were stained for osteopontin, fetuin, and matrix-gla-protein. Serum and urine electrolytes, matrix-gla-protein, fetuin, Vitamin D and intact parathyroid hormone in serum and osteopontin (OPN) in urine were examined. RESULTS: Serum levels of fetuin and matrix-Gla protein as well as urinary levels of OPN showed specific time dependent changes (6 weeks vs. 3 months vs. 6 months; all p<0.0001). In patients with calcifications, urinary levels of OPN were decreased by 55% at 6 weeks and increased thereafter, showing 54% higher levels at 6 months compared to patients without calcification (6 weeks: p<0.01, 6 months: p<0.05). Local protein expression of fetuin-A, matrix-Gla protein and OPN in the graft was specifically increased around calcified plaques, without differences in the mRNA tissue expression. CONCLUSION: Anticalcifying factors show significant changes in the early phase after renal transplantation, which may be important for the prevention of allograft calcification. The differences in OPN indicate an involvement of this factor in the regulation of calcification.

The effect of cinacalcet on bone remodeling and renal function in transplant patients with persistent hyperparathyroidism.

BACKGROUND: Parathyroidectomy is associated with renal functional losses in transplant patients; cinacalcet offers an attractive alternative. METHODS: We performed a prospective observational study in 58 patients with persisting hyperparathyroidism after renal transplantation (Ca≥2.6 mmol/L) and impaired renal transplant function (estimated glomerular filtration rate [eGFR] <50 mL/min). The patients received 30 to 90 mg cinacalcet for 12 months with the target to normalize serum Ca. We measured parathyroid hormone (PTH), serum Ca, serum phosphorus, alkaline phosphatase, bone-specific alkaline phosphatase, osteocalcin, and telopeptide at 0, 1, 2, 3, 6, 9, and 12 months of cinacalcet treatment. Fractional excretion of calcium and phosphorus (n=24) were monitored at 0 and 1 month. RESULTS: At inclusion, creatinine was 181±70 µmol/L, eGFR 43±19 mL/min, PTH 371±279 pg/mL, and Ca 2.73±0.22 mmol/L. We observed nephrocalcinosis in 58% of biopsied patients at enrollment. After cinacalcet, Ca decreased significantly and normalized at nearly any measurement. Phosphorus increased significantly at months 1, 9, and 12. PTH decreased significantly, but only at months 9 and 12 and did not normalize. Bone-specific alkaline phosphatase increased significantly (>normal) by month 12. eGFR decreased and serum creatinine increased at all time points. The Δ(creatinine) % increase correlated significantly with the Δ(PTH) % decrease at month 1 and 12. Telopeptide and alkaline phosphatase correlated with PTH and telopeptide also correlated with serum creatinine. CONCLUSION: Calcium-phosphorus homeostasis in hypercalcemic renal transplant patients normalizes under cinacalcet and PTH decreases, albeit not to normal. The renal functional decline could be PTH mediated, analogous to the effects observed after parathyroidectomy.

Circulating concentrations of follistatin-like 1 in healthy individuals and patients with acute coronary syndrome as assessed by an immunoluminometric sandwich assay.

BACKGROUND: Follistatin-like 1 (FSTL1) is a 308-amino acid secreted glycoprotein. Tissue levels of FSTL1 are induced in animal models and patients with chronic inflammatory and cardiovascular disease. We hypothesized that FSTL1 can be measured in the human circulation and used as a biomarker in acute coronary syndrome (ACS). METHODS: We developed an immunoluminometric assay (ILMA), assessed the preanalytic characteristics of FSTL1, and determined circulating FSTL1 concentrations in 120 apparently healthy individuals and 216 patients with ACS. RESULTS: The assay had a limit of detection of 0.17 microg/L, limit of quantification of 1.02 microg/L, intraassay imprecision of < or =12.7%, and interassay imprecision of < or =15.4%. Selectivity was demonstrated with size-exclusion chromatography and lack of cross-reactivity with related proteins. The assay was not appreciably influenced by unrelated biological substances. FSTL1 in serum or whole blood was stable at room temperature for 48 h and was resistant to 4 freeze-thaw cycles. Measured FSTL1 concentrations in citrated plasma and heparin-treated plasma were 18% and 17% lower, respectively, than concentrations measured in serum. Apparently healthy individuals presented with a median FSTL1 serum concentration of 7.18 (range 1.06-18.49) microg/L. Serum FSTL1 concentrations were increased in ACS and related to the risk of all-cause mortality during follow-up. CONCLUSIONS: The ILMA permits detection of FSTL1 in human serum and plasma. We expect that the favorable preanalytic characteristics of FSTL1 and the reference limits defined here for apparently healthy individuals will facilitate future studies of FSTL1 as a biomarker in various disease settings, including ACS.

Angiopoietin 2 and cardiovascular disease in dialysis and kidney transplantation.

BACKGROUND: Accelerated atherosclerosis in patients with chronic kidney disease (CKD) is still incompletely understood. Angiopoietin 1 (Ang-1) and Ang-2 are 55-kDa antagonistic nonredundant gatekeepers of endothelial activation and thus are potential important factors in accelerated atherosclerosis. We aimed to study: (1) angiopoietin levels in patients treated by means of dialysis and kidney transplantation, (2) the association of altered angiopoietin levels with atherosclerosis, and (3) changes in altered levels after renal transplantation. STUDY DESIGN: Cross-sectional and longitudinal observational study. SETTING & PARTICIPANTS: 117 patients with CKD (61 hemodialysis [HD] patients, 24 peritoneal dialysis [PD] patients, and 32 renal transplant recipients) and 22 healthy controls. PREDICTOR: Treatment by means of HD or PD or renal transplantation versus healthy controls. OUTCOME: Serum Ang-1 and Ang-2 levels and ratio and changes in levels before and 3 months after transplantation. Correlations of angiopoietin levels with the presence and severity of coronary heart disease and peripheral arterial disease. MEASUREMENTS: Ang-1 and Ang-2 were measured in sera by using an immunoradiometric sandwich assay and enzyme-linked immunosorbent assay, respectively. Coronary heart disease was scored by using coronary angiography, and peripheral arterial disease, by using ultrasonography. RESULTS: Ang-1 level was decreased in HD patients compared with controls (29.1 +/- 12 versus 45.3 +/- 11.5 ng/mL; P < 0.001). In contrast, Ang-2 level was increased (HD, 8.7 +/- 0.64; PD, 6.48 +/- 8.1 ng/mL versus controls, 0.88 +/- 0.43 ng/mL; P < 0.001). Ang levels in renal transplant recipients were not different from healthy controls. Longitudinally, individual Ang-2 levels decreased after kidney transplantation (P = 0.01). In addition, in patients with CKD, Ang-2 level correlated significantly with scores of coronary heart disease (r = 0.486; P < 0.001) and peripheral arterial disease (r = 0.648; P < 0.001). LIMITATIONS: Cross-sectional study design. CONCLUSIONS: Circulating Ang-2 level was increased in patients treated with dialysis, although the mechanism is unknown. Kidney transplantation normalized circulating Ang-2 levels after 3 months. In addition, Ang-2 might be a mediator (and thus a marker) that accounts for accelerated atherosclerosis in dialysis patients.

Circulating angiopoietin-2 is a marker and potential mediator of endothelial cell detachment in ANCA-associated vasculitis with renal involvement.

BACKGROUND: The endothelial-specific angiopoietin (Ang)-Tie ligand-receptor system has been identified as a non-redundant regulator of endothelial cell detachment in vitro. Binding of circulating angiopoietin-2 (Ang-2) to the Tie2 receptor antagonizes Tie2 signalling and leads to disassembly of cell-cell junctions. Here, we ask whether circulating Ang-2 correlates with the severity of endothelial damage in ANCA-associated vasculitis (AAV) with renal involvement. METHODS: Ang-2 was measured in sera obtained from 45 patients with AAV and 20 healthy controls by in-house ELISA. The disease activity was monitored by BVAS and the enumeration of circulating endothelial cells (CECs). RESULTS: Ang-2 was significantly elevated in active AAV with renal involvement compared to controls and patients in remission. In contrast, Ang-2 was normal in patients with active granulomatous disease limited to the respiratory tract. Linear regression analysis demonstrated a strong association of Ang-2 with BVAS (r(s)(2) = 0.49 P < 0.0001) and the number of CECs (r(s)(2) = 0.48 P < 0.001). An Ang-2 cut-off value >4.15 ng/ml for a positive result yielded 100% specificity and 65% sensitivity for active systemic vasculitis. The positive predictive value was 99% and the negative predictive value 84%. CONCLUSIONS: Circulating Ang-2 is elevated and closely correlates with BVAS and CEC numbers in AAV with renal involvement. These data indicate that Ang-2 might be a potential mediator of endothelial cell detachment in AAV.