Objective: Malignant hypertension as borne out by uncontrolled hypertension with accelerated target organ damage has a variable and often dire prognosis. Loss of kidney function is a hallmark of the condition and is frequently accompanied by thrombotic microangiopathy (TMA). Design and method: Here we present the case of a patient with malignant hypertension, who was successfully treated using a combination of in-label and off-label medication according to the following pathophysiological concepts: 1) Innate immunity has been identified as a player in blood pressure (BP) control, 2) the complement inhibitor eculizumab has become available for treating atypical hemolytic uremic syndrome (aHUS), which shares many features of malignant hypertension, 3) endothelin (ET) antagonism, although not currently approved for these indications, has been shown to be effective for treating proteinuria and as a possible adjunct for the treatment of resistant hypertension. Results: A 40year-old man was referred to our hypertension clinic with uncontrolled hypertension and an accelerated loss of kidney function. His history included an excessive use of NSAR. However, serum creatinine had been in the normal range (1,07 mg/dl) six months previously. Two months previously arterial hypertension had been diagnosed at the same time as a serum creatinine of 2,03 mg/dl (MDRD creatinine (cr)-clearance 36 ml/min) with a proteinuria of 600 mg/l. A kidney biopsy had shown stenosing arteriolosclerosis and ischemic glomerular collapse consistent with malignant hypertension. There were signs of former episodes of TMA, but no signs of a fresh TMA. When we saw the patient, there was no laboratory evidence of hemolysis but complement factor C3c was low (0,7 g/l) and CRP was chronically elevated (Fig.1). We refrained from a repeat kidney biopsy because of abnormal platelet function assays. The patient had been admitted to hospital several times for hypertensive urgencies, antihypertensive medication had been stepped up to contain 7 drugs and kidney function deteriorated rapidly (Fig. 1, max. serum creatinine 4,4 mg/dl, MDRD cr-clearance 15 ml/min).According to the principles outlined above we introduced the dual ET receptor antagonist bosentan (31,25 mg bid, stepped up to 125-0-62,5 mg). An ACE inhibitor was withdrawn. When extended complement analyses showed a discrete elevation of C3d (60 mU/l, reference <40) and sC5b-9 (682 ng/ml, reference <320), we initiated eculizumab (900 mg/week for five weeks, then 1200 mg every two weeks). Serum creatinine started to decrease after 7 days and after 13 months is still in slow decline (2,87 mg/dl, MDRD cr-clearance 25 ml/min, 24 h cr-clearance 46 ml/min/1,73 m2). Proteinuria, having peaked at 3084 mg/g creatinine, decreased to 513 mg/g creatinine. Currently BP is in the upper range of normal according to ambulatory self-measurements. Antihypertensive therapy consists of bosentan plus amlodipin 5 mg bid, torasemide 5 mg, carvedilol 12,5 mg and candesartan 8-0-4 mg. Genetic testing revealed a previously unknown complement factor (CF) I mutation (p.G269V(GGT > GTT)), an equally unknown missense variation in CFH (p.W32Q(TGG > GGC)), a variation with unknown significance in CFB (p.W32Q (TGG > CAG)) together with a portfolio of 16 additional polymorphisms, some of which harbor associations with HUS, membranoproliferative glomerulonephritis (MPGN) and aging related macula degeneration (AMD). A complement screen 9 months into eculizumab treatment revealed nearly complete inhibition of total complement function(CH50, AH50), but C3d (83 mu/l) and sC5b-9 (475 ng/ml) were still elevated. Normalization of CRP was only achieved part of the time. The patient has recently suffered a clinically mild meningococcal plus H1N1 infection during which eculizumab was withdrawn for safety reasons. In view of the complex genetic variations we are currently following a concept of watchful waiting as regards a restart of complement inhibition, while bosentan treatment is being continued. Conclusions: This complex case is the first to demonstrate that complement inhibition is a viable approach for the treatment of malignant hypertension if the complement system is involved. We propose that all patients with signs of malignant hypertension should be carefully screened for complement involvement, keeping in mind, that no overt hemolysis has to be present. Data should be collected in a study or a registry. It is difficult to determine the relative contribution of eculizumab and bosentan on reduction of BP and proteinuria. Very limited data on the effects of eculizumab on proteinuria suggest that it has no or little sustained effect. From the existing database it is likely that bosentan has been the drug eliciting proteinuria reduction. Its interactions with complement remain to be further investigated. To name one putative mechanism: Others have described ET to be involved in heparan sulfate shedding of the endothelial glycocalyx and heparan sulfate is the binding site for factor H. Finally we presume that the effects on BP are secondary to structural improvements in the kidneys that might be accessible to a repeat biopsy and may have been caused by either agent or both.

Objective: Cigarette smoking is an independent risk factor for arterial hypertension and renal damage, respectively. Impaired renal function and arterial hypertension are so closely interrelated that in a clinical setting it is often difficult to determine which came first. Physiologically, renal hemodynamic autoregulation is finely tuned to protect the glomerula from fluctuations in blood pressure. Little is known about subclinical effects of smoking on renal hemodynamics and parameters of renal function in humans in vivo. We examined the associations of smoking with systemic and renal hemodynamics and renal function parameters in healthy individuals. Design and method: Data from 196 potential living kidney donors were analysed retrospectively. Mean arterial blood pressure (MAP), effective renal plasma flow (ERPF) and creatinine clearance had been measured. We additionally calculated parameters of renal hemodynamics. Data were analyzed for the effects of smoking and sex dependent on age and MAP. Results: Systemic and renal hemodynamic parameters did not differ between smokers and non-smokers. In non-smokers of both sexes MAP was negatively correlated with ERPF, and higher MAP was associated with increased renal vascular resistance and afferent arteriolar resistance, with glomerular pressure (PG) remaining constant. However, in male, but not in female smokers, ERPF and PG increased with MAP (Fig. 1). A correlation of age with a steeper decline in ERPF in male smokers was lost in multiple regression analysis.Conclusions: Our study is the first to show that renal autoregulation in smokers may vary dependent on sex. As compared to women, smoking men may be more susceptible to smoking-induced alterations of intrarenal hemodynamics. We cautiously propose an increased glomerular hydrostatic pressure in male smokers to be one putative mechanism linking smoking and renal dysfunction, the development of systemic arterial hypertension and cardiovascular disease in men.

OBJECTIVES:Programmed death (PD)-1 is a cell death receptor that, upon stimulation, leads to apoptosis. Previous studies have shown alteration of PD-1 expression on T cells and PD-1 genes in patients with systemic lupus erythematosus (SLE). The aim of this study was to assess the expression of this receptor on effector T cells in patients with SLE.METHOD:In this study we enrolled 32 SLE patients and 31 healthy controls. T cells from peripheral blood were analysed by flow cytometry for the expression of PD-1. Interferon (IFN)-γ and interleukin (IL)-17-producing cells were investigated for the expression of this co-stimulatory marker.RESULTS:Percentages of CD4(+) T cells expressing PD-1 were significantly increased in patients with SLE compared to healthy controls. The percentage of PD-1 expression was correlated with the production of INF-γ (r = 0.83, p < 0.0001). We also investigated the production of IL-17 by PD-1(+) CD3(+) T cells. Inactive patients (3.2 ± 1.2% vs. 5.9 ± 3.5%, p = 0.002) and patients without lupus nephritis (LN) (3.2 ± 1.5% vs. 5.9 ± 3.5%, p = 0.005) showed lower levels of IL-17 compared to healthy controls.CONCLUSION:We have demonstrated increased expression of PD-1 on CD4(+) T cells in SLE patients and an association between PD-1 expression on CD4(+) T cells and IFN-γ expression on CD3(+) T cells. We have also shown that there is an altered subset of PD-1(+) T cells in inactive patients and patients without LN producing lower amounts of IL-17.

Objective: We have shown recently that angiotensin II (ANGII) type 1 receptor-antagonism inhibits endothelin (ET-1)-mediated vasoconstriction in young men and women. We now performed a study on the putative influence of age and menopause on ET-1-induced vascular responses and on the effect of ANGII-antagonism on these responses, respectively. Methods: 20 postmenopausal women (group 1: 56 ± 4 years) without hormone replacement and 21 premenopausal women (group 2: 24 ± 3 years, P < 0.001 vs. group 1) were included in a double blind, randomized, placebo controlled study. We used a Laser Doppler imager (moor LDI V 5.0, Axminister, UK) to evaluate changes in skin blood flow following intradermal injection of ET-1 (10–18, 10–16, 10–14, 10–12 mol) after oral intake of placebo (plac) or the ANGII-receptor antagonist valsartan (Vals, 80 mg). Oestradiol and progesterone serum levels were measured with enzyme immunoassay. Data were analyzed with ANOVA of the time-effect curves or t-test and are expressed as arbitrary perfusion units (PU, mean ± SD). Results: Following placebo postmenopausal women responded less to higher ET-1-doses (mean max. constriction plac + ET-1, group 1 vs. group 2: ET-12 -86 ± 79 PU vs. -234 ± 81 PU, P < 0.001; ET-14–44 ± 58 PU vs. -139 ± 128 PU, P < 0.001; ET-16 and ET-18, P > 0.05). In the presence of ANG II-antagonism mean max. vasoconstriction was significantly reduced in both groups (P < 0.001). In the presence of ANGII-antagonism the mean overall vascular response to ET-1 was vasodilation (ANGII + ET-1 group 1: + 23 ± 31 PU, P < 0.001 vs. baseline; group 2: +29 ± 77 PU, P < 0.05 vs. baseline) with no difference between groups (P > 0.05). Female sex hormone levels were similar in both groups (group 1 vs. 2: estradiol 10 ± 17pg/ml vs. 20 ± 35pg/ml; progesterone 0.5 ± 0.3ng/ml vs. 0.6 ± 0.3ng/ml; all P > 0.05). Conclusions: Age but not endogenous estradiol and progesterone seems to have influenced vascular responses to ET-1 in our study. Similar to our previous results obtained in healthy young men and women ANGII-antagonism not only inhibited ET-1-induced vasoconstriction but led to ET-1 mediated vasodilation. This effect of ANGII-antagonism seems to be independent of age and hormonal status in women.

Background Measuring arterial stiffness using pulse wave velocity (PWV) has become an important tool to assess vascular function and cardiovascular mortality. For subject with hypertension, end-stage renal disease and diabetes, PWV has been shown to predict cardiovascular and all-cause mortality. We hypothesize that PWV would also predict mortality in subjects who have undergone kidney transplantation. Methods A cohort of 330 patients with renal transplantation was studied with a mean age at entry 51.4 ± 0.75 years. Mean follow-up was 3.8 years (± 0.7 years); 16 deaths occurred during follow-up. At entry, together with standard clinical and biochemical parameters, PWV was determined from pressure tracing over carotid and femoral arteries. Results With increasing PWV, there was a significant increase in age, systolic blood pressure and pulse pressure. In addition, subjects with higher PWV also exhibited more frequently the presence of coronary heart disease. On the basis of Cox analyses, PWV and systolic blood pressure emerged as predictors of all-cause mortality. Conclusion These results provide evidence that PWV is a strong predictor of all-cause mortality in the population of renal transplant recipients.

Objective: In the vasculature insulin activates two distinct signaling pathways that result in secretion of nitric oxide (NO) and endothelin (ET-1), respectively. NO, stimulated by higher insulin doses, is thought to be the underlying agent in insulin-mediated, endothelium-dependent vasodilation. However, we have shown that at low doses insulin causes vasoconstriction in the human microcirculation. We postulated that ET-1 stimulated by insulin could be responsible for this vasoconstriction. In an earlier study we found, that insulin at a dose, that by itself caused vasoconstriction, inhibited vasodilation to an ET-1-type-A-receptor (ET-A)-antagonist, suggesting increased insulin-mediated ET-1-activity. The role of ET-1-type-B (ET-B)-receptors in this setting remained to be identified and was the focus of the present study. Methods: 18 healthy women and men (25 ± 4 years) were studied. We used a Laser-Doppler-Imager (moor LDI-V5.0, Axminister,UK) to measure changes in skin blood flow. 10-7 IU insulin (Insuman Rapid®, Sanofi,Germany) were injected intradermally alone or following injection of the ET-A-antagonist BQ123 10-8 mol, the ET-B-antagonist BQ788 10-8 mol (Bachem,Switzerland) and BQ123 10–8+BQ788 10–8 mol in combination. Effects of BQ123 10–8 mol and BQ788 (10–8 and 10–10 mol) were also recorded. Injection sites were scanned over 30 min. Data are presented as arbitrary perfusion units (PU) and are given as mean ± SD. Two-way ANOVA was used to analyze time-effect responses. Results: Again insulin led to mild but significant vasoconstriction (P < 0.0001 vs. baseline) and reduced BQ123-mediated vasodilation (BQ123 vs. BQ123+insulin: +177 ± 60 vs. +87 ± 39PU, P < 0.0001). ET-B-blockade with BQ788 at the lower dose (10–10 mol) produced vasoconstriction (−24 ± 8PU, P < 0.0001 vs. baseline), which at the higher dose (10–8 mol) was no longer present. In the presence of ET-B-blockade (BQ788 10–8 mol) insulin induced vasodilation (+104 ± 32PU, P < 0.0001 vs. baseline). Blockade of both ET-A and ET-B-receptors induced pronounced vasodilation that was not different from vasodilation to ET-A-blockade alone. However, in the presence of BQ788 insulin no longer affected vasodilation induced by BQ123. Conclusions: Vasoconstrictor effects of low insulin doses in the peripheral microcirculation of healthy humans seem to be mediated via ET-B-receptors.

In Deutschland sterben Frauen häufiger als Männer an kardiovaskulären Erkrankungen. Mehr als zwei Drittel der Patienten, deren Tod direkt auf eine Bluthochdruckerkrankung zurückgeführt wird, sind Frauen. Obwohl die arterielle Hypertonie als wesentlicher kardiovaskulärer Risikofaktor bekannt ist und zahlreiche Medikamente zur Blutdruckeinstellung zur Verfügung stehen, sind weniger als 30% der Hypertoniepatienten in Deutschland ausreichend therapiert. Blutdruckwerte weisen bei Frauen und Männern altersabhängig deutliche Unterschiede auf. Der bei prämenopausalen Frauen niedrigere Blutdruck wird als mitursächlich für das bei jüngeren Frauen im Vergleich zu Männern geringere kardiovaskuläre Risiko angesehen. Menopausale Hormonumstellungen scheinen daran beteiligt zu sein, dass sich das kardiovaskuläre Risiko in höherem Alter angleicht. Alte Frauen leiden häufiger an arterieller Hypertonie als gleichaltrige Männer. Derzeit werden Frauen und Männer nach gleichen Regeln antihypertensiv behandelt, da nach der Studienlage eine adäquate Blutdruckeinstellung das kardiovaskuläre Risiko beider Geschlechter senkt. Die Datenlage zu möglicherweise geschlechtsspezifisch unterschiedlichen (Neben-)Wirkungen bzw. unterschiedlicher Effektivität einzelner Antihypertensivaklassen erweitert sich nur langsam.