[Membranoproliferative glomerulonephritis and C3 glomerulopathy]. / Membranoproliferative Glomerulonephritis und C3­Glomerulopathie.

Based on an increasingly better pathophysiological understanding over the last 10 years, in 2010 a new classification of glomerulonephritis with dominant or codominant C3 deposits was introduced and the predominant subgoup was termed C3 glomerulopathy (C3G). In the current classification, immune complex mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) form a disease spectrum which is very heterogeneous in terms of pathophysiology and the clinical course. Recent evidence suggests that IC-MPGN and C3G share more pathophysiological aspects with respect to secondary causes, autoantibodies and genetic aspects than had been suggested with the creation of the new classification. Knowledge of the underlying pathophysiology is important for guiding the diagnostic steps for clarification of secondary causes. Comprehensive complement analysis, accompanied by antibody screening and genetic analysis, should be consistently carried out. Although not systematically validated in clinical trials, the published evidence provides a robust foundation for the use of available treatment approaches for these diseases that are often rapidly progressive and often return after renal transplantation.

[Human genetics in atypical hemolytic uremic syndrome-its role in diagnosis and treatment]. / Humangenetik beim atypischen hämolytisch-urämischen Syndrom ­ Rolle in Diagnostik und Therapie.

The atypical hemolytic uremic syndrome (aHUS), one of the three major forms of thrombotic microangiopathy, is characterized by genetic alterations in the area of the complement cascade, which can be detected in 40%-60% of all patients with aHUS. Mutations in over 10 different genes have now been identified. The most frequent and clinically relevant of these are mutations that result in a decreased or absent function of factor H, the formation of hybrid genes, or the formation of autoantibodies against factor H. Although genetics are not required for the diagnosis of aHUS, it is of great importance for the decision on how long to treat with the C5 inhibitor eculizumab. Also, knowledge of genetic alterations is absolutely essential if a living related donor is considered, in order to protect the living donor and recipient from developing aHUS.

[Invasive treatment of hypertension : Update 2016]. / Interventionelle Hypertonietherapie : Update 2016.

Invasive treatment methods-more specifically renal denervation and baroreceptor activator therapy-have been used for the treatment of therapy-resistant hypertension for several years now. In particular, renal denervation has aroused great interest because it was easy to perform and the first studies provided very promising results. Meanwhile, however, three randomized, blinded studies have been published, and none showed a significant benefit of renal denervation compared to a sham procedure. In addition, in several studies it was demonstrated that intensification of drug therapy, particularly with spironolactone, is at least comparable. Carotid sinus node baroreceptor activator therapy tends to be superior to renal denervation, but the probe currently used is not optimal. The first results by inserting an arteriovenous shunt between the iliac artery and vein are promising, but lack long-term safety data. Currently, all invasive treatment procedures should be performed within the framework of studies or accurate register surveys.

[Rare forms of hypertension : From pheochromocytoma to vasculitis]. / Seltene Formen der Hypertonie : Vom Phäochromozytom zur Vaskulitis.

Secondary hypertension affects only 5-10 % of hypertensive patients. Screening is expensive and time-consuming and should be performed only in patients for whom there is a high clinical suspicion of secondary hypertension. Clinical signs of secondary forms of hypertension are new-onset hypertension in patients without other risk factors (i.e., family history, obesity, etc.), sudden increase of blood pressure (BP) in a previously stable patient, increased BP in prepubertal children, resistant hypertension, and severe hypertension or hypertensive emergencies. In adults, renal parenchymal and vascular diseases as well as obstructive sleep apnea are the most common causes of secondary hypertension. Medication-induced hypertension and non-adherence to medication have to be ruled out. Of the endocrine causes associated with hypertension, primary aldosteronism is the most common. Other endocrine causes of hypertension such as thyroid disease (hypo- or hyperthyroidism), hypercortisolism (Cushing's syndrome), hyperparathyroidism, and pheochromocytoma are rare. Monogenetic forms of hypertension are mostly of tubular origin and associated with alterations in mineralocorticoid handling or signaling. Rare causes of hypertension also include inflammatory vascular disease. Acute forms of vasculitis may present as "malignant" hypertension with associated thrombotic microangiopathy and organ damage/failure. It is important to diagnose these rare forms of hypertension in order to prevent acute organ damage in these patients or unnecessary invasive treatment strategies.

[Interventional strategies in hypertension management]. / Interventionelle Strategien zur Behandlung der Hypertonie.

A number of invasive treatment approaches have become established in the management of severe treatment-resistant hypertension in recent years, including renal denervation and baroreceptor activation therapy. Both methods achieve their antihypertensive effect by influencing the autonomic nervous system. Renal denervation in particular has stimulated considerable interest, since it is simple to perform and initial studies have yielded highly promising results. However, enthusiasm has waned significantly since the initial euphoria. This is due to the fact that the first randomized placebo-controlled double-blind study showed the method to have no significant effect on blood pressure. This experience illustrates the importance of conducting double-blind studies. On the other hand, these results should not lead to renal denervation being shelved. On the contrary, it is worth attempting to improve the treatment and develop criteria to identify which patients it is likely to benefit. Although experience with baroreceptor activation therapy is significantly more limited, similar conclusions can be drawn on it, despite the fact that-in contrast to renal denervation-it achieved a blood pressure reduction of around 10 mmHg in a double-blind study. A potential novel treatment approach lies in creating an arteriovenous shunt between the iliac artery and vein, which has a particularly marked effect on diastolic blood pressure by reducing peripheral resistance. Therapy using brain stimulation of areas in the brainstem region responsible for blood pressure regulation is still at an experimental stage.

Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.

BACKGROUND: Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. METHODS: We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). RESULTS: A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. CONCLUSIONS: Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]).

[Treatment of typical hemolytic-uremic syndrome. Knowledge gained from analyses of the 2011 E. coli outbreak]. / Therapie des typischen hämolytisch-urämischen Syndroms. Erkenntnisse aus dem E.-coli-Ausbruch 2011.

Shiga toxin-associated hemolytic uremic syndrome (HUS) is an entity of thrombotic microangiopathy characterized by hemolytic anemia, thrombocytopenia, central nervous symptoms, and renal insufficiency. In May 2011, an outbreak of enterohemorrhagic Escherichia coli (EHEC; O104:H4) occurred in Northern Germany. By the end of July 2011, the outbreak was over but nearly 4000 patients had an EHEC infection, 855 cases of hemolytic-uraemic syndrome were reported to the Robert Koch Institute, and there were 35 (4.1%) deaths. Shiga toxin-induced HUS is a rare disease and no controlled clinical trials on therapeutic options are available. First analyses of this outbreak suggest that therapeutic plasma exchange, which was used in the majority of patients, had no benefit and might even be harmful. The role of eculizumab, a monoclonal antibody which inhibits the complement system, is being examined in a multicenter study: the results have not been published yet. Promising is the use of some antibiotics. This would change a paradigm that antibiotics should be avoided. Ongoing and future analyses of the epidemic should be awaited before a final recommendation regarding the different treatment strategies can be made.

[Therapeutic targets in arterial hypertension and diabetes mellitus. Can medical prevention be harmful?]. / Behandlungsziele bei Bluthochdruck und Diabetes mellitus. Kann medikamentöse Prävention übertrieben werden?

Arterial hypertension contributes considerably to the increased cardiorenal risk of patients with diabetes mellitus type 2. Therefore guideline-writing authorities recommend starting antihypertensive treatment generously, with the aim of reducing blood pressure to levels to < 130/80 mmHg. Nevertheless, results of several recent studies have challenged the currently prevailing paradigm "the lower the better" in hypertension management. A similar paradigm also seems to hold true for the management of blood glucose in these patients. Detailed analyses have shown an increased risk of coronary events by targeting both lower blood pressure and blood glucose levels, especially in those with established cardiovascular disease and especially coronary artery disease--thus, the concept of "the lower the better" should be reconsidered in this group of patients.

[Albuminuria : prognostic marker or therapeutic goal?]. / Albuminurie : Prognostischer Marker oder therapeutisches Ziel?

Microalbuminuria has most often been linked with renal disease in diabetic patients. However, accumulating data demonstrate that the development of albuminuria is closely associated with cardiovascular and renal disease in both diabetic and non-diabetic patients. The role of albuminuria in the pathogenesis of these clinical conditions remains controversial. While reductions in albuminuria have been associated with improved outcomes, the evidence for lower levels of albuminuria (microalbuminuria and normoalbuminuria) is inconclusive. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers have demonstrated some success in treating or delaying the onset of microalbuminuria. However, it remains to be established whether these effects result in meaningful reductions in clinical renal or cardiovascular events.

An erythropoietin gene polymorphism in the hypoxia-responsive element at position 3434 is possibly associated with hypertension.

BACKGROUND/AIMS: Several polymorphisms of vasoactive hormones have been implicated in hypertension. Erythropoietin (EPO) interacts with vasoactive substances, such as angiotensin II. Previously detected single nucleotide polymorphisms in the hypoxia-responsive element of EPO might be associated with hypertension and hypertensive end organ damages. METHODS: 400 hypertensive patients and 200 age- and gender-matched normotensive controls were genotyped for an EPO polymorphism [cytosine (C)/thymine (T) single nucleotide polymorphism] at position 3434. Patients were grouped according to their genotype into the CC group (CC genotype) and the CT/TT group (CT and TT genotype). BP was measured by ambulatory BP monitoring. RESULTS: The CC genotype was present in 87% of hypertensive patients and in 78.5% of controls (p = 0.007). In addition, patients with the CC genotype had higher BP levels compared with CT/TT genotypes (BPsys 143.7 ± 20.4 vs. 136.1 ± 13.5 mm Hg, p = 0.01, and BPdias 85.8 ± 11.6 vs. 82.4 ± 8.9, p = 0.043) despite a nearly identical number of antihypertensive drugs (2.3 ± 1.5 vs. 2.3 ± 1.6; p = 0.257). 100% of the small number of patients with end-stage renal disease (n = 15) had the CC genotype. CONCLUSION: The CC genotype of the EPO gene at position 3434 is more frequently found in patients with hypertension and is associated with higher BP levels.

[Diabetic nephropathy]. / Diabetische Nephropathie.

Diabetic nephropathy is the most common cause of end-stage renal disease. Since the disease progresses very slowly and usually takes more than 20 years before terminal renal failure occurs, early intervention is of great importance in order to prevent this disabling complication. A good control of diabetes with HbA(1c) levels around 7% is desirable. At least as important is the treatment of elevated blood pressure values. The target value for patients with diabetes has been adjusted in the last year and is now 130-139/80-85 mmHg. Should (micro-)albuminuria or renal insufficiency be present the blood pressure target is <130/80 mmHg. For the control of hypertension the use of ACE inhibitors or angiotensin receptor blockers is recommended. In addition, the control of other risk factors and appropriate therapeutic intervention is required. A multifactorial intervention leads to the best results and can avoid the occurrence or progression of diabetic kidney disease and other micro- and/or macrovascular complications.

[Aortic valve stenosis: transcatheter aortic valve implantation (TAVI) ­ transarterial or transapical approach]. / Aortenklappenstenosen: Kathetergestützte Aortenklappenimplantation (TAVI) ­ transarterieller oder transapikaler Zugang.

The calcified aortic stenosis is the dominating valve disease. Patients affected are most common elderly people in the 8 (th) or 9 (th) decade of their life who often show associated comorbidities like reduced left ventricular function, impaired renal function, pulmonary hypertension, and further diseases (Diabetes mellitus, stroke, COPD). In many cases perioperative morbidity and mortality are too high for surgical valve replacement and up to 30 % of patients are rejected. Nevertheless, prognosis of aortic stenosis is worse if the typical symptoms like dyspnea on exertion, syncope, and angina occur. The transcatheter aortic valve implantation is a new method treating this particular group of patients. The aortic valve bioprothesis consists of a balloon-expandable stent or a self-expandable frame, in which a valve of bovine or porcine pericardium is incorporated. The implantation is performed by retrograde access via the femoral or subclavian artery; the balloon-expandable prosthesis can also be implanted by transapical approach. Recently, the PARTNER trial and other studies demonstrate a high implantation success rate and better survival in comparison to standard therapy but exhibit also cerebral vascular and peripheral vascular complications. A further reduction of the available delivery systems and new types of valves which are under experimental tests and clinical evaluation contribute to this development.

Blood pressure telemonitoring is useful to achieve blood pressure control in inadequately treated patients with arterial hypertension.

Failing to reach blood pressure (BP) goals is one of the main problems in hypertension management. Especially in high-risk patients, intensive monitoring including frequently office visits or new techniques to monitor home BP is required. A total of 60 patients with uncontrolled hypertension were included and randomized into a group with telemetric BP monitoring (TBPM) (n=30) and a control group receiving standard care (n=30). During the 3-month study period, patients received in addition to their antihypertensive pre-treatment up to 2 × 300 mg irbesartan to achieve the required target BP. All patients were instructed to measure their BP once daily in the morning. In the TBPM group automatic alerts were generated by the central database server using pre-defined algorithms and patients were subsequently contacted by the physician. At baseline mean 24-h ambulant BP monitoring (ABPM) was 143.3±11.1/82.6±9.9 mm Hg in the TBPM group and 141.4±12.6/82.1±6.5 mm Hg in the standard care group. During treatment mean systolic BP showed a more intensive decrease in the TBPM vs control group (-17.0±11.1 mm Hg vs -9.8±13.7 mm Hg; P=0.032). Patients in the TBPM group had a more pronounced night dipping and a higher reduction of mean pulse pressure than controls (-8.1±5.9 mm Hg vs -2.8±7.4 mm Hg, P=0.004). After 3 months, TBPM-treated patients were given a higher mean daily dose of irbesartan (375±187 mg vs 222±147 mg in controls; P=<0.001). We demonstrated that with TBPM a more effective and faster titration of the antihypertensive agent is possible. The alarm criteria chosen were useful to improve BP control.

Determinants of urinary albumin excretion within the normal range in patients with type 2 diabetes: the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study.

AIMS/HYPOTHESIS: In contrast to microalbuminuric type 2 diabetic patients, the factors correlated with urinary albumin excretion are less well known in normoalbuminuric patients. This may be important because even within the normoalbuminuric range, higher rates of albuminuria are known to be associated with higher renal and cardiovascular risk. METHODS: At the time of screening for the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) Study, the urinary albumin/creatinine ratio (UACR) was 0.44 mg/mmol in 4,449 type 2 diabetic patients. The independent correlates of UACR were analysed. RESULTS: Independent correlates of UACR during baseline were (in descending order): night-time systolic BP (r(s) = 0.19); HbA(1c) (r(s) = 0.18); mean 24 h systolic BP (r(s) = 0.16); fasting blood glucose (r(s) = 0.16); night-time diastolic BP (r(s) = 0.12); office systolic BP, sitting (r(s) = 0.11), standing (r(s) = 0.10); estimated GFR (r(s) = 0.10); heart rate, sitting (r(s) = 0.10); haemoglobin (r(s) = -0.10); triacylglycerol (r(s) = 0.09); and uric acid (r(s) = -0.08; all p

Chronic erythropoietin treatment affects different molecular pathways of diabetic cardiomyopathy in mouse.

BACKGROUND: Recent studies in mice experimental models with acute ischaemic injury revealed that erythropoietin (EPO) has numerous tissue-protective effects in the heart, brain and kidneys. We therefore explored the tissue-protective properties of chronic EPO treatment in an experimental model of the db/db mouse with diabetic heart injury. MATERIAL AND METHODS: We randomly treated 11 db/db mice with placebo (saline), 0.4 microg of the continuous erythropoietin receptor activator (CERA) per week (n = 11) or 1.2 microg CERA per week (n = 11) for 14 weeks, and analysed cardiac tissue. The lower CERA dose was a non-haematologically effective dose, whereas the second increased the haematocrit. RESULTS: Compared with mice in the placebo group, CERA-treated mice had a reduction in TGF-beta(1) and collagen I expression in cardiac tissue (P < 0.01 vs. higher dose CERA). In addition, an increased expression of the pro-survival intracellular pathway p-AKT was observed (P < 0.05 vs. higher dose CERA). The values for the lower C.E.R.A had an intermediate nonsignificant effect. Furthermore, we were able to show that atrial natriuretic peptide (ANP) expression was increased in both CERA groups. CONCLUSIONS: Chronic treatment with CERA protects cardiac tissue in diabetic animals, i.e. it inhibits molecular pathways of cardiac fibrosis, and the effects are dose-dependent.

Targeting the protein kinase C family in the diabetic kidney: lessons from analysis of mutant mice.

The protein kinase C (PKC) superfamily comprises proteins that are activated in response to various pathogenic stimuli in the diabetic state. Hyperglycaemia is the predominant stimulus that induces the activation of distinct PKC isoforms within a cell, each mediating specific functions, probably through differential subcellular localisation. The contribution of individual PKC isoforms can be directly addressed in vivo using innovative PKC-isoform-specific knockout (KO) mouse models, which are providing key insights into the physiological function of PKC isoform diversity in the development of diabetic nephropathy. Such studies can be a valuable complementary approach to more commonly used pharmacological analyses using agents such as ruboxistaurin mesylate (Arxxant, LY333531), which is claimed to specifically inhibit the PKC-beta-isoform. As expected given the multiple and specific properties of the isoforms in vitro, deletion of different PKC isoform signalling pathways leads to distinct phenotypes in mice. Notably, KOs of the individual PKCs assigned specific non-redundant biological functions to each isoform, which were not compensated for by the others. Thus, PKC isoform specificity and cellular diversity seem to be responsible for the divergent outcomes leading to albuminuria and/or renal fibrosis according to studies on the streptozotocin-induced mouse model of diabetes. This review discusses the role of individual PKC isoforms in diabetic nephropathy and their potential therapeutic implications. Defining and targeting mediators of increased intracellular activation in the diabetic microvasculature will have important clinical and therapeutic benefits and help in the design of novel effective therapies in the near future.

Nephrin loss in experimental diabetic nephropathy is prevented by deletion of protein kinase C alpha signaling in-vivo.

Albuminuria in diabetic nephropathy is due to endothelial dysfunction, a loss of negative charges in the basement membrane, and changes a of the slit-membrane diaphragm composition. We have recently shown that protein kinase C alpha (PKCalpha)-deficient mice are protected against the development of albuminuria under diabetic conditions. We here tested the hypothesis that PKCalpha mediates the hyperglycemia-induced downregulation of the slit-diaphragm protein nephrin. After 8 weeks of streptozotocin (STZ)-induced hyperglycemia the expression of glomerular nephrin was significantly reduced. In contrast, other slit-diaphragm proteins such as podocin and CD2AP were unaltered in diabetic state. In PKCalpha-/- mice, hyperglycemia-induced downregulation of nephrin was prevented. Podocin and CD2AP remained unchanged. In addition, the nephrin messenger RNA expression was also reduced in hyperglycemic wild-type mice but remained unaltered in PKCalpha-/- mice. We postulate that the underlying mechanism of the hyperglycemia-induced regulation of various proteins of the glomerular filtration barrier is a PKCalpha-dependent regulation of the Wilms' Tumor Suppressor (WT1) which previously has been shown to act as a direct transcription factor on the nephrin promoter. Our data suggest that PKCalpha activation may be an important intracellular signaling pathway in the regulation of nephrin expression and glomerular albumin permeability in the diabetic state.

Life-threatening complications of extracorporeal treatment in patients with severe eosinophilia.

We report three patients with massive eosinophilia of different etiology who developed bronchoconstriction, hypotension, and shock shortly after dialysis or leukapheresis had been begun. In two cases, ethylene oxide-free materials had been used ruling out an allergic reaction related to this compound. Degranulation of eosinophils with release of eosinophil peroxidase may have caused the observed adverse reactions, as suggested by in vitro experiments with blood from the three patients. Our observations draw attention to the fact that extracorporeal therapies may initiate life-threatening complications in patients with severe eosinophilia.

Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice.

Caveolae are plasma membrane invaginations that may play an important role in numerous cellular processes including transport, signaling, and tumor suppression. By targeted disruption of caveolin-1, the main protein component of caveolae, we generated mice that lacked caveolae. The absence of this organelle impaired nitric oxide and calcium signaling in the cardiovascular system, causing aberrations in endothelium-dependent relaxation, contractility, and maintenance of myogenic tone. In addition, the lungs of knockout animals displayed thickening of alveolar septa caused by uncontrolled endothelial cell proliferation and fibrosis, resulting in severe physical limitations in caveolin-1-disrupted mice. Thus, caveolin-1 and caveolae play a fundamental role in organizing multiple signaling pathways in the cell.