Jens Nürnberger

Everolimus in Patients with Autosomal Dominant Polycystic Kidney Disease

BACKGROUND Autosomal dominant polycystic kidney disease (ADPKD) is a slowly progressive hereditary disorder that usually leads to end-stage renal disease. Although the underlying gene mutations were identified several years ago, efficacious therapy to curtail cyst growth and prevent renal failure is not available. Experimental and observational studies suggest that the mammalian target of rapamycin (mTOR) pathway plays a critical role in cyst growth. METHODS In this 2-year, double-blind trial, we randomly assigned 433 patients with ADPKD to receive either placebo or the mTOR inhibitor everolimus. The primary outcome was the change in total kidney volume, as measured on magnetic resonance imaging, at 12 and 24 months. RESULTS Total kidney volume increased between baseline and 1 year by 102 ml in the everolimus group, versus 157 ml in the placebo group (P=0.02) and between baseline and 2 years by 230 ml and 301 ml, respectively (P=0.06). Cyst volume increased by 76 ml in the everolimus group and 98 ml in the placebo group after 1 year (P=0.27) and by 181 ml and 215 ml, respectively, after 2 years (P=0.28). Parenchymal volume increased by 26 ml in the everolimus group and 62 ml in the placebo group after 1 year (P=0.003) and by 56 ml and 93 ml, respectively, after 2 years (P=0.11). The mean decrement in the estimated glomerular filtration rate after 24 months was 8.9 ml per minute per 1.73 m2 of body-surface area in the everolimus group versus 7.7 ml per minute in the placebo group (P=0.15). Drug-specific adverse events were more common in the everolimus group; the rate of infection was similar in the two groups. CONCLUSIONS Within the 2-year study period,as compared with placebo, everolimus slowed the increase in total kidney volume of patients with ADPKD but did not slow the progression of renal impairment [corrected]. (Funded by Novartis; EudraCT number, 2006-001485-16; ClinicalTrials.gov number, NCT00414440.)

Eculizumab for Atypical Hemolytic–Uremic Syndrome

To the Editor: Atypical hemolytic–uremic syndrome is a disease of uncontrolled complement activation associated with a high mortality rate, and most cases progress to end-stage renal disease.1 Abou...

Best supportive care and therapeutic plasma exchange with or without eculizumab in Shiga-toxin-producing E. coli O104:H4 induced haemolytic–uraemic syndrome: an analysis of the German STEC-HUS registry

BACKGROUND May 22nd marks the beginning of a Shiga-toxin-producing Escherichia coli (STEC) O104:H4 outbreak in Northern Germany. By its end on 27 July, it had claimed 53 deaths among 2987 STEC and 855 confirmed haemolytic-uraemic syndrome (HUS) cases. METHODS To describe short-term effectiveness of best supportive care (BSC), therapeutic plasma exchange (TPE) and TPE with eculizumab (TPE-Ecu) in 631 patients with suspected HUS treated in 84 hospitals in Germany, Sweden and the Netherlands using the web-based registry of the DGfN (online since 27 May). RESULTS Of 631 entries, 491 fulfilled the definition of HUS (median age 46 years; 71% females). The median (inter-quartile range) hospital stay was 22 (14-31) days. Two hundred and eighty-one (57%) patients underwent dialysis and 114 (23%) mechanical ventilation. Fifty-seven patients received BSC, 241 TPE and 193 TPE-Ecu. Treatment strategy was dependent on disease severity (laboratory signs of haemolysis, thrombocytopenia, peak creatinine level, need for dialysis, neurological symptoms, frequency of seizures) which was lower in BSC than in TPE and TPE-Ecu patients. At study endpoint (hospital discharge or death), the median creatinine was lower in BSC [1.1 mg/dL (0.9-1.3)] than in TPE [1.2 mg/dL (1.0-1.5), P < 0.05] and TPE-Ecu [1.4 mg/dL (1.0-2.2), P < 0.001], while need for dialysis was not different between BSC (0.0%, n = 0), TPE (3.7%; n = 9) and TPE-Ecu (4.7%, n = 9). Seizures were absent in BSC and rare in TPE (0.4%; n = 1) and TPE-Ecu (2.6%; n = 5) patients. Total hospital mortality in HUS patients was 4.1% (n = 20) and did not differ significantly between the TPE and TPE-Ecu groups. CONCLUSIONS Despite frequent renal impairment, advanced neurological disorders and severe respiratory failure, short-term outcome was better than expected when compared with previous reports. Within the limitations of a retrospective registry analysis, our data do not support the notion of a short-term benefit of Ecu in comparison to TPE alone in the treatment of STEC-HUS. A randomized trial comparing BSC, TPE and Ecu seems to be prudent and necessary prior to establishing new treatment guidelines for STEC-HUS.

Diastolic blood pressure is an important determinant of augmentation index and pulse wave velocity in young, healthy males

Pulse wave velocity (PWV) and augmentation index are widely used measures of arterial stiffness. The purpose of this study was to evaluate the role of blood pressure as a determinant of both indices independent of potentially confounding factors including gender, age and cardiovascular disorders. A total of 77 young, healthy subjects were investigated under resting conditions. Augmentation index was derived by pulse wave analysis using carotid applanation tonometry. PWV was determined from pressure tracing over the carotid and femoral artery. The relations between stiffness markers and haemodynamic parameters were analysed by simple (r) and multiple (β) regression analysis. Using simple regression analysis, augmentation index was correlated to age (r=0.292, P=0.0105), diastolic blood pressure (DBP, r=0.483, P<0.0001), mean arterial blood pressure (MAP, r=0.381, P=0.0007), pulse pressure (r=−0.414, P=0.0002) and total peripheral resistance (r=0.266, P=0.0204). After multiple regression analysis, augmentation index remained significantly correlated only to DBP (β=0.347, P=0.0051). Using simple regression analysis, PWV was correlated to age (r=0.304, P=0.0067), systolic blood pressure (r=0.280, P=0.0129). DBP (r=0.455, P<0.0001), MAP (r=0.446, P<0.0001) and heart rate (r=0.348, P=0.0018). After multiple regression analysis, PWV remained correlated only to age (β=0.218, P=0.0422) and DBP (β=0.4105, P=0.0316). In summary, DBP is an important determinant of augmentation index and PWV in young, healthy males. Further studies are needed to characterize the impact of blood pressure on arterial stiffness in other populations including females and older subjects.

New Treatment Options for Atypical Hemolytic Uremic Syndrome with the Complement Inhibitor Eculizumab

Hemolytic uremic syndrome (HUS) is a disease characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and renal impairment. Often HUS is triggered by Shiga-like toxin- producing ESCHERICHIA COLI. Less common is atypical HUS (aHUS), which is caused by defective complement control. aHUS is associated with mutations in genes encoding complement regulatory proteins in ~50% of patients with this syndrome. Furthermore, autoantibodies that inactivate to factor H have also been linked to the disease. Initial triggers include infections, use of endothelial-affecting drugs, malignancies, transplantation, and pregnancy. Advances in our understanding of the pathogenesis of atypical HUS suggest that complement inhibition may be used as treatment for the disease. We discuss the potential benefit of the complement inhibitor eculizumab for the treatment of aHUS.

Effect of the C825T Polymorphism of the G Protein β3 Subunit on the Systolic Blood Pressure–Lowering Effect of Clonidine in Young, Healthy Male Subjects

The T allele of the C825T polymorphism in the gene encoding the G‐protein β3 subunit (GNB3) is associated with hypertension. An enhanced signal transduction in response to α2‐adrenergic receptor stimulation has been shown in carriers of the T allele in vitro. We hypothesized that T allele carriers would show an enhanced antihypertensive response to stimulation of central α2‐adrenergic receptors by clonidine. We compared the response to intravenous clonidine in 30 young, healthy male subjects with and without the T allele (15 CC, 10 CT, and 5 TT). Clonidine lowered blood pressure and total peripheral resistance, lengthened the duration of electromechanical systole (QS2c), and slowed down pulse wave velocity. Carriers of the T allele showed significantly greater reductions in systolic blood pressure (P = .009; mean change ± SEM: CC, −8.9 ± 0.5; CT and TT, −10.6 ± 0.4) and total peripheral resistance (P < .0001; mean change ± SEM: CC, 40 ± 17; CT and TT, −48 ± 14) and more marked lengthening of QS2c (P = .002; mean change ± SEM: CC, 2.2 ± 0.5; CT and TT, 4.7 ± 0.6) and slowing of pulse wave velocity (P = .012; mean change ± SEM: CC, −0.25 ± 0.02; CT and TT, −0.33 ± 0.03). The results of this study suggest that the 825T allele may be a relevant pharmacogenetic marker in the use of centrally acting sympatholytic drugs.

Association of ambulatory arterial stiffness index and brachial pulse pressure is restricted to dippers.

Background The ambulatory arterial stiffness index (AASI) is a new index that reflects the dynamic relation between diastolic and systolic blood pressure through the circadian blood pressure rhythm. It was the aim of this study to investigate the association between AASI, dipping status and pulse pressure as a classical indicator of arterial stiffness in normotensive and hypertensive subjects. Methods One hundred and twelve individuals were evaluated for a kidney donation to a relative at the University Hospital Essen, Germany. In this context routine 24-h ambulatory blood pressure measurements were performed. A nocturnal reduction in diastolic blood pressure of >10% was defined as ‘dipping’. We determined the diurnal and nocturnal blood pressure and brachial pulse pressure values and computed AASI for each participant. Results AASI was a strong predictor for diastolic and systolic nocturnal blood pressure fall (r = −0.55 and −0.48, respectively; P < 0.001). Additionally, AASI predicted the status of ‘dipping/nondipping’. ‘Dippers’ showed significantly lower AASI than ‘nondippers’ in both normotensive and hypertensive subjects. Dippers, but not nondippers, demonstrated an association between AASI and brachial pulse pressure. Discussion AASI is strongly correlated with nocturnal blood pressure fall and is increased in nondipping independent of blood pressure. The role of AASI as a potential marker for arterial stiffness depends, in this study, on the characterization of the dipping status.

Ambulatory Norepinephrine Treatment of Severe Autonomic Orthostatic Hypotension

OBJECTIVES This study was designed to establish a patient-controlled, ambulatory norepinephrine treatment of refractory orthostatic hypotension due to primary autonomic failure. BACKGROUND Autonomic dysfunction leads to disabling postural hypotension. Particularly in primary autonomic dysfunction, repeated syncope and immobilization can be the result. Medical treatment of orthostatic hypotension often fails in advanced cases. METHODS Ambulatory, patient-controlled norepinephrine therapy was initiated in six patients with orthostatic hypotension due to primary autonomic failure that had been refractory to conventional treatment. Before this therapy, three patients were bedridden; one was immobilized in a wheelchair. All had recurrent syncope and tolerated upright tilt-table testing for less than 15 min despite extensive medical treatment. For ambulatory treatment, a port-a-cath system was implanted and, using a CADD ambulatory infusion pump, norepinephrine was infused in individually adjusted dosages. RESULTS Norepinephrine infusion therapy enabled all patients to sit, stay and walk around for more than 45 min. One patient died after a five-year treatment period, another after nine months because of nonhemorrhagic brain stem infarctions, both in the absence of norepinephrine treatment. The remaining four patients are still mobile after a period of 19, 10, 9 and 7 months, respectively. None of them has suffered complications due to arterial hypo- or hypertension, and there has been no infection of the infusion system. CONCLUSIONS In these selected patients with refractory orthostatic hypotension due to primary autonomic dysfunction, ambulatory norepinephrine infusion therapy has proved to be a promising new therapeutic option. Further long-term studies including more patients are necessary to assess additional indications, reliability and safety of this new method.

The T-allele of the C825T polymorphism is associated with higher arterial stiffness in young healthy males

Arterial stiffening is the major cause of increasing systolic blood pressure in arterial hypertension. Increased arterial stiffness is one major mechanism responsible for morbidity and mortality in hypertension. A C825T polymorphism was identified in the gene encoding the G-protein β3 subunit (GNB3), and an association of the T-allele with hypertension was demonstrated in several studies. In order to identify a pathogenetic link between hypertension and arterial stiffness, we compared two indices of arterial stiffness, pulse wave velocity (PWV) and augmentation index, in young, healthy men with and without the 825T-allele under resting conditions. PWV was determined from pressure tracing over carotid and femoral arteries in 99 subjects (CC: n=43; CT&TT: n=56). Augmentation index was derived in 72 subjects (CC: n=30; CT&TT: n=42) by pulse wave analysis using radial applanation tonometry. Carriers of the 825T-allele exhibited a significantly higher PWV compared to subjects with the CC genotype (6.0±0.1 m/s (TC&TT) vs 5.7±0.1 m/s (CC); P=0.0251). There was also a significant difference (P = 0.0448) in augmentation index between carriers of the T-allele (CT&TT: 3.4±2.9%) and controls with the CC -genotype (−5.0±4.1 %). There was no difference in any other anthropometric (age, height, weight, body mass index) or haemodynamic (heart rate, peripheral and central blood pressure). In summary, the C825T polymorphism is associated with higher arterial stiffness in young, healthy males. Arterial stiffening may pathogenetically contribute to the development of hypertension in carriers of the T-allele.

The Invs Gene Encodes a Microtubule-Associated Protein

Microtubule networks are important for many vital processes such as mitosis, cell polarity, and differentiation. Ciliary architecture and function closely depend on the microtubule cytoskeleton, and recent studies suggest a role of apical cilia of renal epithelia in the pathogenesis of polycystic kidney disease. This study evaluates the localization, potential interacting partners, and functional aspects of the Invs gene product inversin. Only recently, INVS has been identified as the gene that is mutated in nephronophthisis type 2, an autosomal recessive polycystic kidney disease. Using immunoprecipitation and co-pelleting assays, we show that the Invs gene product inversin forms a stable complex with tubulin in cultured renal epithelial cells. Inversin localizes to several components of the cytoskeleton including ciliary, random, and polarized microtubule pools. During cell divison, inversin is recruited to mitotic spindle fibers. After microtubule depolymerization using colcemid inversin and tubulin staining is no longer characterized by a network pattern but by homogeneous, diffuse distribution. Inversin does not coprecipitate with tubulin after addition of colcemid. After removal of colcemid, inversin immunofluorescence reappears together with tubulin in centrioles. Treatment with the microtubule stabilizing agent paclitaxel leads to severe alteration of the microtubule cytoskeleton with bundling and formation of long spindles of tubulin and inversin. In conclusion, inversin is closely associated with the microtubule cytoskeleton, and its spatial distribution is dependent on tubulin polymerization. Hence, altered inversin-tubulin interaction may impair ciliary function and thereby contribute to cyst development in nephronophthisis.