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Herzinsuffizienz (HI) ist die haufigste kardiovaskulare Diagnose bei Patienten mit chronischer Niereninsuffizienz (CNI) im Endstadium. Ein gemeinsames Begleitsymptom dieser doppelt belasteten und auserst vulnerablen Patientengruppe ist die Anamie. Aufgrund neuerer Studiendaten mit Eisencarboxymaltose wird intravenoses (i. v.) Eisen auch als Therapieoption bei HI intensiv diskutiert. Damit stellt sich die Frage, ob eine Gabe von i. v. Eisen bei CNI-Patienten mit HI zu erwagen ware, auch wenn diese unter dem Blickwinkel der reinen Anamiekontrolle eigentlich nicht behandlungsbedurftig sind. Im Hinblick auf die aktuelle Studienevidenz ist es vorerst zu fruh, i. v. Eisen bei CNI-Patienten auch zur Therapie einer HI einzusetzen. Aktuell sollte i. v. Eisen auch bei CNI-Patienten mit HI zur Anamietherapie appliziert und die Empfehlungen hinsichtlich der maximalen Serum-Ferritin-Spiegel beachtet werden. Aufgrund der heterogenen Empfehlungen zur Obergrenze ist jedoch eine individuelle Nutzen-Risiko-Analyse fur jeden Patienten notwendig.

Anamie hat im hoheren Lebensalter eine hohe Pravalenz und kommt als Eisenmangelanamie mit absolutem Eisenmangel, als Anamie chronischer Erkrankungen mit funktionellem Eisenmangel oder als unerklarbare Anamie vor. Bei funktionellem Eisenmangel ist Hepcidin erhoht, wodurch die enterale Eisenresorption vermindert wird. Eine intravenose Eisengabe kann dieses Problem beheben. Die Datenlage dazu ist bei geriatrischen Patienten dunn. In drei nicht-interventionellen Studien wurden Wirksamkeit und Vertraglichkeit einer intravenosen Eisengabe (Eisencarboxymaltose, Ferinject®) an drei Patientengruppen mit funktionellem Eisenmangel unterschiedlicher Genese (Tumorerkrankungen, chronische Nierenerkrankungen [CKD] und chronisch entzundliche Darmerkrankungen [CED]) untersucht. Subanalyse der Studiendaten im geriatrischen Kollektiv von 264 Patienten im Alter von 70–90 Jahren (76,9 ± 5,2 Jahre); durchschnittlich wurden 1200 mg Eisen (746 mg bis 1575 mg) pro Patient infundiert. Signifikanter Anstieg von Hamoglobin (p 0,001) und Transferrinsattigung (p < 0,05) in der Gruppe der nephrologischen Patienten; bei den gastroenterologischen Patienten signifikanter Anstieg nur bei Hamoglobin (p < 0,05) und Transferrinsattigung (p < 0,05), jedoch nicht bei Ferritin. In der Gruppe der onkologischen Patienten kam es sowohl bei Hamoglobin als auch bei Ferritin zu einem hoch signifikanten Anstieg (p < 0,0001) und bei der Transferrinsattigung zu einem signifikanten Anstieg (p = 0,02). Mudigkeit, Konzentrationsschwache und Dyspnoe-Symptomatik verbesserten sich in der CKD- und CED-Gruppe. Es traten keine schwerwiegenden Nebenwirkungen auf. Zusammenfassend lasst sich daraus schliesen, dass der Einsatz von Eisencarboxymaltose auch bei geriatrischen Patienten mit funktionellem Eisenmangel gut vertraglich und effektiv erfolgen kann.

Fabry disease is a progressive and life-threatening glycolipid storage disorder affecting both males and females. The primary driver of the disease is the accumulation of glycolipids (globotriaosylceramide [GL-3]) in a variety of cell types, including vascular endothelial cells, a range of renal cell types, cardiomyocytes and neurons, which is caused by deficient activity of the lysosomal enzyme, alpha-galactosidase. The disease typically presents during childhood or adolescence. First manifestations reflect involvement of small nerve fibres of the peripheral and autonomic nervous systems. With age, severe complications involving the kidneys, heart and brain cause considerable morbidity and premature death. Outside the US, enzyme replacement therapy (ERT) with agalsidase alfa 0.2 mg/kg every other week (EOW) and agalsidase beta 1.0 mg/kg EOW is available for the treatment of patients with Fabry disease, while agalsidase beta 1.0 mg/kg EOW is the only approved drug in the US. To analyse the evidence for ERT, a systematic review of the literature was performed to identify prospectively designed randomized, controlled trials (RCTs) and open-label studies on the efficacy of agalsidase alfa and agalsidase beta. MEDLINE and EMBASE databases were searched; inclusion criteria for the systematic review were prospectively designed clinical studies evaluating ERT with quantifiable endpoints: double-blind and open-label studies were eligible. Exclusion criteria were review articles, case reports, case studies, letters to the editor and articles based on registry data (Fabry Outcome Survey or Fabry Registry). In addition, any studies with a retrospective design or data based on post hoc analyses were excluded. The evidence was reviewed with respect to the clinical benefits of ERT at the level of the end organ. A total of 9 RCTs and 23 open-label studies were identified for inclusion. The efficacy of ERT in Fabry disease has been measured against a variety of endpoints, the majority of which were subclinical parameters rather than clinical outcomes. Plasma levels of GL-3 together with accumulation in the kidney, heart and skin were the most commonly studied endpoints, followed by renal endpoints of proteinuria and glomerular filtration rate, whereas cardiac and neurological endpoints were not commonly studied. To date, only one RCT with ERT defined hard clinical outcomes in the form of cardiac, renal or cerebrovascular events, or death as its primary endpoint. The currently available data from prospective RCTs and open-label studies in patients with Fabry disease are more robust for ERT at a dose of 1 mg/kg EOW than a dose of 0.2 mg/kg EOW, although the beneficial effects of ERT with either dose or preparation are variable.

Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by a deficient activity of the enzyme α-galactosidase A, resulting in a vasculopathic involvement of various organ systems, e.g. cerebral structures. Marked cerebral vasculopathy with subsequent white matter lesions (WML) are a frequent finding in FD patients. Recent studies discussed an association between cerebral white matter changes and sleep-related disturbances of breathing, which may lead to excessive daytime sleepiness (EDS). A 56-year-old Caucasian female FD patient with EDS was admitted to our sleep laboratory. Overnight polysomnography showed a Cheyne-Stokes respiration pattern with significant O2 desaturation. MR imaging revealed confluent WML including the brain stem, but no renal or cardiac involvement. We then evaluated the clinical data of 49 genetically proven FD patients (27 males; mean age 43 years) from our FD centre. With a frequency of 68%, EDS exceeds the prevalence of other common symptoms of FD (angiokeratomas 61%; acroparaesthesia 51%; renal involvement 29%; cardiac involvement 27%), and the prevalence of chronic fatigue (48%). EDS was independently associated with the physical component summary of the SF-36 data (corrected R2 = −0.323, p < 0.001). EDS and age explained a quarter of variance in mental component summary (corrected R2 = −0.253, p < 0.001). We conclude that EDS is a common and underdiagnosed symptom in FD patients, accompanied by a significant impact on quality of life. EDS might be caused by central breathing disorders due to an affection of brain regions associated with respiratory control in FD.

1Department of Nephrology, University Hospital of Lund, Sweden, 2Renal Division, Brigham and Women’s Hospital, Boston, MA, USA, 3Departments of Nephrology and of Human Genetics, Faculty of Medicine, Hospital Sao Joao, Porto, Portugal, 4Department of Nephrology, Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Madrid, Spain, 5Department of Medicine, University of Muenster, Muenster, Germany, 6Medical Department, Haukeland University Hospital and Institute of Medicine, University of Bergen, Bergen, Norway, 7Division of Nephrology, Department of Medicine, University of Wurzburg, Germany, 8Genzyme Corp., Framingham, MA and 9Division of Nephrology, Department of Medicine and Physiology, University of Alabama, Birmingham, AL, USA

Der Morbus Fabry ist eine seltene genetische Erkrankung, bei der es zu einer progressiven Speicherung von Sphingolipiden (Globotriaosylceramid) in den Lysosomen aller Korperzellen kommt. Die Einlagerungen finden in den verschiedensten Organen statt, so dass mehrere Fachgebiete der Medizin in der Diagnostik und Therapie bei Patienten mit Morbus Fabry gefordert sind. Diese Ubersicht stellt exemplarisch die Aufgaben verschiedener Disziplinen (Kardiologie, Nephrologie und Neurologie) dar, deren limitierende Organschadigung den Verlauf der Erkrankung bestimmt. Die in der Diagnostik involvierten Disziplinen (Ophthalmologie und Dermatologie) haben ihre besondere Rolle in der moglichst fruhen Erfassung der betroffenen Patienten. Die derzeitige Herausforderung besteht in der Auswahl der die Enzymersatztherapie begleitenden Supportivmasnahmen.

Background: Cinacalcet, a novel calcimimetic, simultaneously lowers parathyroid hormone (PTH), phosphorus (P), calcium (Ca) and Ca x P in patients who are on dialysis with secondary hyperparathyroidism (sHPT) associated with CKD. Previous studies have required cinacalcct to be administered during the dialysis session and at the same time on non-dialysis days. The aim of the SENSOR study was to demonstrate that cinacalcet given in a more clinically practical manner with the first major meal after dialysis is noninferior to cinacalcet given with food during the dialysis session. Methods: In this open-label study dialysis patients with poorly controlled sHPT (intact PTH (iPTH) > 300 pg/ml) were randomized to receive cinacalcet either daily with their post-dialysis meal (n = 337) or with food during the dialysis session (n = 336). The primary endpoint was the proportions of patients with mean iPTH ≤ 300 pg/ml (≤ 31.8 pmol/l) at Weeks 11 and 13 of a 21 -week treatment period. Secondary endpoints included the proportion of patients with Ca x P < 55 mg 2 /dl 2 (< 4.44 mmol 2 /l 2 ) at Weeks 11 and 13 and patients who discontinued the study due to nausea or vomiting. Results: Comparable proportions of patients in the cinacalcet "during dialysis" and "post-dialysis meal" groups had a mean iPTH ≤ 300 pg/ml (54 vs. 57%, respectively, 95% confidence interval (CI) difference -4, +10%) and Ca x P < 55 mg 2 /dl 2 (78 vs. 73%, respectively, 95% Cl difference - 11, +2%) at Weeks 11 and 13. The groups were also comparable at Week 21. Cinacalcet was well tolerated, with < 3% of patients in both groups discontinuing due to nausea or vomiting. A combined post-hoc analysis of both groups showed the incidence of nausea and vomiting was lower if cinacalcet was administered during the evening. Conclusions: Administering cinacalcet with the first main meal after dialysis was as effective as administration with food during the dialysis session. Cinacalcet was well tolerated. The incidence of gastrointestinal adverse events appeared to be lower when cinacalcet was administered in the evening.

Rare diseases provide the physician with an exciting opportunity to escape from what may be perceived as boring routine. This endeavour, however, may hold dangers, particularly if the physician has never before encountered the disease in real life. All too easily, an open-mind approach is abandoned. From then on, new data will be used in a relentless quest to support a pre-formed diagnosis [1]. To illustrate this common and dangerous mechanism of error, we present the case of a 70-year-old patient with systemic lupus erythematosus with renal impairment and proteinuria, in whom renal biopsy seemed to provide us with a rare and interesting diagnosis.

Current iron supplementation practice in geriatric patients is erratic and lacks evidence-based recommendations. Despite potential benefits in this population, intravenous iron supplementation is often withheld due to concerns regarding pharmacy expense, perceived safety issues, and doubts regarding efficacy in elderly patients. This retrospective, observational cohort study aimed to evaluate the safety and efficacy of intravenous ferric carboxymaltose (FCM, Ferinject) in patients aged >75 years with iron deficiency anaemia (IDA). Within a twelve-month data extraction period, the charts of 405 hospitalised patients aged 65–101 years were retrospectively analysed for IDA, defined according to WHO criteria for anaemia (haemoglobin: n= 5/13.2%). AE incidence was comparable with that observed in patients

Contrast medium-induced nephropathy (CIN) is a serious complication with increasing frequency and an unfavorable prognosis. Previous analyses of surrogate parameters have suggested beneficial effects of hemodialysis that are assessed in this randomized clinical trial. We performed a prospective single-center trial in 424 consecutive patients with serum creatinine concentrations between 1.3- 3.5 mg/dl who underwent elective coronary angiography. Patients were randomized to one of three treatment strategies with all patients receiving pre- and postprocedural hydration: One group received no additional therapy, patients in the second group were hemodialyzed once, and the third group received oral N-acetylcysteine. The frequency of CIN (defined as an increase in serum creatinineor=0.5 mg/dl) from 48 to 72 h after catheterization was 6.1% in the hydration-only group, 15.9% with hemodialysis treatment, and 5.3% in the N-ACC group (intention-to-treat analysis; P=0.008). There were no differences between the treatment groups with regard to increased (or=0.5 mg/dl) serum creatinine concentrations after 30-60 days (4.8%, 5.1%, and 3.1%, respectively; P=0.700). Analyses of long-term follow-up (range 63 to 1316 days) by Cox regressions models of the study groups found quite similar survival rates (P=0.500). In contrast to other (retrospective) studies, long-term survival of patients with vs those without CIN within 72 h was not different, but patients who still had elevated creatinine concentrations at 30-60 days suffered from a markedly higher 2-year mortality (46% vs 17%, P=0.002). In conclusion, hemodialysis in addition to hydration therapy for the prevention of CIN provided no evidence for any outcome benefit but evidence for probable harm. Increased creatinine concentrations at 30-60 days, but not within 72 h, were associated with markedly reduced long-term survival.

We quantified the glomerular expression of thrombospondin-1 (THBS1, also known as TSP-1), transforming growth factor beta 1 (TGFB1, also known as TGF-beta1) and connective tissue growth factor (CTGF) at each stage of diabetic nephropathy. We also examined the roles of THBS1 and CTGF in mediating high-glucose- and glycated-albumin-induced synthesis of the matrix protein, fibronectin, by mesangial cells.THBS1, latent and active TGFB1, and CTGF, were detected by immunohistochemistry and in situ hybridisation in biopsies from 19 insulin-dependent diabetic patients with incipient, manifest and advanced diabetic nephropathy, and in 11 control kidneys. Findings were quantified by image analysis. Human mesangial cells were cultured with normal or high glucose, albumin or glycated albumin (Amadori product), +/-THBS1 or CTGF antisense oligonucleotides, or with peptide W, an inhibitor of TGFB1 bioactivation by THBS1. Proteins were measured by western blot analysis or ELISA.In glomeruli of normal kidneys, mRNA and protein levels for THBS1, latent-TGFB1 and CTGF were low. They were increased in the incipient stage of diabetic nephropathy, predominantly in mesangial areas, with further increases at later stages of the disease. Little or no active TGFB1 immunostaining was detected prior to manifest diabetic nephropathy. In contrast to high-glucose conditions, increases in fibronectin synthesis that were stimulated by glycated albumin were not dependent on THBS1 activation of latent TGFB1. However, increased fibronectin synthesis in both conditions required CTGF.Increased glomerular expression of all three factors occurs from the earliest stage of diabetic nephropathy. In contrast to THBS1, CTGF is required for mesangial synthesis of fibronectin stimulated by high glucose or glycated albumin, and is thus a potential therapeutic target.

PDGF and nitric oxide (NO) have been shown to participate in the progression of several forms of glomerulonephritis. A potential influence of NO on PDGF-mediated signaling cascades was therefore examined. Treatment of rat mesangial cells (MC) with the NO donors diethylenetriamine NO (DETA-NO) or spermine-NONOate resulted in a time- and dose-dependent upregulation of PDGF receptor alpha (PDGFRalpha) but not PDGFRbeta mRNA levels. Administration of DETA-NO also induced PDGFRalpha protein expression that was paralleled also by an enhanced receptor phosphorylation. Further experiments using 3-(5-hydroxymethyl-2-furyl)-1-benzylindazole (YC-1), an activator of the soluble guanylyl cyclase (sGC), the membrane-soluble cyclic GMP (cGMP) analog 8-Bromo-PET-cGMP, and the inhibitors of sGC ODQ and NS2028 suggest that elevated cGMP levels are responsible for the effects of NO. Importantly, NO-dependent autophosphorylation of PDGFRalpha drastically augmented PDGF-AA-evoked phosphorylation of PKB/Akt, a classical downstream target of PDGFRalpha signaling. Furthermore, in a rat model of anti-Thy-1 glomerulonephritis, expression and phosphorylation of PDGFRalpha but not PDGFRbeta expression was markedly reduced in nephritic animals that were treated with the inducible NO synthase inhibitor L-N6(1-iminoethyl)lysine(dihydrochloride) (L-NIL) compared with non-L-NIL-treated nephritic rats as demonstrated by Western blotting and immunohistochemistry. Taken together, the data suggest that NO modulates PDGFRalpha-triggered signaling in a cGMP-dependent manner by induction of PDGFRalpha expression in MC and in a rat model of mesangioproliferative glomerulonephritis. The mechanistic details of this regulation have to be elucidated in further experiments.

Since recent studies demonstrated an impaired outcome after percutaneous coronary interventions (PCI) in patients with chronic renal failure but did not address the aetiology of renal failure, we now analysed the outcome of patients with diabetic nephropathy in 721 consecutive patients undergoing PCI. Diabetic nephropathy was present in 37 patients (5.1%), and diabetes alone in 126 patients (17.5%); 178 patients (24.7%) suffered from renal insufficiency of other causes; the other 380 patients (52.7%) were used as controls. Although angiographic success rates were similar in the subgroups (94–97%), 30-day and long-term mortality after 4 years was significantly higher in patients with diabetic nephropathy (8.1 and 27%, respectively) than in diabetics (1.6 and 8.7%, respectively), patients with renal insufficiency (3.9 and 16.8%, respectively), or controls (2.4 and 5.0%, respectively, each p < 0.001, log-rank test). Treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with a marked decrease in 2-year mortality in patients with diabetic nephropathy (19.4 vs. 33.3%, respectively, p = 0.02, log-rank test).

As a major heparan sulfate proteoglycan (PG) in basement membranes, perlecan has been linked to tumor invasion, metastasis, and angiogenesis. Here we produced epidermal tumors in immunocompromised rats by injection of mouse RT101 tumor cells. Tumor sections stained with species-specific perlecan antibodies, together with immuno-electron microscopy, showed that perlecan distributed around blood vessels was of both host and tumor cell origin. Tumor-derived perlecan was also distributed throughout the tumor matrix. Blood vessels stained with rat-specific PECAM-1 antibody showed their host origin. RT101 cells also expressed two other basement membrane heparan sulfate PGs, agrin and type XVIII collagen. Antisense targeting of perlecan inhibited tumor cell growth in vitro, while exogenous recombinant perlecan, but not heparin, restored the growth of antisense perlecan-expressing cells, suggesting that perlecan core protein, rather than heparan sulfate chains from perlecan, agrin, or type XVIII collagen, regulates tumor cell growth. However, perlecan core protein requirement was not related to fibroblast growth factor-7 binding because RT101 cells were unresponsive to and lacked receptors for this growth factor. In vivo, antisense perlecan-transfected cells generated no tumors, whereas untransfected and vector-transfected cells formed tumors with obvious neovascularization, suggesting that tumor perlecan rather than host perlecan controls tumor growth and angiogenesis.

There is growing evidence that the two small leucine-rich proteoglycans biglycan and decorin regulate the assembly of connective tissues and alter cell behavior during development and pathological processes. In this study, we have used an experimental animal model of unilateral ureteral ligation and mice deficient in either biglycan or decorin. We discovered that pressure-induced injury to the wild-type kidneys led to overexpression of decorin, biglycan, fibrillin-1, and fibrillin-2. In contrast, in biglycan-deficient kidneys the overexpression of fibrillin-1 was markedly attenuated and this was associated with cystic dilatation of Bowman’s capsule and proximal tubules. Notably, we found that in ligated kidneys from decorin-null mice, fibrillin-1 expression was initially enhanced to the same extent as in wild-type animals. However, long-term obstruction resulted in down-regulation of fibrillin-1 and concurrent cystic dilatation of Bowman’s capsule in 33% of kidneys at 5 months after obstruction. In all of the genotypes, no differences in fibrillin-2 expression were observed. These in vivo data correlated with a significant induction of fibrillin-1 expression in renal fibroblasts and mesangial cells by recombinant biglycan and decorin. Our results indicate a novel role for decorin and biglycan during pressure-induced renal injury by stimulating fibrillin-1 expression.

Aims It has recently been proposed that anaemia is an independent risk factor for development of cardiovascular disease in the general population. The impact of anaemia on long-term survival of patients with manifest coronary heart disease (CHD) has not been assessed so far. In this study, we examined the influence of haemoglobin concentrations on the outcome after percutaneous coronary interventions (PCI). Methods and results In a retrospective cohort study, we analysed in-hospital and long-term mortality in all male patients admitted to our institution for elective PCI from 1998 to 1999. In 689 cases, complete follow-up information could be obtained (98.4%). Depending on their baseline haemoglobin, patients were divided in quintiles. In all subgroups, angiographic success after PCI (90–94%) was comparably high and in-hospital mortality was low (0–0.7%). During follow-up (median 697 days), patients in the lowest haemoglobin quintile (≤12.9 g/dl) were significantly more likely to suffer from all-cause death (22.2%) than those of the other quintiles (3.7–12.1%; estimated mortality rates from Kaplan–Meier models, P

BACKGROUND Endothelial function of large arteries is impaired in chronic haemodialysis patients and oxidative stress due to the dialysis procedure has been suggested as a causal factor. However, it is not clear whether different types of dialysis membranes affect endothelial function differently. Therefore we determined endothelium-dependent, flow-mediated dilatation (FMD) of the brachial artery as well as markers of oxidative stress immediately before and after haemodialysis (HD) with either a cellulosic cuprophane or a synthetic polysulphone dialyser in a blinded, randomized, cross-over study. METHODS Twelve haemodialysis patients (age 55+/-3 years, time on dialysis 20+/-2 months, mean fluid change -1782+/-21 ml, systolic/diastolic blood pressure 139/75 mmHg) were included. Using a multi-gate-pulsed Doppler system (echo-tracking device) brachial artery FMD and nitroglycerine-induced, endothelium-independent vasodilatation (NMD) were measured. Patients were randomized to HD with either a polysulphone or a cuprophane membrane and were crossed over to the other filter. Investigators were blinded to the type of membrane used. Serum concentrations of oxidized LDL (oxLDL) and alpha-tocopherol as markers of oxidative stress were measured before and after each dialysis session. RESULTS Data are given as mean+/-SEM. Treatment with polysulphone filter HD did not significantly affect FMD (baseline 9.3+/-2.0% vs after HD 9.6+/-1.8%). After dialysis with a cuprophane membrane FMD decreased from 9.4+/-2.1 to 7.4+/-1.8% (P

In patients after renal transplantation functional arterial vessel wall properties are impaired. Whether 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have a sustained effect on endothelial function and arterial distensibility in patients after renal transplantation is not clear. The authors studied the effects of a long-term therapy with fluvastatin on large artery distensibility and flow-mediated vasodilation (FMD) in hypercholesterolemic patients after renal transplantation in a prospective, blinded, and randomized trial.Twenty-six patients who had undergone renal transplantation were assigned randomly to either fluvastatin, 40 mg/d (n = 13) or placebo (n = 13) and underwent follow-up for 3 years. At baseline and after 6, 12, and 36 months of treatment, carotid and brachial artery distensibility, endothelium-dependent FMD, and nitroglycerine-induced vasodilation (NMD) of the brachial artery were measured by a echo-tracking device.A significant decrease in total and low-density cholesterol was observed after 6, 12, and 36 months in patients treated with fluvastatin but not in the placebo group. FMD increased with fluvastatin from 4.6 +/- 2% to 12.4 +/- 2% after 12 months; this improvement was sustained with 13.4 +/- 3% after 36 months (P0.05). However, placebo did not alter FMD (P0.001 for trend difference between groups by analysis of covariance). Endothelium-independent NMD was similar in both groups at baseline and during therapy. Neither carotid nor brachial artery distensibility coefficients were altered by either treatment.HMG-CoA reductase inhibitor therapy over 3 years results in a significant and sustained improvement of endothelial function in hypercholesterolemic patients after renal transplantation. However, this is not accompanied by a beneficial effect on impaired large artery distensibility even after long-term therapy with fluvastatin.

Background. The pathophysiology leading to pulmonary side effects during haemodialysis and haemodiafiltration is not yet fully understood. Chronic microembolization, which can be demonstrated by pulsed Doppler ultrasound, may be one cause. Methods. The study cohort consisted of 24 long-term dialysis patients undergoing haemodialysis (n = 21) and online-haemodiafiltration (n = 3), respectively. The subclavian vein downstream to the venous access was investigated during different phases of the procedure using a 2-MHz pulsed ultrasound device. Results. In all periods investigated (connection, dialysis, disconnection), numerous microembolic signals (MES) were found in the subclavian vein. The numbers of MES detected during haemodiafiltration (314-709 MES per 10 min) were higher than during haemodialysis (0-81 MES per 10 min). Conclusions. The composition (gaseous or solid) and origin (pump, tubing system or shunt) of the microemboli detected remains unclear. Chronic microembolization may be one cause of pulmonary complications of haemodialysis and haemodiafiltration. The detection method described in this article will help us to better understand this process and to determine what role microemboli might play in pulmonary and central nervous system disorders. It may also help to optimize the devices and techniques used.

Background. Anemia is a common condition in the elderly and a significant risk factor for increased morbidity and mortality, reducing not only functional capacity and mobility but also quality of life. Currently, few data are available regarding anemia in hospitalized geriatric patients. Our retrospective study investigated epidemiology and causes of anemia in 405 hospitalized geriatric patients.Methods. Data analysis was performed using laboratory parameters determined during routine hospital admission procedures (hemoglobin, ferritin, transferrin saturation, C-reactive protein, vitamin B12, folic acid, and creatinine) in addition to medical history and demographics.Results. Anemia affected approximately two-thirds of subjects. Of 386 patients with recorded hemoglobin values, 66.3% were anemic according to WHO criteria, mostly (85.1%) in a mild form. Anemia was primarily due to iron deficiency (65%), frequently due to underlying chronic infection (62.1%), or of mixed etiology involving a combination of chronic disease and iron deficiency, with absolute iron deficiency playing a comparatively minor role.Conclusion. Greater awareness of anemia in the elderly is warranted due to its high prevalence and negative effect on outcomes, hospitalization duration, and mortality. Geriatric patients should be routinely screened for anemia and etiological causes of anemia individually assessed to allow timely initiation of appropriate therapy.

Background : Creatinine is an important clinical laboratory parameter for the evaluation of kidney function. It is essential to determine its concentration in serum of patients suffering from renal insufficiency. During hemodialysis treatment, the measurement of creatinine in the effluent dialysate or ultrafiltrate may give additional information on the efficiency of the extracorporal procedure. Therefore, enzyme sensors with co-immobilized creatinine amidohydrolase, creatine amidinohydrolase and sarcosine oxidase have been used to determine creatinine. Methods : Enzymatically generated hydrogen peroxide has amperometrically been detected at a platinum-working electrode. To exclude electroactive compounds of the sample matrix, which might interfere with the electrochemical measurement, the sensors have additionally been modified by a Nafion membrane. Results : Such sensors showed a linear detection range of 0.06–1.7 mg/dl for creatinine. Diluting the sample with measuring buffer, it has also been possible to measure pathological creatinine concentrations up to 11 mg/dl. A good correlation between creatinine concentrations in serum, dialysate and ultrafiltrate determined by the presented enzyme sensors and those obtained by both, conventional colorimetric Jaffe and enzymatic measurements have been achieved. Conclusion : Further developments will aim at the integration of this measuring principle into the concept to low-cost disposable planar sensors.

Background. Disturbances of functional properties of large arteries contribute to increased cardiovascular morbidity and mortality in patients with end-stage renal disease. However, it is not clear whether haemodialysis per se acutely affects mechanical vessel wall properties or endothelial function. Methods. Twenty-five chronic haemodialysis patients (mean ± standard error of the mean (SEM): age 52 ± 5 years; time on dialysis 63 ± 7 months; blood pressure 132 ± 4/72 ± 2 mmHg) were studied before and immediately after a haemodialysis (HD) session using a polysulphone dialyser (ultrafiltration 1460 ± 54 ml), as well as on the following day. Blood pressure was measured with an automatic sphygmomanometer and applanation tonometry. End-diastolic diameter and distension of the brachial and carotid arteries were measured by Doppler frequency analysis of vessel wall movements in M-mode using a multigate pulsed Doppler system and aortic pulse wave velocity (PWV) by an automatic device (Complior®). Endothelial function was determined as brachial artery flow-mediated dilation (FMD) and compared with endothelium-independent t nitroglycerine-induced dilation (NMD). Results. FMD was 7.9 ± 1.8% in patients before HD and did not change significantly after HD or in the dialysis-free intervall (6.7 ± 2.1 and 7.1 ± 2.0%, respectively; NS). The same was true for NMD and PWV (12.6 ± 0.8 m/s before HD, 12.8 ± 0.8 m/s after HD, and 11.9 ± 0.7 m/s on the HD-free day). Carotid distensibility coefficients decreased significantly during HD (from 18.1 ± 1.9 × 10 -3 /kPa to 16.7 ± 2.2 × 10 3 /kPa, P

Objective: Percutaneous transluminal coronary angioplasty (PTCA) in patients on maintenance hemodialysis leads to high rates of restenosis and postinterventional complications. The additional influence of diabetes mellitus on the results of PTCA in patients with diabetic nephropathy and reduced but sufficient renal function has not been investigated before. Methods: In a retrospective case-control study, 51 patients with reduced renal function were compared to 71 matched controls. Patients with elevated creatinine values were divided in two subgroups: diabetic nephropathy (diabetes, n = 15) and stable renal insufficiency (renal failure, n = 36). Results: The control group had normal renal function (creatinine: 1.0 ± 0.01) and a mean survival time of 3.6 ± 0.8 years. Patients with renal failure showed a mean survival time of 2.7 ± 0.3 years (p < 0.001), creatinine values of 2.0 ± 0.2 and elevated fibrinogen values of 401 ± 28 (p < 0.01). Patients with diabetes (creatinine: 2.2 ± 0.2) had a significantly higher mortality rate with a reduced mean survival time of 1.25 ± 0.3 years (p < 0.001), postinterventional acute renal failure (n = 2, p < 0.01) and Re-PTCA (n = 2, p < 0.05). Discussion: Patients with reduced but stable renal function showed a higher mortality than comparable patients from the control group. The group of patients with diabetic nephropathy has a poor prognosis after PTCA even though renal function was only moderately reduced.

Small proteoglycans of normal adult human kidney: Distinct expression patterns of decorin, biglycan, fibromodulin, and lumican. Background Among the members of the small leucine-rich proteoglycan family, decorin, biglycan, and fibromodulin have been proposed to be potent modulators of transforming growth factor-β (TGF-β) activity, thereby playing an important role in the pathogenesis of fibrotic kidney diseases. Furthermore, decorin expression influences the expression of p21 WAF1/CIP1 , which has been related to kidney hypertrophy and hyperplasia. However, none of the members of this proteoglycan family have been investigated in normal adult human kidney cortex, thus making it impossible to correlate disease-mediated alterations of their expression with the normal situation in vivo. Methods The chondroitin/dermatan sulfate proteoglycans, decorin and biglycan, and the keratan sulfate proteoglycans, fibromodulin and lumican, were investigated in normal human adult renal cortex by immunohistochemistry on the light and electron microscopic level and by in situ hybridization. Northern blot and reverse transcription-polymerase chain reaction (RT-PCR) methods were used to get an estimate of their expression in isolated glomeruli. Decorin excretion with the urine was measured by Western blotting. Results Two bands of decorin and a single band of biglycan mRNA were identified in Northern blots of isolated glomeruli. Amplification by RT-PCR was required to detect the signals for fibromodulin and lumican. All four proteoglycans were preferentially expressed in the renal interstitium with accumulations around tubules. Weak expression was found in the mesangial matrix. Biglycan was expressed by glomerular endothelial cells and, together with fibromodulin, was synthesized and deposited in distal tubular cells and collecting ducts. Immunogold labeling indicated the presence of the proteoglycans in the glomerular basement membrane, which was interpreted as a result of glomerular filtration. Indirect evidence suggested tubular reuptake of decorin after glomerular filtration. Conclusion The data indicate that the different cells of the adult human kidney are characterized by a distinct expression pattern of the four small proteoglycans. It is suggested that these proteoglycans may have distinct pathophysiological roles depending upon whether they are expressed by mesangial cells, endothelial cells, epithelial cells, or cells of the tubulointerstitium.

Effects of bicarbonate- and lactate-buffered replacement fluids on cardiovascular outcome in CVVH patients.BackgroundBicarbonate-buffered replacement fluid (RF-bic) in continuous venovenous hemofiltration (CVVH) may be superior to lactate-buffered replacement fluid (RF-lac) in acute renal failure. In an open, randomized, multicenter study, we investigated the effects of RF-bic and RF-lac on cardiovascular outcome in patients requiring CVVH following acute renal failure.MethodsOne hundred seventeen patients between the age of 18 and 80 years were randomized to CVVH either with RF-bic (N = 61) or RF-lac (N = 56). Patients were treated with CVVH for five days or until either renal function was restored or the patient was removed from the study. Data were analyzed on day 5 or according to the “last observation carried forward” (LOCF) option. Adverse events were classified according to the WHO-Adverse Reaction Terminology system.ResultsBlood lactate levels were significantly lower and blood bicarbonate levels were significantly higher in patients treated with RF-bic than in those treated with RF-lac (lactate, 17.4 ± 8.5 vs. 28.7 ± 10.4 mg/dL, P < 0.05; bicarbonate, 23.7 ± 0.4 vs. 21.8 ± 0.5 mmol/L, P < 0.01). The number of hypotensive crises was lower in RF-bic–treated patients than in RF-lac–treated patients (RF-bic 14 out of 61 patients, RF-lac in 29 out of 56 patients; 0.26 ± 0.09 vs. 0.60 ± 0.31 episodes per 24 h, P < 0.05). Nine out of 61 patients (15%) treated with RF-bic and 21 out of 56 patients (38%) treated with RF-lac developed cardiovascular events during CVVH therapy (P < 0.01). A multiple regression analysis showed that the occurrence of cardiovascular events was dependent on replacement fluid and previous cardiovascular disease and not on age or blood pressure. Patients with cardiac failure died less frequently in the group treated with RF-bic (7 out of 24, 29%) than in the group treated with RF-lac (12 out of 21, 57%, P = 0.058). In patients with septic shock, lethality was comparable in both groups (RF-bic, 10 out of 27, 37%; RF-lac, 7 out of 20, 35%, P = NS).ConclusionsThe results show that the administration of RF-bic solution was superior in normalizing acidosis of patients without the risk of alkalosis. The data also suggest that the use of RF-bic during CVVH reduces cardiovascular events in critically ill patients with acute renal failure, particularly those with previous cardiovascular disease or heart failure.

Die Inzidenz des akuten Nierenversagens (ANV) im Bereich der Intensivmedizin hat in den letzten Jahrzehnten deutlich zugenommen. Das Auftreten eines ANV bei Intensivpatienten gilt prognostisch als ungunstig. So liegt die Letalitat bei Multiorganversagen mit ANV bei 50 bis 90%. Hinsichtlich der extrakorporalen Nierenersatztherapie haben zahlreiche Verfahren Eingang in die Intensivmedizin gefunden, wobei man im Prinzip mit den allermeisten Techniken bei korrekter Indikationsstellung und sachkundiger Handhabung einen adaquaten Ersatz der exkretorischen Nierenfunktion gewahrleisten kann: So bestechend einfach die arteriovenosen Verfahren (CAVH und CAVHD) auch sein mogen, so wurden sie doch in den letzten Jahren wegen ihrer geringen Effektivitat zugunsten venovenoser, pumpengestutzter Techniken (CVVH und CVVHD) weitgehend verlassen. Dagegen besteht im Schrifttum keine Einigkeit daruber, ob die kontinuierlichen den intermittierenden Nierenersatzverfahren uberlegen sind. In praxi werden heute bei Patienten mit Oligurie und Kreislaufinsuffizienz zumeist kontinuierliche Verfahren eingesetzt. Basierend auf der derzeitigen Datenlage ware es aber durchaus auch vertretbar, mittels taglicher, prolongierter (intermittierender) Hamodialyse zu behandeln. Entscheidend fur das Outcome ist hochstwahrscheinlich allein die quantitativ ausreichende Entgiftung (Filtration von 36 bis 48 l/24 h oder tagliche Hamodialyse mit einer Dauer von 3 bis 4 h; Ziel-BUN unter 50 mg/dl), weniger das angewandte Verfahren selbst. Ferner gibt es gute Hinweise dafur, das die Verwendung von Filtern bzw. Dialysatoren mit biokompatiblen Membranmaterialien (keine Komplement- und Leukozytenaktivierung) anzustreben ist und das bei grosvolumiger Hamofiltration bicarbonathaltige Substitutionslosungen bevorzugt werden sollten. Die extrakorporale Nierenersatztherapie im Rahmen der Intensivmedizin hat sich in den letzten Jahren erheblich fortentwickelt. An dieser Stelle sollte es jedoch nicht versamt werden, auf die eminente Bedeutung der betreuenden Arzte und des Pflegepersonals hinzuweisen, deren “kontinuierliches” Engagement eine unabdingbare Voraussetzung fur eine erfolgreiche extrakorporale Nierenersatztherapie darstellt.

Die Beitrage der Rubrik „Weiterbildung“ sollen dem Wissensstand der Facharztprufung fur den Urologen entsprechen und zugleich dem Facharzt als Repetitorium dienen. Die Rubrik beschrankt sich auf gesicherte Aussagen zum Thema.

Hypochromic red blood cells and reticulocytes. The management of recombinant human erythropoietin (rHuEPO) treatment in hemodialysis patients requires close monitoring of iron status, because the pharmacologically stimulated erythropoiesis is particularly dependent on a continuous supply of iron. Parameters commonly measured to assess iron status are serum ferritin and the transferrin saturation. Both are indirect measures of iron availability for hemoglobin synthesis and frequently do not permit an assessment of the adequacy of iron supply to the erythron. Using flow cytometry, cell volume and hemoglobin concentration can be measured in individual red blood cells and reticulocytes. Based on these techniques, two parameters have proved to be particularly useful in identifying iron-deficient erythropoiesis. (a) The percentage of hypochromic erythrocytes (defined as red blood cells with a hemoglobin concentration of less than 28g/dl) has been shown to detect insufficient marrow iron supply with a fairly good accuracy. (b) More recently, determination of the content of hemoglobin in reticulocytes (CHr) has been suggested by a number of authors to be even more sensitive in detecting iron-deficient erythropoiesis. For those who have access to an H*3 hematology analyzer, both indices can be determined at the time of a routine blood count at a minimal incremental cost.

independent cardiac hypertrophy in mice with cardiomyocyterestricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A. J Clin Invest 2003; 111: 1399–1407 8. Dvorak P, Kramer HJ, Backer A et al. Blockade of endothelin receptors attenuates end-organ damage in homozygous hypertensive ren-2 transgenic rats. Kidney Blood Press Res 2004; 27: 248–258 9. Gupta S, Young D, Sen S. Inhibition of NF-kB induces regression of cardiac hypertrophy, independent of blood pressure control, in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 2005; 289: H20–H29 10. Schmieder RE, Messerli FH, Garavaglia GE, Nunez BD. Dietary salt intake. A determinant of cardiac involvement in essential hypertension. Circulation 1988; 78: 951–956 11. Kupari M, Koskinen P, Virolainen J. Correlates of left ventricular mass in a population sample aged 36 to 37 years. Focus on lifestyle and salt intake. Circulation 1994; 89: 1041–1050 12. Safar ME, Thuilliez C, Richard V, Benetos A. Pressureindependent contribution of sodium on large artery structure and function in hypertension. Cardiovasc Res 2000; 46: 269–276 13. Morgan T, Brunner H, Aubert J et al. Cardiac hypertrophy depends upon sleep blood pressure: A study in rats. J Hypertens 2000; 18: 445–451 14. Yuan B, Leenen F. Dietary sodium intake and left ventricular hypertrophy in nomotensive rats. Am J Physiol 1991; 261: H1397–H1401 15. Wang Q, Hummler E, Nussberger J et al. Blood pressure, cardiac and renal responses to salt and DOCA in mice: role of renin genes. J Am Soc Nephrol 2002; 13: 1509–1516 16. Wang Q, Burnier M. Sodium modulates the mineralocorticoidinduced cardiac and renal hypertrophy independently of blood pressure in one-renin gene mice. J Hypertension 2004; 22 [Suppl. 1]: S10 (abstract) 17. Wang Q, Clement S, Gabbiani G et al. Chronic hyperaldosteronism in a transgenic mouse model fails to induce cardiac remodelling and fibrosis under normal salt diet. Am J Physiol 2004; 286: F1178–F1184 18. Wang Q, Domenighetti A, Pedrazzini T, Burnier M. Potassium supplementation reduces cardiac and renal hypertrophy independent of blood pressure in DOCA/salt mice. Hypertension 2005; 46: 547–554 19. Evans SJ, Levi AJ, Jones JV. Low magnesium enhances the proarrhythmic effect of low potassium in the hypertrophied rat heart but not in the normal rat heart. J Hypertens 1996; 14: 635–44 20. Wang Q, Burnier M. What is the normal blood pressure in onerenin gene deoxycorticosterone – acetate/salt mice with cardiac hypertrophy? J Hypertens 2007, in press (abstract)

Decorin, biglycan and their endocytosis receptor in rat renal cortex. Background Among the small proteoglycans, biglycan and decorin have been proposed to be potent modulators of TGF-β-mediated inflammatory kidney diseases. They were considered to become induced during glomerulonephritis and to subsequently inactivate the cytokine. Methods Decorin and biglycan as well as their endocytosis receptor were investigated in normal rat renal cortex, in anti-Thy-1 glomerulonephritis, in polycystic kidneys, in the remnant kidney following 5/6-nephrectomy, and in kidneys from the Milan normotensive strain by immunohistochemistry and in situ hybridization. Northern blots were used for the detection of mRNA expression for decorin and biglycan in isolated glomeruli. Functional aspects of the endocytosis of decorin and biglycan were studied in cultured mesangial cells. Results In the normal adult rat kidney decorin was expressed preferentially by Bowman's capsule and by interstitial connective tissue cells, but only in trace amounts by mesangial cells. In contrast, biglycan was found in tubular epithelial cells, in association with glomerular capillaries, podocytes and occasionally in the mesangium. In the tubulointerstitium of diseased kidneys (polycystic kidneys, 5/6-nephrectomy, kidneys from the Milan normotensive strain) there was a general up-regulation of decorin expression, while biglycan was localized only in distinct foci of fibrotic lesions. Glomerulosclerosis (5/6-nephrectomy, Milan normotensive strain) was associated with an increased staining for both decorin and biglycan within glomeruli. However, even in the anti-Thy-1 model of an acute mesangioproliferative glomerulonephritis where the greatest accumulation of decorin was found there was only a slight enhancement of decorin mRNA in isolated glomeruli. Decorin and biglycan become degraded upon receptor-mediated endocytosis. Immunohistochemical investigations indicated that the pattern of expression of the receptor protein correlated well with the immunolocalization of both decorin and biglycan. In vitro experiments with cultured mesangial cells provided direct evidence for the expression of the receptor and for the cell's capability to endocytose decorin as well as biglycan. Conclusions Decorin and biglycan are characterized by a distinct expression pattern in the normal rat kidney, whereas the presence of their endocytosis receptor protein correlates with the expression of both proteoglycans. Decorin is almost completely absent in the normal mesangium. Both proteoglycans become up-regulated in various models of renal disease. The mesangial accumulation of decorin in the anti-Thy-1 glomerulonephritis that is observed in spite of the only slightly enhanced mRNA expression could result from decreased decorin turnover and/or increased mesangial retention.

The obese Zucker rat represents a model of obesity combined with insulin resistance and hyperlipidaemia, which over a period of several months develops spontaneous glomerulosclerosis. The present study addressed the question as to whether glomerular sclerosis was associated with alterations in the degradation of matrix components. In the early phase (up to 6 months) glomeruli from obese rats displayed increased total collagen content (+ 64 %) and decreased gelatinolytic activity (− 34 %) as compared to lean control animals. This decline in glomerular gelatinolytic activity was due to a reduction in gelatinase B [matrix metalloproteinase (MMP)-9]. Glomerular MMP-9 mRNA was reduced 4.6 ± 0.6-fold (n = 3; p < 0.05), MMP-9 protein was not detectable by Western blotting and MMP-9 activity was considerably suppressed in gelatin zymograms. MMP-2, in terms of mRNA expression and activity, was unchanged. Tissue inhibitor of metalloproteinases (TIMP)-1 mRNA expression, TIMP-1 protein (immunohistochemistry) and TIMP-1 activity (reverse zymography) were enhanced in glomeruli from obese rats, while TIMP-2 mRNA remained unchanged. Moreover, mRNA for the α1 IV collagen chain was 2.1 ± 0.8-fold higher in glomeruli isolated from obese animals (n = 3; p < 0.05). These findings indicate that matrix expansion in glomeruli from obese Zucker rats is due to both enhanced synthesis of matrix components as well as reduced degradation by matrix metalloproteinases. Apparently the latter effect is based on a reduction in MMP-9 and up-regulation of its inhibitor TIMP-1. [Diabetologia (1997) 40: 1035–1043]

Tubular gelatinase A (MMP-2) and its tissue inhibitors in polycystic kidney disease in the Han:SPRD rat. Thickening of the tubular basement membrane is one of the hallmarks of polycystic kidney disease (PKD). The present study was conducted to investigate the potential role of the matrix metalloproteinase-2 (MMP-2) and its specific tissue inhibitors (TIMP-1 and TIMP-2) in the accumulation of matrix components in PKD. As a model of PKD, two-month-old heterozygous Han:SPRD rats, which are at an early stage of cystogenesis, were used. MMP-2, but not MMP-9 (gelatinase B) nor MMP-3 (stromelysin) could be detected in proximal tubules of the normal rat kidney. The presence of the inhibitors TIMP-1 and TIMP-2 was confirmed on the mRNA level. In tubules from PKD rats MMP-2 activity was lower (31 ± 8 vs. 58 ± 7 U/prep., N = 9, P < 0.05), mRNA of MMP-2 was reduced 4.2 ± 0.6-fold (N = 4, P < 0.05) and enzyme protein was depressed 3.8 ± 0.8-fold (N = 4, P < 0.05). By contrast, TIMP-1 mRNA was 9.0 ± 1.1-fold and TIMP-2 mRNA 3.8 ± 0.7-fold (N = 4, P < 0.05) elevated over controls. Cyst fluid from homozygous rats contained MMP-2 protein and activity. These findings indicate that tubular MMP-2 activity is reduced in PKD, due to down-regulation of MMP-2, up-regulation of TIMP-1 and TIMP-2, and luminal secretion of the enzyme. It is conceivable that these alterations relate to the enhanced matrix accumulation observed in the evolution of PKD.

The effects of cyclosporin A on the activities of lysosomal cysteine proteinases (cathepsin B, H, L+B) in LLC-Pk1 cells were investigated to elucidate their potential role in cyclosporin A-induced nephrotoxicity. Cyclosporin A at lower doses (0.1--1,000 ng/ml) stimulated cathepsin B, H, L+B. In contrast, at a higher dose (10,000 ng/ml), it inhibited these proteinase activities associated with a reduction in protein degradation. In line with the altered proteinase activities, cellular protein content was decreased at the lower dose (10 ng/ml) and increased at the higher dose. The higher dose of cyclosporin A also enhanced cellular lipid peroxide content after an exposure of 4 and 10 h. Co-incubation with superoxide dismutase (40 U/ml) did not ameliorate the inhibition of cathepsin B activity induced by the high dose of cyclosporin A. On the contrary, the calcium channel blocker verapamil (10(-6) M) prevented this inhibition. In conclusion, cyclosporin A exerts a dose-dependent biphasic effect on lysosomal cysteine proteinase activities. A rise in cytosolic Ca2+ concentration, but not an enhanced lipid peroxidation, may be involved in the suppression of cathepsin B activity induced by the higher dose of cyclosporin A. These studies raise the possibility that alterations of tubular proteinase activity may play a role in the cyclosporin A-induced nephrotoxicity.

Bone marrow iron supply may become rate limiting for hemoglobin synthesis during rhEPO-stimulated erythropoiesis. In the present study we followed the occurrence of hemoglobin-deficient red cells as a parameter of iron-deficient erythropoiesis in rhEPO-treated dialysis patients. rhEPO-treated patients with iron overload displayed very low numbers of hypochromic red cells (1%), while those with iron-deficiency had a hypochromic subpopulation of 22% (normal range < 2.5% of circulating red cells). Prior to rhEPO treatment, 10 dialysis patients showed normal numbers of hypochromic red cells (2.1%), despite mild iron deficiency (transferrin saturation: 17%). Once rhEPO (150 U/kg/week) was started, the percentage of hypochromic red cells rose significantly to 15.3% within 4 weeks of therapy. This was readily reversed when intravenous iron (750 mg/4 weeks) was added to the therapeutic regimen (5.5% after 4 weeks of i.v. iron). Taken together, quantitative red cell analysis seems to be a reliable tool to detect iron-deficient erythropoiesis in rhEPO-treated dialysis patients.

IDDM is associated with an increase in kidney size, which is due to cellular hypertrophy and progressive matrix accumulation within the glomerulus and throughout the tubulo-interstitium. The present study addressed the potential role of cysteine and metalloproteinases in renal hypertrophy of short-term diabetes. Three weeks after induction of streptozotocin diabetes in rats, intraglomerular gelatinase activity (streptozotocin: 23 +/- 4 vs control: 44 +/- 3 mU/microgram DNA) and cathepsin L+B activity (streptozotocin: 6.7 +/- 0.8 vs control: 9.3 +/- 0.7 U/microgram DNA) were significantly decreased. Insulin treatment completely prevented the decline in glomerular proteinase activity (gelatinase: 37 +/- 6 mU/microgram DNA; cathepsin L+B: 9.6 +/- 0.9 U/microgram DNA). In isolated proximal tubules a similar pattern of enzyme activity could be observed. Three weeks of diabetes caused a significant decline in cathepsin L+B activity (streptozotocin: 28 +/- 2 vs control: 37 +/- 3 U/microgram DNA). Insulin treatment again prevented the decline in these tubular proteinase activities. In parallel, kidney weight increased by 22% and glomerular protein/DNA ratio rose by 17% in untreated diabetic rats. Diabetic rats receiving insulin displayed a normal glomerular protein/DNA ratio and the kidney weight was increased by only 5%. These results show that renal hypertrophy of early diabetes is closely associated with a decline in both glomerular and tubular proteinase activity. Adequate insulin substitution prevented renal hypertrophy and the reduction in proteinase activity.

Background. Access-related problems are one of the major causes of morbidity in elderly patients with chronic kidney disease. The aim of this study was to assess potential risks and benefits in elderly patients comparing forearm arteriovenous fistula (AVF) and perforating vein AVF below the elbow for primary vascular access. Methods. A retrospective comparison of elderly patients (65.7 6 9.3 years, 70.4% male patients, 36.2% late referral) undergoing primary vascular access surgery using forearm AVF (n ¼ 50) and perforating vein AVF (n ¼ 55) was performed over a 2-year period, including a multivariate analysis of potential risk factors and benefits of primary patency (PP ¼ intervention-free access survival) and secondary patency (SP ¼ access survival until abandonment). Results. Patency rates after 24 months were significantly higher in patients with perforating vein AVF (PP 1 SP: 78.2%) compared to forearm AVF (PP: 62%, SP: 56%, P ¼ 0.04). Presence of diabetes mellitus in patients with forearm AVF was associated with a decreased PP [odds ratio (OR): 3.6, 95% confidence interval (CI): 0.9–13.8] and SP (OR: 4.8, 95% CI: 1.3–17.9), and arterial hypertension was associated with a lower PP (OR: 6.7, 95% CI: 0.8–53.9), whereas the presence of hyperparathyroidism was associated with higher PP and SP (OR: 0.2, 95% CI: 0.1–0.7). In contrast, PP and SP in patients with perforating vein AVF were not influenced by comorbidities. Conclusions. Perforating vein AVF is superior to forearm AVF in elderly patients with diabetes and arterial hypertension due to the proximal fistula location, probably caused by an improved artery distensibility during fistula maturation.

ESRD is a major cause of morbidity and premature mortality in Fabry disease, particularly in classically affected males. The decline of renal function in Fabry nephropathy is adversely affected by male gender, advanced chronic kidney disease (CKD), and severe proteinuria. The diagnosis of Fabry nephropathy may be missed if not specifically addressed in progressive CKD and patients have been first identified in screening programs of dialysis patients. Fabry patients have worse 3-year survival rates on dialysis as compared with nondiabetic controls. The 5-year survival rate of transplanted Fabry patients is also lower than that of controls. However, because Fabry nephropathy does not recur in the allograft and transplanted Fabry patients appear to have better overall outcomes than those maintained on dialysis, kidney transplantation should be recommended as a first choice in renal replacement therapy (RRT) for Fabry disease. Appropriately designed and powered studies are not available to answer the question whether enzyme replacement therapy (ERT) influences outcomes, the course of cardiomyopathy, events, or survival in Fabry patients on RRT. The authors are not aware of compelling indications for ERT in RRT patients because progression of cardiomyopathy was documented during ERT. Whether the excess mortality risk of Fabry patients on RRT can be prevented by ERT is unknown. Despite observational reports of symptomatic improvement, the available evidence supporting ERT for such patients is not compelling enough. To clarify this issue, studies are needed to test the effectiveness of agalsidases in preventing cardiac and cerebrovascular complications in Fabry patients with ESRD.

Improvements in B lymphocyte function have been reported in hemodialysis patients receiving erythropoietin. The present investigation studied whether erythropoietin interferes with B cell function and the mechanisms of this effect. Antibody production by cultured peripheral blood mononuclear cells (PBMC) (7 days) from 15 dialysis patients before and during erythropoietin treatment and from 14 healthy controls was followed. IgG and IgA were formed less in the uremic group than in healthy subjects. After 8 weeks of erythropoietin (hematocrit rose from 19 to 31%) basal IgG formation by PBMC rose from 304 +/- 83 to 566 +/- 49 ng/ml (p less than 0.02), while IgA production rose from 380 +/- 121 to 563 +/- 362 ng/ml (p less than 0.01). IgM production, which appeared to be normal in uremia, remained unchanged during erythropoietin treatment. Production of IgG and IgA stimulated by pokeweed-mitogen was subnormal in uremia, but improved under erythropoietin therapy. To establish whether erythropoietin acted by itself or through correction of the renal anemia, healthy PBMC were directly incubated with 2 U/ml of erythropoietin. Under these conditions production of IgG (+19%), IgA (+28%), and IgM (+32%) was enhanced. Taken together these data indicate a direct stimulant effect of erythropoietin on B lymphocytes in end-stage renal failure.

Adriamycin (ADR)-induced nephropathy is characterized by focal and segmental glomerulosclerosis and is supposed to be an ideal model of chronic progressive renal disease. The aim of our study was to investigate whether there might be an altered activity of glomerular proteinases in ADR nephropathy, thereby aggravating glomerular protein accumulation as an important initiating hallmark of glomerulosclerosis. In fact, we could demonstrate significantly enhanced levels of intraglomerular protein and DNA content in the experimental animals at week 7, 12 and 22 after administration of ADR. When relating intraglomerular proteinase activity, which was measured in ultrasonically destroyed isolated glomeruli, obtained by differential sieving techniques, to the intraglomerular protein and DNA content, this enzyme activity was significantly reduced throughout the observation period. Based on these data, we suggest that this relatively decreased proteinase activity in glomeruli exposed to ADR might play a pathogenetic role in the development of glomerular hypertrophy, an important harbinger of glomerulosclerosis.

In this study we investigated the effect of volume expansion on plasma and atrial concentrations of atrial natriuretic peptide (ANP) in the presence and absence of the parathyroid gland and under normocalcemic and hypocalcemic conditions. After volume expansion ANP concentration in plasma was significantly (p0.001) higher in intact (702 +/- 86 pg/ml) than in hypocalcemic parathyroidectomized (PTX) (271 +/- 38 pg/ml) rats. Plasma ANP of PTX rats rendered normocalcemic with oral calcium supplementation increased to 402 +/- 85 pg/ml after volume expansion. Results from this study suggest that parathyroid hormone (PTH) is required for augmented ANP secretion in response to acute volume loading and alterations of extracellular calcium may modulate volume-induced ANP release in PTX rats. We would discuss that a parathyroid gland-cardiac atria interaction exists and that changes in serum level of PTH may play a role in the regulation of fluid homeostasis via ANP secretion.

Purpose: To evaluate the influence of different membrane materials on the efficiency of iopromide elimination. Material and Methods: Twenty stable patients with chronic renal failure after coronary angiography were investigated for contrast medium elimination during hemodialysis directly after contrast medium application. Results: Clearance during hemodialysis with cuprophan membranes was 102±7 mg/ml in contrast to 153±4 mg/ml in polysulfone membranes. Elimination half-time was 94±5 min in cuprophan and 79±3 min in polysulfone membranes, and the elimination rate after 120 min was 59±2% and 66±1.5%, respectively. Plasma clearance of iopromide was elevated in polysulfone membranes (188±17 ml/min); however, not significantly different to cuprophane membranes (153±11 ml/min). Accordingly, 24-h urinary iopromide excretion was reduced to 26±4 g/24 h vs. 32±7 g/24 h. Conclusion: Hemodialysis for iopromide elimination with polysulfone membranes is more effective than with cuprophan membranes.

Fabry disease is a rare X-linked storage disorder leading to an accumulation of globotriaosylceramides in all cells carrying lysosomes. As the accumulation occurs in most organs, different medical specialties are involved in the diagnostics and therapy of Fabry disease. With this review of the 3 main specialties (cardiology, nephrology, and neurology) and, in addition, the adjacent specialties (ophthalmology and dermatology), we aim to discuss the division-related responsibilities and want to suggest an organ-related additional therapy besides enzyme replacement therapy.

The role of endogenous inducers of inflammation is poorly understood. To produce the proinflammatory master cytokine interleukin (IL)-1beta, macrophages need double stimulation with ligands to both Toll-like receptors (TLRs) for IL-1beta gene transcription and nucleotide-binding oligomerization domain-like receptors for activation of the inflammasome. It is particularly intriguing to define how this complex regulation is mediated in the absence of an infectious trigger. Biglycan, a ubiquitous leucine-rich repeat proteoglycan of the extracellular matrix, interacts with TLR2/4 on macrophages. The objective of this study was to define the role of biglycan in the synthesis and activation of IL-1beta. Here we show that in macrophages, soluble biglycan induces the NLRP3/ASC inflammasome, activating caspase-1 and releasing mature IL-1beta without the need for additional costimulatory factors. This is brought about by the interaction of biglycan with TLR2/4 and purinergic P2X(4)/P2X(7) receptors, which induces receptor cooperativity. Furthermore, reactive oxygen species formation is involved in biglycan-mediated activation of the inflammasome. By signaling through TLR2/4, biglycan stimulates the expression of NLRP3 and pro-IL-1beta mRNA. Both in a model of non-infectious inflammatory renal injury (unilateral ureteral obstruction) and in lipopolysaccharide-induced sepsis, biglycan-deficient mice displayed lower levels of active caspase-1 and mature IL-1beta in the kidney, lung, and circulation. Our results provide evidence for direct activation of the NLRP3 inflammasome by biglycan and describe a fundamental paradigm of how tissue stress or injury is monitored by innate immune receptors detecting the release of the extracellular matrix components and turning such a signal into a robust inflammatory response.