Egbert G. Schulz

The eNOS 786C/T polymorphism in cardiac surgical patients with cardiopulmonary bypass is associated with renal dysfunction

OBJECTIVE Renal dysfunction is one of the most serious complications following cardiac surgery with cardiopulmonary bypass. The causes of renal dysfunction following cardiac surgery are poorly understood. We hypothesised that T-786C endothelial NO synthase (eNOS) polymorphism may lead to an increase in the occurrence of postoperative renal dysfunction following cardiac surgery with cardiopulmonary bypass. METHODS A total of 497 patients undergoing cardiac surgery with cardiopulmonary bypass were included in the study. The T-786C eNOS polymorphism was detected by a polymerase chain reaction. The patients were grouped on the basis of whether they were homozygous or heterozygous for the C allele (TC+CC; n=289) or only homozygous for the T allele (TT; n=208). RESULTS No significance was demonstrated in the preoperative risk factors, with the exclusion of smoking habits (p=0.04) for the C-allele carrier. The administration of anti-lipid agents (p=0.01) and anti-arrhythmics (p=0.01) was significantly lower in the TC/CC group. The TC+CC genotype group had a significantly greater decrease in creatine clearance (p=0.024), the lowest creatine clearance (p=0.004) and more C-allele carriers received acute renal replacement therapy (p=0.04). The usage of norepinephrine (p=0.02) and dobutamine (p=0.02) was significantly higher in C-allele carriers. In the TC+CC genotype group, cross-clamp time (p=0.02) and administration of red cell transfusion (p=0.04) achieved statistically significant difference. The overall in-hospital mortality rate was 8.2% for all patients and was not significant between genotypes. CONCLUSIONS The present findings support the hypothesis that the T-786C eNOS polymorphism may play a role in the development of renal dysfunction and increase the occurrence of renal replacement therapy following cardiac surgery with cardiopulmonary bypass. This polymorphism may be useful in stratifying the risk for the development of postoperative renal dysfunction.

Lipoprotein apheresis – More than just cholesterol reduction?

Lipoprotein apheresis is a well-established extracorporeal treatment in modality of severe hyperlipoproteinemia. Besides the reduction of LDL cholesterol and modifications to physiology of lipoprotein and lipid metabolism, Lipoprotein apheresis may have crucial effects on many other atherogenic factors as vascular inflammation, rheology and gene expressions in blood cells. These different effects of lipoprotein apheresis treatments are reviewed with respect to oxidative stress in plasma, red and white blood cells and in consequence to progression of atherosclerosis. However, in consideration of these reviewed aspects as a factor of biocompatibility lipoprotein apheresis remains safe.

Impact of endothelin-1 Lys198Asn polymorphism on coronary artery disease and endorgan damage in hypertensives.

ObjectiveEndothelin is the most potent endogenous vasoconstrictor and is involved in several vascular disorders such as arterial hypertension. Its intense interaction with other vasoactive hormone systems revealed the consideration about the endothelin gene as an interesting candidate for influencing the development of essential hypertension and hypertensive endorgan damage. The purpose of this study was to investigate the role of endothelin-1 Lys198Asn polymorphism in patients with severe arterial hypertension as well as associated endorgan damages. MethodsIn 400 hypertensive patients and 150 normotensive controls we examined the endothelin-1 Lys198Asn polymorphism by DNA sequencing and patients were divided according to their genotype (GG, GT, and TT). Moreover, the frequency of endothelin-1 Lys198Asn polymorphism was investigated with respect to the prevalence of several actual or historical endorgan damages (renal disorder, coronary artery disease, vascular events, vascular damage, and congestive heart failure) in hypertensive patients. ResultsGenotype distribution for endothelin-1 Lys198Asn polymorphism was 57.3% (GG), 41.3% (GT), and 1.43% (TT) in normotensive individuals; and in hypertensive individuals was 54.75% (GG), 43% (GT) and 2.25% (TT). Genotype distribution was unaffected in patients with severe hypertension, renal disorder, vascular events, vascular damage, and congestive heart failure. We, however, found a significant difference in hypertensive individuals with coronary artery disease and TT genotype (P=0.004). ConclusionHomozygous TT carrier contributes to a higher prevalence of coronary artery disease, especially for three-vessel disease in hypertensive individuals. Thus, the polymorphism at position 198 could serve as a possibility to differentiate high-risk subgroups in the heterogeneous population of hypertensive patients.

Impact of Lipid Apheresis on Egr-1, c-Jun, c-Fos, and Hsp70 Gene Expression in White Blood Cells

Lipid apheresis treatment has been suggested to cause oxidative stress. Cells respond to oxidative stress in many ways, including, among others, altered gene expressions. In the present investigation we investigated whether the gene expression of known stress genes was affected in the WBCs of patients undergoing lipid apheresis. For this purpose cellular early‐growth‐response gene‐1 (Egr‐1), c‐Jun, c‐Fos, and heat shock protein 70 (Hsp70) mRNA expression was followed before and immediately after lipid apheresis treatments (N = 24). Gene expression was determined by quantitative reverse transcription‐polymerase chain reaction. With the exception of c‐Fos, the expression of Egr‐1, c‐Jun, and Hsp70 mRNA was not affected in WBCs by a single lipid apheresis treatment (median [16th percentile; 84th percentile]): Egr‐1, before 0.30 (0.13; 0.53), after 0.31 (0.14; 1.33); c‐Jun, before 0.03 (0.03; 0.16), after 0.05 (0.03; 0.18); Hsp70, before 0.49 (0.23; 1.07), after 0.53 (0.20; 1.61)). Expression of c‐Fos was significantly decreased (P < 0.01) after lipid apheresis treatment (before 2.18 [1.06; 5.27], after 1.65 [0.74; 4.12]). Hsp70 and c‐Fos expression in lipid apheresis patients was not different from that in 35 healthy blood donors, whereas Egr‐1 and c‐Jun were significantly decreased (P < 0.05) in lipid apheresis patients when compared to controls (Egr‐1 0.96 [0.42; 1.83], c‐Jun 0.64 [0.40; 0.98], c‐Fos 2.77 [1.32; 4,02], Hsp70 0.43 [0.28; 0.61]). These results show that lipid apheresis procedures do not induce stress gene expression in WBCs. Therefore, all the lipid apheresis systems used seem to be safe with respect to oxidative stress and other injuries induced in WBCs due to contact with extracorporeal tubing and membranes.

Body weight telemetry is useful to reduce interdialytic weight gain in patients with end-stage renal failure on hemodialysis.

Lacking compliance with liquid intake restrictions is one of the major problems in patients on hemodialysis and causes an increased mortality. In 120 patients on hemodialysis with an average interdialytic weight gain (IWG) exceeding 1.5 kg on at least 2 days during the 4 weeks preceding the intervention, the effect of telemetric body weight measurement (TBWM) on IWG, ultrafiltration rate, and blood pressure was evaluated over a period of 3 months. Patients of the telemetric group (TG) were supplied with automatic scales, which transferred the weight via telemetry on a daily basis. In the case of IWG of more than 0.75 kg/24 h, a telephonic contact was made as required, and in the case of an IWG of more than 1.5 kg, telephonic contacting was obligatory along with the advice of a liquid intake restriction to 0.5 L/day until the next dialysis. The patients of the control group (CG) received standard treatment without telemetric monitoring. We examined specific data of the second interdialytic interval (IDI2) and the average within 1 week. The average difference of IWG between TG and CG was not significant before the start of the study but 0.2 kg (p=0.027) (IDI2)/0.27kg (p=0.001) (WP) at the end of the study, respectively. The average difference in the ultrafiltration rate within 1 week was 19.0 mL/h (p=0.282) (IDI2)/8.2 mL/h (p=0.409) before the start of the study but 28.4 mL/h (p=0.122) (IDI2)/30.9 mL/h (p=0.004) at the end of the study, respectively. Thus, TBWM is a feasible method for optimizing the IWG and reducing the ultrafiltration rate.

Interventionelles dezentrales Telemonitoring: Mögliche Indikationen und Perspektiven einer neuen Methode in der Telemedizin

Telemedicine comprises different concepts aiming to close a spatial distance between practitioner, medical staff and patient. Its functionality can include mere data transmission but extend as well to triggering alarms or enable consultation and therapy suggestions. A special form of telemedicinal application is interventional decentralized telemonitoring. Here practitioner-patient communication is characterized by telemedicinal data collection driven therapy-control and -optimization. To identify feasible indications for the employment of telemonitoring a detailed definition of communicated parameters, alarm rules and algorithms of intervention are required as well as a benefit-cost analysis. The quality of the telemedical application is determined by the medical quality of the resulting actions.

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.

Rasch progrediente Niereninsuffizienz als Primärmanifestation einer systemischen Sarkoidose

Zusammenfassung□ FallberichtEs wird der Fall eines 67jährigen Patienten vorgestellt, der zur Abklärung einer rasch progredienten Niereninsuffizienz stationär aufgenommen wurde. Histologisch konnte als Ursache der Niereninsuffizienz eine interstitielle granulomatöse Nephritis bei Sarkoidose mit Multiogranbeteiligung (lunge, Knochenmark, Leber, Bronchialschleimhaut, evtl. Lunge) gesichert werden. Für eine sarkoidoseassoziierte Calciumnephropathie oder Glomerulonephritis ergab sich kein Anhalt. Gleichzeitig bestand bei dem Patienten eine monoklonale Gammopathie ungewisser Signifikanz (MGUS). Nachdem der Patient zum Zeitpunkt der Diagnosestellung urämisch war, konnte durch die alleinige Gabe von Prednisolon eine weitgehende Normalisierung der Nierenfunktion erreicht werden.□ SchlußfolgerungAls eine sehr seltene Manifestationsform der Sarkoidose kann die interstitielle granulomatöse Nephritis zu einer rasch progredienten Niereninsuffizienz führen, die allerdings sehr gut auf Glucocorticoide anspricht, wenn die Therapie frühzeitig begonnen wird und keine ausgeprägte Fibrosierung vorliegt.Abstract□ Case ReportWe report the history of a 67-year-old patient who was admitted to hospital because of rapidly progressive renal insufficiency. The renal biopsy revealed granulomatous interstitial nephritis. The diagnosis of systemic sarcoidosis was confirmed by typical findings of bronchoalveolar lavage and of transbronchial, liver and bone marrow biopsy. Indications for sarcoidosis-related nephrocalcinosis/nephrolithiasis or glomerulonephritis were absent. simultaneously a monoclonal gammopathy of unknown significance (MGUS) was diagnosed. While the patient having been uremic at the time of diagnosis, the administration of prednisolone effectively improved renal function.□ ConclusionsAs a rare manifestation of sarcoidosis granulomatous interstitial nephritis can cause rapidly progressive renal insufficiency, which can effectively be treated by steroids, if distinct interstitial fibrosis is absent.CASE REPORT We report the history of a 67-year-old patient who was admitted to hospital because of rapidly progressive renal insufficiency. The renal biopsy revealed granulomatous interstitial nephritis. The diagnosis of systemic sarcoidosis was confirmed by typical findings of bronchoalveolar lavage and of transbronchial, liver and bone marrow biopsy. Indications for sarcoidosis-related nephrocalcinosis/nephrolithiasis or glomerulonephritis were absent. Simultaneously a monoclonal gammopathy of unknown significance (MGUS) was diagnosed. While the patient having been uremic at the time of diagnosis, the administration of prednisolone effectively improved renal function. CONCLUSIONS As a rare manifestation of sarcoidosis granulomatous interstitial nephritis can cause rapidly progressive renal insufficiency, which can effectively be treated by steroids, if distinct interstitial fibrosis is absent.

Pharmacokinetics and antihypertensive effects of candesartan cilexetil in patients undergoing haemodialysis: an open-label, single-centre study.

AbstractBackground and Objective: In patients with endstage renal failure (ERF), activation of the renin-angiotensin-aldosterone system plays an important role in the onset and maintenance of arterial hypertension. This study aimed to elucidate the antihypertensive effect, pharmacokinetics and safety of candesartan cilexetil in patients with ERF undergoing haemodialysis. Methods: In 14 anuric hypertensive patients undergoing haemodialysis (mean ± SD 24-hour systolic [SBP]/diastolic [DBP] blood pressure [BP] 142.9±11.1/75.0 ±10.1 mmHg), 24-hour BP measurements on the second interdialysis day per week were performed at baseline and at weeks 4, 12 and 24. All patients started antihypertensive treatment with candesartan cilexetil 4 mg once daily immediately before the start of haemodialysis. Subsequently, the dose was titrated upward to 8 mg once daily until the patient’s mean ambulatory BP measurement (ABPM) values were <130/80 mmHg. Plasma candesartan pharmacokinetics were investigated on days 7 and 14 after starting candesartan cilexetil treatment and after each titration step. Results: After 6 months all patients demonstrated well controlled BP (ABPM mean±SD SBP 129.6±21.7/DBP 69.4±10.4mmHg) and a significantly reduced pulse pressure (from a mean±SD 67.9±13.7mmHg at baseline to a mean±SD 60.2±14.7mmHg at 6 months), without any adverse events. Candesartan plasma concentrations increased over 3 hours followed by a continuous decline. Plasma concentrations remained stable after 7 and 14 days, independent of dosing. However, administration of candesartan cilexetil 8 mg (five patients) resulted in plasma concentrations about 1.4 times higher than those for candesartan cilexetil 4 mg. Conclusion: In this study with small number of patients with ERF undergoing haemodialysis, candesartan cilexetil was effective in lowering BP and pulse pressure without accumulation or associated adverse effects such as elevated potassium or symptomatic hypotension.

Tolerability and Antihypertensive Efficacy of Losartan vs Captopril in Patients with Mild to Moderate Hypertension and Impaired Renal Function

AbstractObjective: This international, multicentre, 16-week, double-blind, parallel, two-arm, randomised study was conducted to compare the effects on blood pressure and tolerability of the angiotensin II (Ang II) AT1 receptor antagonist losartan and captopril in patients with mild to moderate hypertension and impaired renal function. Patients: 102 of the total of 129 patients (mean age 55.2 years) having any form of secondary hypertension except renal artery stenosis were recruited from 18 centres in 10 countries. Mild hypertension was defined as a sitting diastolic blood pressure (SiDBP) of 95 to 105mm Hg, moderate hypertension as 106 to 115mm Hg, while creatinine clearance was required to be in the range of 20 to 60 ml/min/1.73m2. Interventions: The initial 4-week placebo period was followed by 12 weeks of treatment with losartan 50mg, possibly titrated to 100mg, once daily (group 1, n = 64) or 25mg captopril, possibly titrated to 50mg, twice daily (group 2, n = 65). Main Outcome Measures: Antihypertensive efficacy was evaluated by the reduction of blood pressure (BP) after 12 weeks. The main efficacy measurement was the SiDBP. Secondary end-points included sitting systolic and standing BP, creatinine clearance, total proteinuria, total cholesterol, triglycerides and high density lipoprotein cholesterol levels. Tolerability was assessed by the incidence of adverse events and by clinical and laboratory tolerability measurements. Results: After 12 weeks’ administration of losartan a reduction of 12.2 ± 10.2mm Hg in SiDBP and 15.5± 18.0mm Hg in sitting systolic blood pressure (SiSBP) was observed, compared with 11.2± 11.4mm Hg and 15.6± 20.6mm Hg, respectively, in captopril-treated patients. Thus, there was no statistically significant difference between the two groups, which was also consistent with the other parameters recorded. In the losartan group, total proteinuria was significantly decreased at the end of the study. Creatinine clearance, lipids and the proportion of patients with clinical adverse experiences showed no remarkable changes at all in the two groups, although such experiences affecting the respiratory system, especially cough, appeared significantly more often (p < 0.034) in captopril-treated patients. Conclusions: Losartan could be as suitable as captopril as an antihypertensive agent in cases where renal function is impaired.