Cardiovascular disease in the uremic patient : cardio-nephrology symposium

106 Pages·2005·2.299 MB·English

by  Hannelore Hampl, Anatole Besarab

Cardiovascular Disease
in the Uremic Patient
Cardio-Nephrology Symposium, Berlin, May 28, 2005
Guest Editors
H. Hampl, Berlin
A. Besarab, Detroit, Mich.
26 fi gures, 17 tables, 2005
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Vol. 28, No. 5–6, 2005
Contents
269 Editorial Current Issues in Chronic Renal Failure
Hampl, H. (Berlin); Besarab, A. (Detroit, Mich.)
307 Hypoalbuminemia in Renal Failure:
Pathogenesis and Therapeutic Considerations
Managing Coronary Heart Disease in Chronic Uremia Haller, C. (Singen)
270 Coronary Surgery in Patients Requiring Chronic 311 Advances in the Medical Treatment of Pulmonary
Hemodialysis Hypertension
Krabatsch, T.; Yeter, R.; Hetzer, R. (Berlin) Dandel, M.; Lehmkuhl, H.B.; Hetzer, R. (Berlin)
275 Percutaneous Coronary Intervention in Patients with 325 Current Understanding of HIF in Renal Disease
End-Stage Renal Disease Rosenberger, C. (Berlin); Rosen, S. (Boston, Mass.); Heyman, S.N.
Bocksch, W.; Fateh-Moghadam, S.; Mueller, E.; Huehns, S.; (Jerusalem)
Waigand, J.; Dietz, R. (Berlin)
341 Circulating NO Pool in Humans
280 Atherosclerosis and Vascular Calcifi cation in Chronic Rassaf, T.; Kleinbongard, P.; Kelm, M. (Aachen)
Renal Failure
Campean, V.; Neureiter, D.; Varga, I.; Runk, F.; Reiman, A.;
Optimizing Anemia Management
Garlichs, C.; Achenbach, S.; Nonnast-Daniel, B.; Amann, K.
(Erlangen)
349 Angiotensin II in the Failing Heart
290 Infl uence of Different Lipid-Lowering Strategies Short Communication
on Plaque Volume and Plaque Composition Schulz, R.; Heusch, G. (Essen)
in Patients with Coronary Artery Disease:
353 Optimized Heart Failure Therapy and Complete
Role of Intravascular Ultrasound Imaging
Anemia Correction on Left-Ventricular Hypertrophy
Bocksch, W.; Fateh-Moghadam, S.; Huehns, S.; Schartl, M.
in Nondiabetic and Diabetic Patients Undergoing
(Berlin)
Hemodialysis
295 Oxidative Stress in Renal Anemia of Hemodialysis Hampl, H.; Hennig, L.; Rosenberger, C.; Gogoll, L.; Riedel, E.
Patients Is Mitigated by Epoetin Treatment (Berlin); Scherhag, A. (Mannheim)
Siems, W. (Bad Harzburg); Carluccio, F. (Scorrano/Lecce);
363 Anemia Management in Chronic Heart Failure:
Radenkovic, S. (Nis); Grune, T. (Düsseldorf); Hampl, H. (Berlin)
Lessons Learnt from Chronic Kidney Disease
302 Oxysterols Are Increased in Plasma of End-Stage Besarab, A.; Soman, S. (Detroit, Mich.)
Renal Disease Patients
Siems, W.; Quast, S. (Bad Harzburg); Peter, D.; Augustin, W.
(Magdeburg); Carluccio, F. (Scorrano/Lecce); Grune, T. 372 Author Index Vol. 28, No. 5–6, 2005
(Düsseldorf); Sevanian, A. (Los Angeles, Calif.); Hampl, H. 373 Subject Index Vol. 28, No. 5–6, 2005
(Berlin); Wiswedel, I. (Magdeburg); European Group of Clinical
Research on Oxidative Stress
374 Acknowledgement to Referees
375 Author Index Vol. 28, 2005
376 Subject Index Vol. 28, 2005
© 2005 S. Karger AG, Basel
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Kidney Blood Press Res 2005;28:269 Published online: March 7, 2006
DOI: 10.1159/000091132
Editorial

Cardiovascular diseases are the primary cause of death In cardiac failure, an increased sympathetic tone
in patients suffering from chronic renal failure requiring and an activated renin-angiotensin-aldosterone-system
hemodialysis. Uremia as a complex syndrome infl uences (RAAS) initiate the structural and functional transforma-
all cardiac structures – pericardium, myocardium, endo- tion of the myocardium (remodeling). Renal anemia is
cardium as well as the coronary system. The most impor- considered to be most important for the development of
tant manifestations of this complex symptom, which is eccentric left-ventricular hypertrophy (LVH) and arterial
also called ‘uremic heart disease’, are hypertensive and hypertension for the concentric LVH. During LVH max-
anemic heart disease, coronary artery disease and heart imal coronary reserve is already critically reduced, the
valve diseases as a result – among others – of distur- so-called ‘cardiomyocyte-capillary mismatch’. Thus, se-
bances of calcium and phosphate metabolism. In uremic vere LVH predisposes ventricular arrhythmia triggered
patients, heart surgery and the entire perioperative man- by the critically reduced coronary reserve. This often
agement is demanding and has to be done in cooperation leads to sudden death. Therefore, an attempt to cause re-
with the nephrologist. gression of LVH is mandatory.
Oxidative stress has been postulated to be one of the Cardiac mortality in uremic patients depends on mul-
important risk factors for cardiovascular disorders in ure- tifactorial causes. To correct only one cause would not be
mic patients. In general, uremic patients show a reduced effi cient. A multi-interventional therapeutic approach is
number of red blood cells (RBCs). This results in a re- necessary to achieve improvement in cardiac morbidity/
duced antioxidant protection since RBCs are equipped mortality. However, the majority of patients are not re-
with highly effective antioxidant defense. Most of the an- ceiving optimized cardioprotective therapy and complete
tioxidant capacity of the whole blood is localized within anemia correction. Optimized oxygen availability and
the RBCs. Circulating RBCs are mobile radical scaven- correction of hormonal abnormality are needed for the
gers and provide antioxidant protection to other tissues diseased heart to heal. Complete anemia correction is es-
and organs. In uremic patients with anemia, a drastic sential, safe and economical in uremic patients.
oxidative stress is given inducing cardiovascular injury. Nephrologists need to be responsible for the cardiac
The best clinical demonstration to restore antioxidative health. Renal physicians can do a lot of good and bad for
protection is complete anemia correction by means of the cardiac health of their patients.
erythropoietin. Profi ting from interdisciplinary cooperation with car-
Particularly noteworthy is the continuous process of diologists and cardiac surgeons and by using up-to-date,
lipid peroxidation whose products were elevated in ane- suffi cient therapy on pathophysiological baselines against
mic uremic serum. Lipid peroxidation processes result in cardiac insuffi ciency, it should be possible, as shown by
increased oxidized lipoprotein species (oxLDL). They are the following articles, to signifi cantly reduce cardiac mor-
key factors of arteriosclerosis. During complete anemia bidity/mortality in uremic patients.
correction, lipid peroxidation products are signifi cantly Hannelore Hampl
reduced. Anatole Besarab
© 2005 S. Karger AG, Basel
1420–4096/05/0286–0269$22.00/0
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Managing Coronary Heart Disease in Chronic Uremia
Kidney Blood Press Res 2005;28:2 70 – 274 Published online: March 7, 2006
DOI: 10.1159/000090180
Coronary Surgery in Patients Requiring
Chronic Hemodialysis
T. Krabatsch R. Yeter R. Hetzer
Deutsches Herzzentrum Berlin, Klinik für Herz-, Thorax- und Gefässchirurgie, B erlin , Deutschland
Key Words group (11.4 8 1.62 vs. 13.3 8 1.81 mg/dl). These patients
Dialysis (cid:1) End-stage renal insuffi ciency (cid:1) Coronary received signifi cantly higher numbers of blood transfu-
artery disease (cid:1) Cardiac surgery sions (6.7 8 5.6 vs. 2.75 8 3.8), and platelet transfusions.
Conclusion: Our preliminary study indicates that coro-
nary surgery can be performed with acceptable mid-
Abstract term results when the specifi c requirements of this pa-
Background: In uremic patients coronary surgery and tient group are taken into account.
the entire perioperative management is demanding. Copyright © 2005 S. Karger AG, Basel
Methods: We analyzed retrospectively data from all
patients requiring chronic hemodialysis who under-
went coronary artery bypass grafting (CABG) between Introduction
January 1 2001 and December 31 2004 at the Deutsches
Herz zentrum Berlin and compared them to those of a Uremia is a complex syndrome that infl uences all the
randomized nonuremic control group (n = 68), which cardiac structures – the pericardium, the myocardium,
consisted of patients who underwent CABG during the the endocardium and the coronary system.
same period. R esults: During the study period 6315 pa- The most important manifestations of this complex of
tients underwent coronary artery bypass grafting at the symptoms, which is also called ‘uremic heart disease’, are
Deutsches Herzzentrum Berlin. Among these patients, hypertensive heart disease and coronary artery disease.
we identifi ed 71 chronic dialysis patients (1.12%). Among The incidence of heart valve disorders in chronic dialysis
dialysis patients, we recorded a perioperative mortality patients compared to the normal population is also in-
of 5.6%. One-year survival rate was 87.7% among uremic creased [ 1, 2].
patients and 91.0% in the control group; the correspond- When dialysis patients suffer from coronary artery dis-
ing 4-year survival rates were 56.7 and 88.0%, respec- ease, they often have severe diffuse, sometimes even cir-
tively. The incidence of peripheral artery disease was cular, calcifi cations of the coronary arteries, reaching into
signifi cantly higher in the dialysis group. Uremic pa- the periphery of the vessels. This is probably a result of
tients showed signifi cantly lower hemoglobin serum lev- uremia-associated disturbances of the calcium and phos-
els at the time of admission compared to the control phate metabolism. In this context, autonomous parathor-
mone (PTH) release with consequent elevation of calci-
um and phosphate serum levels seems to be important.
T. Krabatsch and R. Yeter contributed equally to the manuscript. Besides this, typical comorbidities such as arterial hyper-
© 2005 S. Karger AG, Basel PD Dr. T. Krabatsch
1420–4096/05/0286–0270$22.00/0 Deutsches Herzzentrum Berlin, Klinik für Herz-, Thorax- und Gefässchirurgie
Fax [phone] Augustenburger Platz 1
E-Mail [email protected] Accessible online at: DE–13353 Berlin (Deutschland)
www.karger.com www.karger.com/kbr Tel. [phone], Fax [phone], E-Mail [email protected]
tension, peripheral artery disease, hyperlipoproteinemia, Table 1. Number of coronary artery bypass
renal anemia and disturbances of the carbohydrate me- operations at the Deutsches Herzzentrum
Berlin during the years 2001–2004 (entire
tabolism play a signifi cant role [ 2] . As a consequence, it
patient group and uremic patients)
is not surprising that cardiovascular diseases are the pri-
mary cause of death in patients requiring chronic hemo-
Year Total CABG in
dialysis. CABG uremic patients
When coronary artery disease in this patient group is
2004 1,450 14 (1.00%)
treated by PTCA or stent implantation, the incidence of
2003 1,604 15 (0.93%)
restenoses is higher than in other coronary patients and
2002 1,600 20 (1.25%)
coronary artery bypass grafting (CABG) seems to achieve 2001 1,661 22 (1.32%)
better results than PTCA or stenting [ 4–7] . 2001–2004 6,315 71 (1.12%)
However, chronic and especially terminal renal insuf-

fi ciency is also an important risk factor for increased mor-

tality and morbidity after cardiac operations. Only 0.5–
1.5% of patients who undergo coronary operations are
eliminate the priming volume. Anticoagulation was established by
uremic. Their perioperative mortality, however, is be-
systemic heparin application. Until 2001 this was adjusted by use
tween 8 and 30%. The highest risk is carried by uremic
of the activated clotting time (ACT, target range 450–600 s). From
patients suffering from diabetes or peripheral artery dis- 2002 onwards, we measured serum heparin levels.
ease [ 1] . Data from dialysis patients were compared to those of a ran-
domized control group (n = 68), which consisted of patients who
Nowadays, most coronary operations are performed
underwent CABG during the same period.
using the extracorporeal circulation. Factors associated
For quantitative parameters we calculated mean and SD.
with this technique such as deviations in fl uid balance Groups were compared using t tests or Pearson’s (cid:1) 2 test. p ! 0.05
and serum electrolyte levels, hemodilution and distur- was considered signifi cant.
bances of the coagulatory system require adjusted peri-
operative management of these patients. Postopera-
tively, they are prone to complications including sep- Results
ticemia, mediastinitis and prolonged bleeding. The
increased incidence of postoperative bleeding may be During the 4 years of the investigation 6,315 patients
explained by a disturbance of platelet function caused underwent coronary artery bypass grafting at the Deut-
by uremia [ 3]. sches Herzzentrum Berlin. Among these patients we
identifi ed 71 chronic dialysis patients ( table 1 ), which
means that 1.12% of our CABG patients were uremic.
We analyzed 14 different preoperative parameters as
Patients and Methods
listed in t able 2 .
In a fi rst step, we analyzed data from all patients requiring Almost 80% of the patients operated on received at
chronic hemodialysis who underwent coronary artery bypass graft- least one arterial bypass graft, and the left internal tho-
ing between January 1 2001 and December 31 2004 at the Deutsch- racic artery (LITA) was our fi rst choice. All intraoperative
es Herzzentrum Berlin. Data were collected retrospectively from
data are given in t able 3. When LITA was not used intra-
patient records and our institute’s electronic data storage systems.
operatively, it was mostly due to emergency operations.
As basis data we analyzed all the factors listed in t ables 2 and
3 . Patients who underwent additional valve operations were ex- Figure 1 compares dialysis patients and the control
cluded from this analysis, as were patients who received successful group with regard to postoperative mortality.
kidney transplantation. However, 11 patients who underwent kid- As expected, we found a lower survival rate in uremic
ney transplantation who developed organ failure of the transplant-
patients during the whole follow-up period. This differ-
ed kidney with subsequent uremia were included.
ence increased further after the fi rst postoperative year.
As a routine procedure all patients underwent hemodialysis on
the day before surgery. Coronary operations were performed using Among dialysis patients we recorded a perioperative
extracorporeal circulation. Until 2004 all patients were operated mortality of 5.6% (4 patients). Heart failure and medias-
on in mild systemic hypothermia (32 ° C) using Kirsch/Haes car-
tinitis were causes of death in 3 of these 4 patients. The
dioplegia (modifi ed Bleese’s solution) for myocardial protection.
perioperative mortality among patients of the control
From 2005 on, all coronary patients were operated on in normo-
group was 2.4% (2 patients, one heart failure, one pneu-
thermia using blood cardioplegia as published by Calafi ore’s group.
During cardiopulmonary bypass, we performed hemofi ltration to monia). One-year survival rate was 91.0% in the control
Coronary Surgery in Uremics Kidney Blood Press Res 2005;28:270–274 271
Table 2. P reoperative data of CABG
Parameter Hemodialysis group Control group
patients requiring chronic hemodialysis
(n = 71) (n = 68)
and control group
mean8SD range mean8SD range
Age, years 63.1810.9 32–81 63.9810.0 37–82
Gender, M:F 56:15 56:12
Duration of terminal renal 4.183.6 1 month to NA NA
insuffi ciency, years 20 years
LVEF, % 48.1813.6 52.8815.1
Absolute % Absolute %
number number
Coronary 1-vessel disease 3 4.23 1 1.5
Coronary 2-vessel disease 13 18.3 12 17.6
Coronary 3-vessel disease 55 77.5 55 80.9
Previous PTCA 27 38.0 19 27.9
Previous stent implantation 23 32.4 15 22.1
Arterial hypertension 63 88.7 55 80.9
Diabetes 29 40.8 20 29.4
Diabetes, insulin dependent 20 28.2 11 16.2
Peripheral arterial disease 35 49.3 9 13.2
Hyperlipidemia 22 31.0 35 51.5

Table 3. Intraoperative data of 71 CABG
Parameter Hemodialysis group Control group
patients requiring chronic hemodialysis
(n = 71) (n = 68)
and control group
absolute % absolute %
number number
Scheduled operations 62 87.3 63 92.6
Emergency operations 9 12.7 5 7.4
LITA + 1 SVG 5 7.0 12 17.6
LITA + 2 SVG 26 36.6 23 33.8
LITA + 3 SVG 21 29.6 23 33.8
LITA (single) bypass 3 4.2 0 0
LITA + radial artery bypass 1 1.4 0 0
LITA + RITA + SVG 1 1.4 1 1.5
1 SVG 1 1.4 1 1.5
2 SVG 4 5.6 3 4.4
3 SVG 9 12.7 5 7.4
SVG = Saphenous vein graft.

group and 87.7 among uremic patients; the correspond- We found no signifi cant differences between the two
ing 4-year survival rates were 88.0 and 56.7%, respec- groups with regard to age, gender, severity of coronary
tively. disease (1-, 2- or 3-vessel disease) or preoperative left ven-
Two patients of the dialysis group required reopera- tricular function. Uremic patients showed a signifi cantly
tion for sternal wound healing disturbance during the lower hemoglobin serum level at the time of admission
postoperative period. This complication was not seen in compared to the control group (11.4 8 1.62 vs. 13.3 8
any patient of the control group. 1.81 mg/dl). Therefore, these patients received signifi -
272 Kidney Blood Press Res 2005;28:270–274 Krabatsch/Yeter/Hetzer
Table 4. Comparison between the dialysis and control groups
Dialysis group Control group p
n % n %
Previous PTCA 27 38.0 19 27.9 <0.206
Previous stent implantation 23 32.4 15 22.1 <0.172
Arterial hypertension 63 88.7 55 80.9 <0.196
Diabetes 29 40.8 20 29.4 <0.158
Diabetes, insulin dependent 20 28.2 11 16.2 <0.090
Peripheral artery disease 35 49.3 9 13.2 <0.001
Previous myocardial infarction 24 33.8 39 57.4 <0.005
Left main stem stenosis 12 16.9 15 22.1 <0.442
Emergency operation 9 12.7 5 7.4 <0.105
LITA graft 57 80.3 59 86.8 <0.304
Transfusion of platelets 15 21.1 2 2.9 <0.005
Mean SD Mean SD
Serum hemoglobin at admission, mg/dl 11.4 1.62 13.3 1.81 <0.001
Transfused blood units 6.7 5.6 2.75 3.8 <0.001
Blood loss via drains (fi rst 24 h), ml 724 657 644 462 <0.919

Comment
Survival functions
1.0 Cardiovascular diseases are the primary cause of death
Control in patients requiring chronic hemodialysis. Hypertensive
heart disease, coronary artery disease and valve disorders
0.8 are the main pathologies in this patient group. Coronary
la
viv artery disease in dialysis patients is characterized by se-
uSr vere peripheral and sometimes circumferential calcifi ca-
0.6
tion of the coronary vessels. Since CABG shows better
Dialysis results than PTCA and stent implantation in dialysis pa-
tients, coronary surgery seems to be an important thera-
0.4
peutic option [ 4–7] . However, dialysis patients suffer
0 higher postoperative mortality and morbidity than other
0 1.0 2.0 3.0 4.0 5.0
surgical coronary patients.
Years
We identifi ed 1.1% uremic patients among our entire
group of CABG patients operated on between 2001 and
2004. At the time of operation uremia had lasted on av-
Fig. 1. Comparison of postoperative mortality after CABG in
uremic patients and the control group using the Kaplan-Meier erage for more than 4 years. Three-quarters of these pa-
method. tients suffered from coronary triple-vessel disease, and in
most left ventricular function was already diminished.
Perioperative mortality among dialysis patients was
5.6%. This accords with data given in the literature [ 1] .
cantly higher numbers of blood transfusions (6.7 8 5.6 Almost 80% of our dialysis patients received at least one
vs. 2.75 8 3.8), although the average blood loss via drain- arterial bypass graft. Herzog et al. [ 8] have considered
age tubes during the fi rst 24 postoperative hours did not arterial grafts to have advantages for dialysis patients.
differ signifi cantly between the two groups (dialysis pa- As expected, we found a lower survival rate in uremic
tients 724 8 657 ml, control group 644 8 462 ml). These patients during the whole follow-up period. This differ-
data are summarized in t able 4. ence increased further after the fi rst postoperative year.
Coronary Surgery in Uremics Kidney Blood Press Res 2005;28:270–274 273
Among uremic patients, we found a signifi cantly high- sis patients. In a signifi cantly higher percentage of our
er number of patients who suffered from additional pe- uremic patients in comparison to the controls substitu-
ripheral artery disease compared to the control group. tion of platelets was needed. Probably this resulted from
As expected, we found renal anemia in our dialysis using extracorporeal circulation as well as from a distur-
patients on admission. Their serum hemoglobin levels bance of platelet function caused by uremia itself [ 3].
were signifi cantly lower, resulting in a higher number of In uremic patients coronary surgery and the entire
blood transfusions required perioperatively. perioperative management is demanding.
Recently Hampl et al. [ 9] have published results which However, surgery can be performed with acceptable
underline the importance of blood substitution in dialysis mid-term results when the specifi c requirements of this
patients. They found that normalization of serum hemo- patient group are taken into account.
globin levels leads to improved cardiac function in dialy-

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274 Kidney Blood Press Res 2005;28:270–274 Krabatsch/Yeter/Hetzer
Managing Coronary Heart Disease in Chronic Uremia
Kidney Blood Press Res 2005;28:2 75 –279 Published online: March 7, 2006
DOI: 10.1159/000090181
Percutaneous Coronary Intervention in
Patients with End-Stage Renal Disease
Wolfgang Bocksch Suzanne Fateh-Moghadam Eda Mueller Sonja Huehns
Juergen Waigand Rainer Dietz
Charité-Campus Virchow-Klinikum, Universitätsmedizin Berlin, B erlin, Germany
Key Words creasing number of patients with mechanically untreat-
Percutaneous coronary intervention (cid:1) End-stage renal able coronary lesions and unprotected left main stem
disease (cid:1) Myocardial infarction (cid:1) Coronary artery disease stenosis. The problem of restenosis and subsequent tar-
get lesion revascularization has been decreased to a min-
imum by the use of drug-eluting stents (DES), even
Abstract though prospective randomized trials including ESRD
Patients with end-stage renal disease (ESRD) represent patients are lacking. In case of acute coronary syndromes,
a growing number of patients in the cardiac catheteriza- the need for immediate coronary angiography and sub-
tion laboratories worldwide. This is a consequence of the sequent revascularization by means of PCI should be
growing absolute number of ESRD patients in developed pointed out.
countries, better noninvasive diagnostic tools, better Copyright © 2005 S. Karger AG, Basel
catheterization facilities and last-but-not-least better ed-
ucation of referring physicians about the incidence and
prognosis of coronary artery disease (CAD) for patients Epidemiology of CAD in ESRD Patients
with ESRD. There is growing evidence of the positive
impact of coronary revascularization on long-term out- In developed countries, the incidence of ESRD is in-
come of these patients. ESRD patients have a high co- creasing dramatically over time with 315,000 ESRD pa-
morbidity and are therefore better candidates for the less tients in the US in 2002 and an estimated number of
invasive approach using percutaneous coronary inter- 520,000 ESRD patients by the year 2010 [ 1]. Cardiac dis-
vention (PCI) rather than coronary artery bypass surgery eases are responsible for 45% of all-cause mortality in
(CABG). From the view of the interventional cardiologist, ESRD patients, whereas 20% of all cardiac deaths are fa-
ESRD patients represent one of the most challenging pa- tal outcomes of acute coronary syndromes [2]. The prev-
tient cohort concerning technical challenges and poten- alence of angiographically signifi cant coronary artery dis-
tial risk of complication for the patient. Percutaneous ease varies between 25% in young, nondiabetic ESRD
coronary intervention (PCI) including debulking tech- patients and 85% in older ESRD patients with a long his-
niques and stent implantation is the current standard tory of diabetes [ 3]. 29% of all myocardial infarctions of
therapy for patients with symptomatic single-vessel dis- ESRD patients occur within the fi rst year of onset of di-
ease (SVD) and the preferred therapy for most patients alysis and 52% within 2 years, respectively [ 4] . These facts
with focal, polyfocal or even diffuse multi-vessel disease points out the need for early diagnosis and treatment of
(MVD). Coronary bypass surgery is reserved for a de- CAD in ESRD patients.
© 2005 S. Karger AG, Basel Priv.-Doz. Dr. med. Wolfgang Bocksch, Department of Internal Medicine-Cardiology
1420–4096/05/0286–0275$22.00/0 Cardiac Catheterization Laboratories, Charité-Campus Virchow-Klinikum
Fax [phone] Universitätsmedizin Berlin, Humboldt Universität zu Berlin and Freie Universität Berlin
E-Mail [email protected] Accessible online at: Augustenburger Platz 1, DE–13353 Berlin (Germany)
www.karger.com www.karger.com/kbr Tel. [phone], Fax [phone], E-Mail [email protected]