Peritoneal Dialysis International, Vol. 22, pp. 48–52
Printed in Canada. All rights reserved.
Copyright 2002 International Society for Peritoneal Dialysis
LACK OF ISOPRENE OVERPRODUCTION DURING PERITONEAL DIALYSIS
Enrico Capodicasa,1 Gianfranco Trovarelli,2 Federica Brunori,2 Luigi Vecchi,3 Carmen Carobi,3
Gianna E. De Medio,3 Maria A. Pelli,4 and Umberto Buoncristiani3
Department of Clinical and Experimental Medicine,1 Institute of Biochemistry and Medical
Chemistry,2 Perugia University Medical School; Nephrology and Dialysis Unit,3
Silvestrini General Hospital; Department of Emergency and General
Surgery,4 Perugia University Medical School, Perugia, Italy
♦ Objective: Isoprene is the constitutive unit of iso-
alysis patients include continuous versus intermit-
prenoid lipids and sterols. However, it is also a potential
tent dialysis, biocompatibility and safety of the pro-
toxic and carcinogenic agent. Recent findings of a marked
cedure, contamination, adequacy in removing small
and prolonged isoprene overproduction induced by hemo-
and large solutes, hemodynamic stability, anticoagu-
dialysis sessions raises the question of isoprene behav-
lation, long-term prognosis, and the incidence of some
ior in patients on peritoneal dialysis. ♦
diseases, including myocardial infarction and cere-
Design: A study with repeated measures per patient and healthy control.
brovascular accidents, infections, amyloidosis, cancer.
♦ Setting: Nephrology and Dialysis Unit and Perugia Uni-
(1–11). Evaluating differences in changes associated
versity Medical School.
with the type of dialysis may be of interest in patho-
♦ Patients: Sixteen consecutive patients on regular con-
physiological and clinical settings. tinuous ambulatory peritoneal dialysis (CAPD) were evalu-
A new metabolic aspect described to date only in
ated. Endogenous isoprene was analyzed using gas
HD patients is the increased breath isoprene exhala-
chromatographic assay of breath isoprene, collected at
tion observed in regular 4-hour (0800 hours, 1200
set times before and after dialysis fluid exchange.
hours,) three-times-weekly maintenance HD (12).
♦ Results: No significant variations were found in breath
Breath isoprene was increased in all patients. The
isoprene concentrations in the different samples from
overproduction was HD-induced, became evident in
each patient, and levels were almost stable within the
the postdialysis period, and followed a biphasic pat-
normal range of healthy controls. ♦ Conclusion: These results show that CAPD, unlike
tern with significantly increased overproduction also
hemodialysis, has little or no effect on isoprene and iso-
persisting the morning after, on the non-HD day (13). prenoid-related lipid turnover. This lack of increased en-
This behavior pattern could have clinical and biologi-
dogenous isoprene synthesis, in addition to being a
cal value because cells depend on isoprenoids derived
distinctive metabolic feature of CAPD, could have impor-
from mevalonate for growth, differentiation, and
tant pathophysiological and clinical implications.
maintenance of homeostatic functions (14); moreover,isoprene is thought to have carcinogenic and toxic
effects (15–18). There are no data on the behaviorpatterns of breath isoprene during PD.
Extracorporeal dialysis, or hemodialysis (HD), and
The aim of this study was to evaluate breath iso-
peritoneal dialysis (PD) — most often continu-
prene patterns in patients undergoing CAPD.
ous ambulatory peritoneal dialysis (CAPD) — are twomodalities of treatment for end-stage renal disease
PATIENTS AND METHODS
considered alternatives, even though there may beremarkable differences in efficacy, physiology, contra-
indications, and complications. Problem areas for di-
Sixteen consecutive patients (8 men and 8 women;
Correspondence to: E. Capodicasa, Department of Clini-
mean ± SD age 62.2 ±13 years, range 29 – 77 years)
cal and Experimental Medicine, Perugia University Schoolof Medicine, Policlincio Montelkuce, via Brunamonti, 06100
on stable CAPD were evaluated. All patients were
treated with standard PD solutions, with lactate as
buffer and glucose as osmotic agent at different con-
Received 4 April 2001; accepted 16 July 2001.
centrations according to individual need. Mean du-
ration of dialysis treatment was 30.4 ± 20.2 months
Water removal is required to avoid aluminum column
(range 9 – 79 months). Each patient had 3 daytime
deactivation and to prevent ice formation in the trap.
exchanges and 1 nighttime exchange. Detailed infor-
During thermal desorption (280°C, 6 minutes, helium
mation on the 16 patients included in the study is
flow 15 mL/min), the desorbed compounds were con-
centrated in a cryogenic trap (–100°C) by liquid ni-trogen. Finally, flash heating sent the volatiles to the
Al O /KCl column (25 m, 0.32 mm, 5.0 µm; Varian–
Chrompack). The temperature program was 50°C for
Isoprene concentration in exhaled breath was de-
2 minutes, increased 8°C/minute to 190°C, and final
termined by gas chromatographic analysis as reported
isotherm 15 minutes. Helium pressure was 80 kPa by
elsewhere (12). Briefly, 1-L Tedlar bags (SKC Inc.,
flame ionization detector (250°C). A software program
Eighty Four, Pennsylvania, USA) were used for col-
(Mosaic, Varian–Chrompack) running on a personal
lecting breath. The first 500 mL was split off (dead
computer was used to analyze chromatograms and
space) and only the end of the alveolar breath was
collected. New and used bags were purged by heliumflow. All bags were tested before sampling. Fixed
amounts of breath samples (100 mL) were absorbedon to a glass tube filled with preconditioned
Exhaled breath was collected from the 16 patients
Carbosieve, Carbotrap, and Carbotrap C (Varian–
(group A) immediately before and after the drainage
Chrompack Italy, Turin, Italy) by suction pump
phase of the first two daytime exchanges, and at the
(25/30 mL/min). Thermo desorption cold trap unit
end of the first and second hours of the dwell period
(TCT) samples tubes were placed on a TCT/purge and
between the two. In a previous study performed in
trap injection (PTI) CP 4001 injector (Varian–
HD patients, the first breath isoprene increase was
Chrompack) and processed automatically. A gentle
detected at the end of dialysis, but became more evi-
preflush (53°C, 4 minutes, helium flow 15 mL/minute)
dent half an hour later; therefore, in one subgroup of
was used to remove the remaining nonadsorbed gas.
6 patients (group A2), refilling after the first drain-
CIN = chronic interstitial nephritis; PKD = polycystic kidney disease; CGN = chronic glomerulonephritis; HNS = hyperten-sive nephrosclerosis. Stay-Safe, Fresenius Medical Care Science and Product Consulting, Bad Homburg, Germany; Fres/S.S3/99, Fresenius;Dianectan S, Laboratoire Aguettan, Lyon, France; Baxter T, Baxter Healthcare Corp. (Renal division), McGaw Park, Illi-nois, USA; Bieffe, Bieffe Medital S.p.a., Milan, Italy; Periline, Haemopharm Health Care, Milan, Italy.
age was delayed for 30 minutes, after which anothersample was collected. In a second subgroup of 4 pa-tients (group A3), who were followed up for 24 hours,exhaled breath was also collected before and after thethird and fourth exchanges.
Data are reported as mean ±SD. Analysis of vari-
ance was done and significance of differences wasassessed by t-test for paired data analysis; a p valueless than 0.05 was assumed significant.
Figure 2 — Breath isoprene during continuous ambulatoryperitoneal dialysis with delayed refilling. In this subset of
In the first part of the study, breath isoprene con-
patients (group A2; n = 6), abdominal refilling after the first
centration was evaluated in samples collected from
drainage was postponed 30 minutes, at which time an extra
the 16 patients in group A during the first morning
sample was collected (t1D). Isoprene levels are reported as
cycle [i.e., before (time 0) and soon after the first peri-
toneal drainage; 1 and 2 hours after the first perito-neal refilling; and before and soon after the second
Finally, Figure 3 shows the behavior pattern in the
peritoneal drainage]. Figure 1 shows breath isoprene
4 patients (group A3) in whom the breath isoprene con-
concentrations at these different sample times. At
centration was measured in all four exchanges. Again,
time 0, isoprene concentration was 5.52 ± 2.25 nmol/L,
no significant differences were found, but there was a
that is, almost identical to the level found in healthy
tendency toward a decrease during the diurnal hours
subjects with normal renal function in our laboratory
in accord with the circadian rhythm of this hydrocarbon
[breath isoprene levels in 89 healthy controls ranged
in normal subjects. Isoprene was not present in fluid
from 1.4 to 10.8 nmol/L (5.06 ± 2.24 nmol/L)]. Con-
used for dialysis and the isoprene concentration in
centrations remained almost stable without signifi-
ambient air was negligible (data not shown).
cant variation over time in samples collected from thesame patient. DISCUSSION
Figure 2 shows no variations in isoprene concen-
tration occurring in the 6 patients in group A2 after
This is the first time that breath isoprene produc-
refilling was postponed for 30 minutes.
tion has been evaluated in PD patients.
Breath isoprene levels were not significantly dif-
ferent from the normal healthy control values before,during, and after a peritoneal exchange. These find-ings suggest that, in CAPD patients, an isoprene en-dogenous overproduction does not occur, unlike in HDpatients, in whom isoprene overproduction persists,for many hours after dialysis ends, in a biphasic be-havior pattern with concentrations remaining high
the next morning (a nondialysis day) (12,13).
The reasons for this different behavior are not
known. An endogenous product of lipid metabolism,isoprene in man is believed to derive from the syn-thetic mevalonate pathway leading to sterols and iso-
prenoid lipids (Figure 4). This metabolic pathwayappears to be strictly regulated at the level of meva-
Figure 1 — Breath isoprene during continuous ambulatory
lonic acid (MVA) (19–22), a low molecular weight,
peritoneal dialysis. Breath samples were collected
water-soluble substance, levels of which are increased
immediately before first morning drainage (t0), soon after
in the plasma of uremic patients before a HD session
first morning drainage (t1), 1 hour after first peritoneal
refilling (t2), 2 hours after first peritoneal refilling (t3),
On the contrary, isoprene (molecular weight 68.12,
immediately before second drainage (t4), and soon aftersecond drainage (t5). Isoprene levels are reported as
melting point –146°C, boiling point 34°C), a volatile
liposoluble substance, is not removed by HD but is
Figure 3 — Time course of breath isoprene during continuous ambulatory peritoneal dialysis. In this subset of patients(group A3; n = 4), breath isoprene concentration was measured at specific time points for all four exchanges of the day. Isoprene levels are reported as mean percentage values ±SD.
determining the different breath isoprene behaviorpattern in HD and CAPD patients.
The first hypothesis is that, in a short space of time,
HD removes great quantities of MVA, and conse-quently the MVA-regulated inhibitory mechanism,and initiates enzymatic induction mechanisms, whichcould result, after the end of the dialysis session, inthe increased respiratory exhalation of isoprene inthe biphasic behavior pattern described elsewhere(13). In CAPD patients, the slower and continuousremoval of hydrosoluble isoprene precursors does notpromote a clear isoprene overproduction.
Alternatively, intermediate mechanisms inducing
isoprene overproduction may involve factors relatedto biocompatibility, to hemodynamic stress, or to otherunknown factors associated with hemodialytic proce-dures per se.
Variations in alveolar respiration do not seem to
play a major role in isoprene emission: in breathsamples from dialyzed patients, no significant varia-tions were found in alveolar levels of other volatilehydrocarbons (e.g., ethane, pentane, isopentane, pro-pane, butane, and isobutane) (data not shown).
Whatever the causal mechanism(s), patients on
HD, unlike those on CAPD, incur an increased iso-prene biosynthesis and a prolonged overexposure con-sequent to repeated dialysis sessions.
Thus, variations in isoprene respiratory exhalation
could reflect the effect of the dialysis session on lipid
Figure 4 — Branched pathway of mevalonate metabolism
metabolism in uremic patients and could have reper-
cussions in terms of cellular and cardiovascular
easily exhaled with alveolar air, in which it can be
physiopathology. High isoprene levels have been re-
measured noninvasively by gas chromatography.
ported in patients with acute myocardial infarction
Differences in continuous and intermittent dialy-
(24). Furthermore, isoprene itself is acknowledged to
sis treatments probably play an important role in
have a possible direct pathogenic role. In fact, chemi-
cally, isoprene [H C=CHC(CH )=CH ] is an analogue
10. Drueke TB. Beta2-microglobulin and amyloidosis.
of butadiene, which is reputed to be a toxic, mutagenic,
Nephrol Dial Transplant 2000; 15(Suppl 1):17–24.
and carcinogenic agent (15–17). In experimental mod-
11. Zima T, Mestek O, Nemecek K, Bartova V, Fialova J,
els, even episodic exposure to isoprene has increased
Tesar V, et al. Trace elements in hemodialysis and con-
the incidence of various neoplasias, even many years
tinuous ambulatory peritoneal dialysis patients. BloodPurif 1998; 1:253–60.
after exposure (18). This hydrocarbon is thus the ob-
12. Capodicasa E, Trovarelli G, De Medio GE, Pelli MA,
ject of growing interest as a potentially harmful nox-
Lippi G, Verdura C, et al. Volatile alkanes and increased
concentrations of isoprene in exhaled air during hemo-
In conclusion, the lack of an increase in isoprene
levels during CAPD appears to be not only a distinc-
13. Trovarelli G, Brunori F, De Medio GE, Timio M, Lippi
tive feature of this type of dialysis, but also a meta-
G, Pelli MA, et al. Onset, time course, and persistence
bolic phenomenon that deserves further investigation
of increased haemodialysis-induced breath isoprene
and that could be of remarkable physiological, clini-
cal, and prognostic interest in these patients.
14. Vishnuvardhan D, Beinfeld MC. Lovastatin is a potent
inhibitor of cholecystokinin secretion in endocrine
tumor cells in culture. Peptides 2000; 21:553–7.
15. Csanady GA, Filser JG. Toxicokinetics of inhaled and
endogenous isoprene in mice, rats, and humans. Chem
The authors thank Dr. Geraldine Anne Boyd for revising
Biol Interact 2001; 135–136:679–85.
the English version of this paper, and Fortuna Gino
16. Bolt HM. Butadiene and isoprene: future studies and
Girolamo and Marinacci Giuliana for their technical
implications. Toxicology 1996; 113:356–60.
17. Melnick RL, Kohn MC. Dose-response analyses of ex-
perimental cancer data. Drug Metab Rev 2000;
18. Melnick RL, Sills RC, Roycroft JH, Chou BJ, Ragan
1. Zoccali C. Cardiovascular risk in uraemic patients—is
HA, Miller RA. Isoprene, an endogenous hydrocarbon
it fully explained by classical risk factors? Nephrol Dial
and industrial chemical, induces multiple organ neo-
plasia in rodents after 26 weeks of inhalation expo-
2. Baigent C, Burbury K, Wheeler D. Premature cardio-
vascular disease in chronic renal failure. Lancet 2000;
19. Brown MS, Goldstein JL. Multivalent feedback regu-
lation of HMG CoA reductase, a control mechanism
3. Herzog CA. Acute myocardial infarction in patients
coordinating isoprenoid synthesis and cell growth.
with end-stage renal disease. Kidney Int Suppl 1999;
20. Correll CC, Edwards PA. Mevalonic acid-dependent
4. Marple JT, MacDougall M. Development of malignancy
degradation of 3-hydroxy-3-methylglutaryl-coen-
in the end-stage renal disease patient. Semin Nephrol
zyme A reductase in vivo and in vitro. J Biol Chem
5. Ishikawa I. Renal cell carcinomas in patients on long-
21. Houten SM, Romeijn GJ, Koster J, Gray RG, Darbyshire
term hemodialysis. Contrib Nephrol 1999; 128:28–44.
P, Smit GP, et al. Identification and characterization
6. Vamvakas S, Bahner U, Heidland A. Increased cancer
of three novel missense mutations in mevalonate ki-
incidence in terminal kidney failure: potential patho-
nase cDNA causing mevalonic aciduria, a disorder of
genetic mechanisms. Schweiz Med Wochenschr 1997;
isoprene biosynthesis. Hum Mol Genet 1999; 8:1523–8.
22. Hinson DD, Chambliss KL, Toth MJ, Tanaka RD,
7. Murphy SW, Foley RN, Barrett BJ, Kent GM, Morgan
Gibson KM. Post-translational regulation of meval-
J, Barre P, et al. Comparative mortality of hemodialy-
onate kinase by intermediates of the cholesterol and
sis and peritoneal dialysis in Canada. Kidney Int 2000;
nonsterol isoprene biosynthetic pathways. J Lipid Res
8. Berkoben MD. Patient mortality in chronic dialysis:
23. Scoppola A, De Paolis P, Menzinger G, Lala A, Di Giulio
comparisons between hemodialysis and peritoneal di-
S. Plasma mevalonate concentrations in uremic pa-
alysis. Curr Opin Nephrol Hypertens 1999; 8:681–3.
tients. Kidney Int 1997; 51:908–12.
9. Miyata T, Ueda Y, Saito A, Kurokawa K. ‘Carbonyl
24. Mendis S, Sobotka PA, Euler DE. Expired hydrocar-
stress’ and dialysis-related amyloidosis. Nephrol Dial
bons in patients with acute myocardial infarction. Free
Transplant 2000; 15(Suppl 1):25–8.
O que são drogas psicotrópicas? Todo mundo já tem uma idéia do significado da palavra droga . Em linguagem comum, de todo o dia ("Ah, mas que droga " ou "logo agora, droga .", ou ainda, "esta droga não vale nada!"), droga tem um significado de coisa ruim, sem quali- dade. Já em linguagem médica, droga é quase sinônimo de medicamento. Dá até para pensar po
Vortrag Dr. Stephan Schleissing Röntgen-Gymnasium Würzburg, 24. Juni 2010 Das Innere röntgen Der Mensch im Blick von Naturwissenschaft und Theologie wo man Hände, Körper, ja das Gehirn durchleuchten kann, – bleibt da noch irgendetwas im Menschen selber unentdeckt, unerkannt und höchst persönlich? Müssen wir uns vor so einem „Röntgenblick“, der auch gut verhüllte Körper