(Hypertension. 1998;31:1201-1202.)
© 1998 American Heart Association, Inc.
Is Plasma Ac-SDKP Level a Reliable Marker of Chronic Angiotensin-Converting Enzyme Inhibition in Hypertensive Patients?
Yannick Le Meur;
; Jean-Claude Aldigier
Service de Néphrologie,
Centre Hospitalier Universitaire,
Limoges, France
Vincent Praloran
Laboratoire d'Hématologie Expérimentale,
Faculté de Médecine,
Limoges, France
To the Editor:
In a recent article, Azizi et al1 suggested
that the plasma levels of N-acetyl-seryl-aspartyl-lysyl-proline
(Ac-SDKP) could be a reliable marker of chronic
angiotensin-converting enzyme (ACE) inhibition in
hypertensive patients treated by ACE inhibitors (ACEI). We
were concerned by their results because some of them contradict while
others agree with several of our very recent findings. The tetrapeptide
Ac-SDKP (molecular weight, 487 D), a physiological
inhibitor of the proliferation of hematopoietic stem
cells2 that is present in normal plasma at
stable concentrations,3 is degraded by ACE both
in vitro and in vivo.4 5 In a previous study in
healthy volunteers, Azizi et al6 showed that a
single oral dose of captopril, an ACEI, transiently increases the
plasma levels of Ac-SDKP. In a recent study, we showed that 15-day
treatment of healthy volunteers by another ACEI (enalapril) permanently
increases the plasma concentrations and daily urinary elimination of
Ac-SDKP by approximately 4-fold and modifies the levels of blood
hematopoietic progenitors.7 In the
Hypertension article cited above, Azizi et
al1 showed that chronic treatment of hypertensive
patients by any type of ACEI permanently increased plasma Ac-SDKP
levels by 5 times compared with levels in non-ACEI hypertensive
patients or healthy control subjects. They thus suggested that plasma
Ac-SDKP levels could be a better marker of the compliance of
hypertensive patients to their chronic ACEI treatment than the
currently used markers of ACE activity, such as plasma renin or
angiotensin II/angiotensin I ratio. Azizi et al
also found evidence that the plasma Ac-SDKP levels correlated to the
creatinine clearance in the ACEI-treated group but not in
the non-ACEI–treated group of patients. These data led them to suggest
that "it is the accumulation of the ACE inhibitor in
plasma associated with renal failure and not renal failure per se that
is responsible for the higher levels of the peptide when the renal
clearance of ACE inhibitors is impaired." However, they
mentioned that this point warranted further investigation because
"only very few non-ACEI patients had severe renal
insufficiency."
The results of an investigation that we recently performed in 56
uremic patients (21 being treated with an ACEI) and 51 healthy control
subjects contradict this hypothesis. The creatinine
clearance of these chronic renal failure (CRF) patients (calculated
with the Crockroft formula) ranged from 4 to 82 mL/min (median, 18.65
mL/min). The plasma concentrations of Ac-SDKP were significantly higher
(P<0.01) in CRF patients without ACEI (range, 0.83 to 11.69
pmol/mL; median, 2.74 pmol/mL) than in controls (range, 0.4 to 6
pmol/mL; median, 1.5 pmol/mL). Plasma Ac-SDKP was still much higher in
CRF patients with ACEI (range, 1.37 to 40.2 pmol/mL; median, 12.15
pmol/mL). We also showed that in CRF patients without ACEI, the plasma
levels of Ac-SDKP inversely correlated with the creatinine
clearance (r=-0.57, P<0.01). Conversely, unlike
Azizi et al,1 we did not find a similar
correlation in ACEI patients. Moreover, some of our ACEI-treated CRF
patients did not have higher levels of plasma Ac-SDKP than
non-ACEI–treated CRF patients or even than healthy control subjects.
Therefore, at least in our study, Ac-SDKP cannot discriminate patients
taking from those not taking an ACEI. This could be explained by the
fact that our CRF patients, with different degrees of renal
insufficiency, received different types and dosages of ACEI. Together
with those of our previous study,7 our
present data confirm that the renal elimination of Ac-SDKP plays a
major role in the mechanisms regulating its plasma levels, as could be
expected from the low molecular weight (487 D) of Ac-SDKP. These data
contradict the hypothesis of Azizi et al mentioned above.
In consideration of the well-known direct effect of Ac-SDKP on
the cycling of hematopoietic progenitors,8 Azizi
et al also suggest that chronic accumulation of Ac-SDKP in plasma
during ACEI treatment could participate in the alterations of
hematopoiesis observed in CRF and renal transplant patients. This
hypothesis is supported by our recent results showing a decrease of
blood committed hematopoietic progenitors (BFU-E and CFU-GM),
contrasting with an increase of early progenitors (CFU-mix) in
ACEI-treated healthy controls.7 In addition, it
is interesting that Mrug et al9 very recently
showed that angiotensin II increases the in vitro
proliferation of erythroid progenitors. Therefore, a significant
increase in Ac-SDKP (which inhibits the proliferation of primitive
hematopoietic progenitors) together with a decrease of
angiotensin II (which activates late erythropoietic
progenitors) in the plasma of ACEI-treated patients could reduce the
erythroid commitment of primitive hematopoietic progenitors, as well as
the proliferation and differentiation of later committed erythroid
precursors in CRF patients. These aspects of potential therapeutic
interest warrant further investigations.
References
1.
Azizi M, Ezan E, Nicolet L, Grognet JM, Ménard J.
High plasma level of N-acetyl-seryl-aspartyl-lysyl-proline: a new
marker of chronic angiotensin-converting enzyme inhibition.
Hypertension. 1997;30:1015–1019.[Abstract/Free Full Text]
2.
Guigon M, Bonnet D. Inhibitory peptides in
hematopoiesis. Exp Hematol. 1995;23:477–481.[Medline]
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3.
Frindel E, Montpezat JP. The
physiological role of the endogenous
CFU-S inhibitor acetyl-N-Ser-Asp-Lys-pro (Ac-SDKP).
Leukemia. 1989;3:753–755.[Medline]
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4.
Rieger KJ, Saez-Servent N, Papet MP, Wdzieczak-Bakala J, Morgat
JL, Thierry J, Voelter W, Lenfant M. Involvement of human plasma
angiotensin I-converting enzyme in the degradation of the
haemoregulatory peptide N-acetyl-seryl-aspartyl-lysyl-proline.
Biochem J. 1993;296:1–6.
5.
Rousseau A, Michaud A, Chauvet MT, Lenfant M, Corvol P. The
hematoregulatory peptide N-acetyl-Ser-Asp-Lys-pro is a natural and
specific substrate of the N-terminal active site of human
angiotensin-converting enzyme. J Biol Chem. 1995;270:3656–3661.[Abstract/Free Full Text]
6.
Azizi M, Rousseau A, Ezan E, Guyene TT, Michelet S, Grognet JM,
Lenfant M, Corvol P, Ménard J. Acute
angiotensin-converting enzyme inhibition increases the
plasma level of the natural stem cell regulator
N-acetyl-seryl-aspartyl-lysyl-proline. J Clin Invest. 1996;97:839–844.[Medline]
[Order article via Infotrieve]
7.
Comte L, Lorgeot V, Volkov L, Allegraud A, Aldigier JC,
Praloran V. Effects of the angiotensin-converting enzyme
inhibitor enalapril on blood haematopoietic progenitors and
acetyl-N-Ser-Asp-Lys-Pro concentrations. Eur J Clin
Invest. 1997;27:788–790.[Medline]
[Order article via Infotrieve]
8.
Bonnet D, Lemoine FM, Pontvert-Delucq S, Baillou C, Najman A,
Guigon M. Direct and reversible inhibitory effect of the
tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (Seraspenide) on the growth of
human CD 34+ subpopulations in response to growth factors.
Blood. 1993;82:3307–3314.[Abstract/Free Full Text]
9.
Mrug M, Stopka T, Julian BA, Prohal JF, Prohal JT.
Angiotensin II stimulates proliferation of normal early
erythroid progenitors. J Clin Invest. 1997;100:2310–2314.[Medline]
[Order article via Infotrieve]
Response
Michel Azizi
Broussais Hospital Clinical Investigation Center,
INSERM and Assistance Publique des Hôpitaux de Paris,
Paris, France
Eric Ezan
Service de Pharmacologie et d'Immunologie CEA, Gif-sur-Yvette, France
We are very pleased that Le Meur et al read in detail our
article showing that plasma Ac-SDKP concentration is
consistently high when ACE is chronically
inhibited1 and that they presented their
own recent results on hematopoietic cells.2 Both
results show the importance of the ACEI-induced increase in
endogenous Ac-SDKP levels in
plasma1 3 and possibly also in tissues, not only
in accounting for the hematologic effect of ACEIs (in particular for
conditions such as CRF4) but also as a new
therapeutic strategy to prevent hematologic toxicity of anticancer
chemotherapy.5 6
The discussion on the absence or presence of a relationship between
plasma Ac-SDKP levels and creatinine clearance may not be
useful and perhaps may be even misleading. Both studies found (1 ) lower
Ac-SDKP levels in patients with normal renal function than in patients
with renal dysfunction and (2 ) a further increase in plasma Ac-SDKP
levels in ACEI-treated patients with CRF. Therefore, the data of Le
Meur et al agree with our results more than they contradict them. The
presence or absence of a correlation may be due to multiple minor
problems: selection of different patients and of different types and
doses of ACEIs, aberrant values, inappropriate statistical tests, and
above all, low power of both studies.
Our last point of concern is that plasma Ac-SDKP determination
did not detect chronic ACE inhibition in some of their patients with
CRF, the number of whom was not reported. This is in contradiction to
the pharmacokinetics of the exogenous peptide,7
the metabolism of the peptide (for which no enzymatic
pathway other than that involving ACE exists8),
the pharmacokinetics of all ACEIs that accumulate in plasma and tissues
during renal failure,9 and their own data showing
urinary elimination of the peptide.2 Other than a
possible problem in the timing of the blood sampling, which was not
reported in the study of Le Meur et al (blood taken after dialysis or
more than 24 hours after intake of a low dose of an ACEI in a patient
with a mild degree of renal failure), the only other possible
explanation is lack of compliance with the ACEI treatment by the
patients. This emphasizes that the determination of plasma Ac-SDKP is a
very sensitive method for the detection of an ACEI in the body, which
can be used by physicians to check their patients' compliance with a
simple measurement.1
References
1.
Azizi M, Ezan E, Nicolet L, Grognet JM, Ménard J.
High plasma level of N-acetyl-seryl-aspartyl-lysyl-proline: a new
marker of chronic angiotensin-converting enzyme inhibition.
Hypertension. 1997;30:1015–1019.
2.
Comte L, Lorgeot V, Volkov L, Allegraud A, Aldigier JC,
Praloran V. Effects of the angiotensin-converting enzyme
inhibitor enalapril on blood haematopoietic progenitors and
acetyl-N-Ser-Asp-Lys-Pro concentrations. Eur J Clin
Invest. 1997;27:788–790.
3.
Azizi M, Rousseau A, Ezan E, Guyene TT, Michelet S, Grognet JM,
Lenfant M, Corvol P, Ménard J. Acute
angiotensin-converting enzyme inhibition increases the
plasma level of the natural stem cell regulator
N-acetyl-seryl-aspartyl-lysyl-proline. J Clin Invest. 1996;97:839–844.
4.
Hirakata H, Onoyama K, Iseki K, Kumagai H, Fujimi S, Omae T.
Worsening of anemia induced by long-term use of captopril in
hemodialysis patients. Am J Nephrol. 1984;4:355–360.[Medline]
[Order article via Infotrieve]
5.
Bogden AE, Carde P, Deschamps de Paillette E, Moreau J-P,
Tubiana M, Frindel E. Amelioration of chemotherapy-induced toxicity by
cotreatment with AcSDKP, a tetrapeptide inhibitor of
hematopoietic stem cell proliferation. Ann NY Acad Sci. 1991;628:126–139.[Medline]
[Order article via Infotrieve]
6.
Carde P, Chastang C, Goncalves E, Mathieu-Tubiana N, Vuillemin
E, Delwail V, Corbion O, Vekhoff A, Isnard F, Ferrero J-M,
Garcia-Giralt E, Gimonet J-F, Stoppa A-M, Léger-Picherit E, Fadel
E, Monpezat J-P, Munck J-N, Domenge C, Khayat D, Guilhot F.
Séraspénide (acétyl SDKP): étude en phase I-II
d'un inhibiteur de l'hématopoièse la protégeant de
la toxicité de monochimiothérapies aracytine et ifosfamide.
CR Acad Sci Paris. 1992;315:545–550.
7.
Ezan E, Carde P, Le Kerneau J, Ardouin T, Thomas F, Isnard
F, Deschamps de Paillette E, Grognet JM. Pharmacokinetics in healthy
volunteers and patients of NAc-SDKP (Seraspenide), a negative regulator
of hematopoiesis. Drug Metab Dispos. 1994;22:843–848.[Abstract]
8.
Rieger KJ, Saez-Servent N, Papet MP, Wdzieczak-Bakala J, Morgat
JL, Thierry J, Voelter W, Lenfant M. Involvement of human plasma
angiotensin I-converting enzyme in the degradation of the
haemoregulatory peptide N-acetyl-seryl-aspartyl-lysyl-proline.
Biochem J. 1993;296:1–6.
9.
Hoyer J, Schulte KL, Lenz T. Clinical pharmacokinetics of
angiotensin converting enzyme (ACE) inhibitors
in renal failure. Clin Pharmacokinet. 1993;24:230–254.[Medline]
[Order article via Infotrieve]
