Effect of hydroxyethylstarch in brain-dead kidney donors on renal
function in kidney-transplant recipients
M L Cittanova, I Leblanc, Ch Legendre, C Mouquet, B Riou, P Coriat
Plasma-volume expansion is necessary in brain-dead
Background Hydroxyethylstarch used as a plasma-volume potential organ donors mainly because of diabetes
ex pander in brain-dead kidney donors has been suggested insipidus, loss of sympathetic tone, and vasoplegia.1–3
to induce osmotic-nephrosis-like lesions. We have studied In a retrospective study, low-molecular-weight
its effect on kidney-transplant function. hydroxyethylstarch used as a plasma-volume expander
Methods 52 patients who had received hydroxyethylstarch
seemed to cause histological lesions resembling osmotic
nephrosis in about 80% of kidney recipients.4 However,
or iodinated contrast-media before brain death w ere
the impact of these lesions on transplanted kidney
ex cluded. 69 other brain-dead patients were prospectively
function could not be assessed. We therefore prospectively
included over 18 months and randomised into two groups.
studied the effects on renal function in kidney-transplant
In the hydroxyethylstarch-gelatin group, patients received recipients of administering hydroxyethylstarch plus gelatin
hydroxyethylstarch up to 33 mL/kg for colloid plasma- or gelatin alone to brain-dead potential donors.
volume expansion, and afterwards received modified fluid
gelatin. In the gelatin-only group, patients received only Patients and methods
modified fluid gelatin as colloid plasma-volume expander. Over 18 months, 121 brain-dead5 patients were diagnosed in our
Multiple organs were procured in 29 cases, which included intensive care unit. 52 patients who received hydroxyethylstarch
the kidneys in 27 cases (hydroxyethylstarch-gelatin 15, or iodinated contrast-media6 before the diagnosis of brain death
gelatin-only 12). were excluded. 69 patients were randomised into two groups
(figure 1). This protocol was approved by our local ethics
Findings There were no significant differences in the committee. Because of emergency, the family was not informed
characteristics of patients between the two groups of about randomisation. If the family refused consent later, the
kidney donors or of recipients (except for a small imbalance individual was withdrawn from the study. No family that agreed
in sex in the recipients). During the first 8 days after to multiple organ procurement refused consent to randomisation.
Among these 69, multiple organs were obtained in 29,
transplantation, nine of 27 ( 33%) patients required
including kidneys in 27 cases. Multiple organ procurement was
ex trarenal haemodialysis or haemodiafiltration in the not possible in 40 patients because of relatives’ refusal (25),
hydroxyethylstarch-gelatin group compared with one of 20 cardiac arrest (7), cancer (1), sepsis (2), viral hepatitis or HIV
(5%) in the gelatin-only group (p=0·029). Serum creatinine infection (3), and coroner’s refusal (2). We therefore studied 27
concentrations were significantly lower in the gelatin-only organ donors. Multiple organ recipients were excluded from the
group than in the other group (p=0·009). 10 days after final analysis (four received gelatin, three received
transplantation, mean ( SD) serum creatinine w as, hydroxyethylstarch). There were thus 15 donors in the
hydroxyethylstarch group and 12 in the gelatin-only group.
respectively, 145 (70) and 312 (259) µmol/L. All organ donors received fluid expansion according to
Interpretation These data suggest that hydroxyethylstarch transoesophageal echographic data. 7–9 Hypovolaemia was
diagnosed when left-ventricular end-diastolic area (LVEDa) was
used as a plasma-volume expander in brain-dead donors
below 5·5 cm2/m2. We also gave fluid expansion to patients with
impairs immediate renal function in kidney-transplant normal LVEDa but virtual obliteration of the left ventricle cavity
recipients. at the end of systole, which could be considered to reflect mild
hypovolaemia. Catecholamine doses were adjusted to obtain a
Lancet 1996; 348: 1620–22
mean arterial pressure between 60 and 100 mm Hg, after fluid
loading if necessary. In the hydroxyethylstarch group, brain-dead
patients needing colloids received hydroxyethylstarch (Elohes,
121 brain-dead donors considered
52 ex cluded
69 randomised; including 27
Département d’Anesthésie-Réanimation, Hôpital Pitié-Salpêtrière, 15 got hydrox yethylstarch- 12 got gelatin only
Paris (M L Cittanova MD, I Leblanc MD, C Mouquet MD PhD, gelatin
B Riou MD PhD, Prof P Coriat MD); and Service de Transplantation et
Réanimation, Hôpital Necker, Paris, France (Prof Ch Legendre MD)
Kidneys went to 27 Kidneys went to 20
Correspondence to: Dr M L Cittanova, Département d’Anesthésie- recipients recipients
Réanimation, Groupe hospitalier Pitié-Salpêtrière, 75651 Paris
Cedex 13, France Figure 1: Flowchart of participants
1620 Vol 348 • December 14, 1996
Gelatin-only group Hydroxyethylstarch- Gelatin-only group Hydroxyethylstarch-
(n=12) gelatin group (n=15) (n=20) gelatin group (n=27)
Age (years) 40 (17) 38 (12) Age (years) 44 (11) 44 (11)
Men/women 8/4 11/4 Men /women 9/11 20/7*
Brain-death duration (h) 16 (7) 16 (7) Mannitol administration 14 (70%) 18 (67%)
Dopamine administration 10 (83%) 9 (60%) Dopamine administration 11 (55%) 14 (52%)
Other catecholamine administration 4 (33%) 6 (40%) Mean frusemide requirement (mg) 500 (250) 630 (380)
Transfusion requirement 4 (33%) 5 (33%) Cold ischaemia duration (min) 1452 (482) 1591 (479)
Diabetes insipidus 11 (92%) 11 (73%) Warm ischaemia duration (min) 45 (10) 39 (12)
Crystalloid loading (mL) 1417 (1379) 873 (700) Preservation solution 3/17 2/25
Colloid loading (mL) 2875 (1384) 2300 (775) (UW/Euro-Collins)
Gelatin loading (mL) 2875 (1384) 200 (368) Early cyclosporin administration 5 (25%) 9 (33%)
Hydroxyethylstarch loading (mL) ·· 2100 (660) *p<0·05. UW=University of Wisconsin.
Data are mean (SD) or number (%) of patients. Table 2: Characteristics of kidney-transplant recipients
Table 1: Characteristics of brain-dead kidney donors
[SD]) 84  µmol/L in the hydroxyethylstarch group
Laboratoires Fresenius, Louvier, France) up to the maximum versus 89  µmol/L in the gelatin-only group.
recommended dose (33 mL/kg), and then gelatin (Plasmion,
There were no significant differences in age, cold and
Laboratoires Bellon, Neuilly sur Seine, France) when necessary
(n=4). In the gelatin-only group, patients received only gelatin for
warm ischaemia duration, preservation solution used,
plasma-volume expansion. frusemide, dopamine, and mannitol administration during
The following were recorded in brain-dead donors: age, sex, the 24 h after transplantation, and early cyclosporin
cause and duration of brain death, volume and nature of administration (table 2) between the two groups of kidney
crystalloid and colloid administered, need for dopamine or other recipients. There were more women in the
inotropic support, transfusion requirement, diabetes insipidus, hydroxyethylstarch group. Three kidney recipients in
and serum creatinine just before organ procurement. the hydroxyethylstarch-gelatin group received
Organs were procured according to our clinical practice. Either hydroxyethylstarch after transplantation.
Euro-Collins or UW-modified solution was used for kidney One out of 20 (5%) kidney recipients in the gelatin-only
preservation (UW=University of Wisconsin). Kidneys were
group needed extrarenal haemodialysis or
subsequently allocated to recipients in various transplant units.
The surgeons and physicians in charge of the kidney recipients haemodiafiltration during the first 8 days, compared with
were not aware of the kind of plasma expander used in the nine out of 27 (33%) recipients in the hydroxyethylstarch-
donors. In kidney-transplant recipients, the following were gelatin group (p=0·029). Serum creatinine for the first 10
recorded: age, sex, cold and warm ischaemia duration,
preservation solution used, frusemide, dopamine, and mannitol Gelatin
administration during the 24 h after transplantation, early 1000 Hydroxyethylstarch
cyclosporin administration (within the first week), use of
hydroxyethylstarch as plasma-volume expander (three patients),
Serum creatinine (µmol/L)
haemodialysis or haemodiafiltration requirement during the first
8 days, and serum creatinine on days 1, 2, 5, and 10. At one
institution, routine renal biopsies were done within 6 weeks of
transplantation; nine specimens were examined.
We compared the groups using 2 or Fisher’s tests, t tests, and 500
repeated-measures analysis of variance. All p values were two-
tailed, and p<0·05 was considered significant. To calculate the
sample size, we assumed a 20% frequency of extrarenal 250
haemodialysis or haemodiafiltration requirement in the controls
(gelatin-only group). 80 kidney recipients were required in each
group to detect a difference of at least 20%, with and values 0
of 0·05 and 0·20, respectively. An interim analysis of serum 0 1 2 5 10
creatinine values was done after 20 recipients had been analysed Days after transplantation
in each group, with the Haybittle-Peto approach in which
Figure 2: Serum creatinine after transplantation (mean, SD)
significance was tested at the 0·01 level in the interim analysis and
at 0·05 in the final analysis.10 The decision to stop the study was
taken after this interim analysis. We used NCSS 6.0 software
(BMDP Company, Los Angeles).
There were no significant differences in age, sex, cause
and duration of brain death, need for dopamine or other
inotropic support, and transfusion requirement between
the two groups (table 1). Although not significant, more
crystalloids and colloids were administered in the gelatin-
only group. However, it should be pointed out that
hydroxyethylstarch is considered to provide greater
volume and duration of plasma expansion than gelatin.11
Moreover, although not significant, the greater frequency
of diabetes insipidus in the gelatin-only group may have
led to greater crystalloid administration to compensate Figure 3: Kidney biopsy specimen
diuresis. No adverse reaction to either expander was Normal proximal tubule (white arrow) with osmotic-nephrosis-like
lesions in most tubules (black arrow) in patient of hydroxyethylstarch -
observed. Also, there was no significant difference in gelatin group (3400, trichrome Masson). Courtesy of L H Noël (Hôpital
serum creatinine level before organ procurement (mean Necker, Paris).
Vol 348 • December 14, 1996 1621
days after tranplantation was significantly lower in the extrarenal haemodialysis or haemodiafiltration in the
gelatin-only group than in the hydroxyethylstarch-gelatin hydroxyethylstarch-gelatin group probably decreased that
group (p=0·009) (figure 2). Nine renal-biopsy specimens group’s mean serum creatinine. The renal biopsies in nine
were examined (six in the gelatin-only group). All three kidney recipients showed osmotic-nephrosis-like lesions
specimens in the hydroxyethylstarch-gelatin group had only in the hydroxyethylstarch-gelatin group. Mostly
osmotic-nephrosis-like lesions in the tubules (figure 3). proximal but also distal tubules were affected. These
lesions were found in kidney-transplant biopsy specimens
Discussion as long as 2 years after transplantation (data from ChL),
In this prospective randomised study we found that which suggests a thesaurisoma mechanism.
administration of hydroxyethylstarch to brain-dead kidney
donors worsened the prognosis of renal transplantation.
We saw a higher frequency of extrarenal haemodialysis or References
haemodiafiltration during the first 8 days, and increased 1 Luksza AR. Brain-dead kidney donor: selection, care, and
serum creatinine during the first 10 days. administration. BMJ 1979; 1: 1316–19.
Low-molecular weight hydroxyethylstarch was 2 Goldstein D, DeKing D, Delong DJ, et al. Autonomic cardiovascular
state after severe brain injury and brain death in children. Crit Care
introduced in France in 1991. Its potential toxicity in Med 1983; 21: 228–33.
brain-dead kidney donors for kidney recipients has been 3 Bodenham A, Park GR. Care of the multiple organ donor. Intensive
suspected since 1993.4 In a retrospective study, Legendre Care Med 1989; 15: 340–48.
et al4 established that in kidney donors hydroxyethylstarch 4 Legendre Ch, Thervet E, Page B, et al. Hydroxyethylstarch and
osmotic-nephrosis-like lesions in kidney transplantation. Lancet 1993;
induced osmotic-nephrosis-like lesions, but without 342: 248.
obvious detriment in renal function in the recipient. This 5 Kofke WA, Darby JM. Evaluation and certification of brain death.
osmotic nephrosis involved proximal and distal tubules, In: Grande CM, ed. Textbook of trauma anesthesia and critical care.
whereas the osmotic nephrosis induced by other plasma- St Louis: Mosby Year Book; 1993: 994–1006.
6 Solomon R, Werner C, Mann D, et al. Effects of saline, mannitol, and
volume expanders involves proximal tubules only.12,13 furosemide on acute decreases in renal function induced by
Since this work, the potential renal toxicity of low- radiocontrast agents. N Engl J Med 1994; 331: 1416–20.
molecular-weight hydroxyethylstarch for brain-dead organ 7 Riou B, Dreux S, Roche S, et al. Circulating cardiac troponin T in
donors has only been examined in another retrospective potential heart transplant donors. Circulation 1995; 92: 409–14.
8 Riou B, Kalfon P, Arock M, et al. Cardiovascular consequences of
study, which showed no toxicity.14 Low-molecular-weight
severe hypophosphataemia in brain-dead patients. Br J Anaesth 1995;
hydroxyethylstarch has also been used as a preservative 74: 424–29.
solution in the recipient.15,16 However, Waldhausen et al17 9 Feigenbaum H. Echographic measurements and normal values. In:
reported two cases of acute deterioration of an already Feigenbaum H, ed. Echocardiography. 4th ed. Philadelphia: Lea &
Febiger; 1986: 621–39.
existing nephropathy after administration of
10 O’Brien PC, Shampo MA. Statistical considerations for performing
hydroxyethylstarch. multiple tests in a single experiment 6: testing accumulating data
We chose two endpoints to evaluate the effects of repeatedly over time. Mayo Clin Proc 1988; 63: 1245–50.
hydroxyethylstarch administration to kidney donors on 11 Baron JF. Low molecular weight hydroxyethyl starches. In: Baron JF,
immediate post-transplantation kidney function (serum ed. Plasma volume expansion. Paris: Arnette Blackwell, 1992: 121–32.
12 Maunsbach AB, Madden SC, Latta H. Light and electron microscopic
creatinine during the first 10 days and requirement for changes in proximal tubules of rats after administration of glucose,
haemodialysis or haemodiafiltration during the first 8 mannitol, sucrose or dextran. Lab Invest 1962; 11: 421–26.
days). We chose these indices because they are relatively 13 Di Scala VA, Mauntner W, Cohen JA, et al. Tubular alterations
objective, and used in many studies.18,19 We only assessed produced by osmotic diuresis with mannitol. Ann Intern Med 1965; 63:
the effect of fluid-loading on donor’s renal function for the 14 Coronel B, Larent V, Mercatello A, et al. L’hydroxyéthylamidon peut-
first 10 days, because delayed renal-function impairment il être utilisé lors de la réanimation des sujets en état de mort cérébrale
may be due to many (especially immunological) factors. pour don d’organe? Ann Fr Anesth Réanim 1994; 13: 10–16.
The impact of delayed graft function on allograft survival 15 Hoffmann RM, Stratta RJ, D’Allessandro AM, et al. Combined cold
storage-perfusion preservation with a new synthetic perfusate.
is controversial. However, most series show positive Transplantation 1989; 47: 32–37.
correlations between initial graft function and graft 16 Baatard R, Pradier F, Dantal J, et al. Prospective randomized
survival.20,21 comparison of University of Wisconsin and UW-modified, lacking
Among the 47 recipients studied, one of 20 required Hydroxyethyl-starch, cold-storage solutions in kidney transplantation.
Transplantation 1993; 55: 31–35.
haemodialysis or haemodiafiltration in the gelatin-only 17 Waldhausen P, Kiesewetter H, Leipnitz G, et al. Hydroxyethylstarch-
group compared with nine of 27 in the induced transient renal failure in preexisting glomerular damage. Acta
hydroxyethylstarch-gelatin group. The lowest percentage Med Austr 1991; 18 (suppl 1): 52–55.
of delayed graft function in kidney-transplant recipients is 18 Dawidson I, Berglin E, Brynger H, et al. Intravascular volumes and
colloid dynamics in relation to fluid management in living related
around 5%,22 close to that (7%) in our institution up to kidney donors and recipients. Crit Care Med 1987; 15: 631–36.
1990. By contrast, since 1992, when hydroxyethylstarch 19 Willms CD, Dawidson I, Dickerman R, et al. Intraoperative blood
was introduced in our institution, graft function has been volume expansion induces primary renal function after renal
delayed in 15–20% of the transplanted kidneys. Our transplantation: a study of 96 paired cadaver kidneys. Transplant Proc
1991; 23: 1338–39.
present results suggest that hydroxyethylstarch may have
20 Gjertson DW, Terasaki PI. The large center variation in half-lives of
been one of the factors involved. kidney transplants. Transplantation 1992; 53: 357–62.
Serum creatinine was significantly lower in the gelatin- 21 Cecka JM, Cho YW, Terasaki PI. Analyses of the UNOS Scientific
only group. Although serum creatinine is an imperfect Renal Transplant Registry at three years-early events affecting
transplant success. Transplantation 1992; 53: 59–64.
indicator of renal function assessment, its lowering by low-
22 Carlier M, Squifflet JP, Pirson Y, et al. Confirmation of the crucial role
molecular hydroxyethylstarch suggests noticeable toxicity of the recipient’s maximal hydration on early diuresis of the human
in this group of patients. Furthermore, the more frequent cadaver renal allograft. Transplantation 1983; 36: 455–56.
1622 Vol 348 • December 14, 1996