Effect of hydroxyethylstarch in brain dead kidney donors on renal

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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

Summary                                                               Introduction
                                                                      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
                                                                                              kidney donors

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

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                                                                                                                                                             THE LANCET

                                        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 [38] µmol/L in the hydroxyethylstarch group
Laboratoires Fresenius, Louvier, France) up to the maximum                          versus 89 [29] 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).

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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.

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