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Clinical Study
Am J Nephrol 1995;15:473-479
Enrique Grussa
Carmen Bern is3
Jose Francisco Tomasb
Cesar Garcia-Cantona
Angela Figuerab
Jose Luis M ot ellón3
Vicente Paraísoa
Juan Antonio Trover3
Jose Maria Fernandez-Rañadab
Acute Renal Failure in Patients
following Bone Marrow
Transplantation: Prevalence,
Risk Factors and Outcome
Departments of
a Nephrology and
b Hematology, Princesa Hospital. Autónoma
University, Madrid, Spain
To assess the prevalence, risk factors, clinical causes and outcome of acute
renal failure (ARF) following bone marrow transplantation (BMT), a retro­
spective analysis of 275 patients was undertaken. ARF was diagnosed in 72
patients (26%) and occurred in 81.9% within the first month. The three main
clinical causes were multifactorial (36%), nephrotoxic (29%), and veno-occlusive disease of the liver (VOD) 15%. The prevalence was higher in allogeneic
BMT (36%) than in autologous BMT (6.5%). Risk factors related to the devel­
opment of ARF were preexisting VOD and age older than 25 years. Logistic
regression in allogeneic BMT confirmed this association (VOD, odds ratio 3.8;
age ofer than 25, odds ratio 1.9). Underlying disease, graft-versus-host disease,
sepsis, conditioning therapy, and sex were not associated with ARF. Seven­
teen cases of ARF required hemodialysis (24%) mainly in association with
VOD (70.5%). The overall mortality from ARF was 45.8%, the dialyzed group
having the highest mortality (88%). Survival in the ARF group was contin­
uously worse up to 3 months and the actuarial survival at 10 years was 29.7
versus 53.2%. We conclude that ARF is a common complication mainly in
allogeneic BMT and carries a grave prognosis. VOD and age were risk factors
for ARF.
Bone marrow transplantation (BMT) has emerged in
recent years as a major form of treatment for a wide range
of hematologic, immunologic, metabolic and neoplastic
diseases. In summary the main steps of BMT are: (1) highdose chemoradiotherapy treatment (conditioning regi­
men) in order to obtain a potent immunosuppressive state
September 2. 1994
March 14, 1995
in the recipient that permits engraftment and also to
remove unwanted malignant cell populations, and (2) in­
fusion of a source of stem cells from a donor (allogeneic
BMT) or from the same patient (autologous BMT). In
spite of advances in the technical aspects of transplanta­
tion, disease relapse and regimen-related toxic deaths are
the main causes of BMT failure. Major complications and
toxicities of BMT are immunologic problems (graft-ver-
Dr. Enrique Gruss
Department of Nephrology
Princcsa Hospital
Zazuar 8 ,9°A. E3
E—28031 Madrid (Spain)
© 1995 S. Karger AG, Basel
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Key Words
Acute renal failure
Bone marrow transplantation
Veno-occlusive disease, liver
Type of transplant
Underlying disease
Conditioning therapy
Age. years
66 (36%)
28.2 ±9.6
24.7 ± 10.8
p< 0.01
p < 0.001
p < 0.001
pcO .O l
AL = Acute leukemia; CML = chronic myelogenous leukemia;
AA = aplastic anemia; Cy-TBI = cyclophosphamide-total body irra­
diation; Bu-Cy = busulfan-cyclophosphamide.
sus-host disease, GVHD), opportunistic infections, inter­
stitial pneumonitis and organ complications such as venoocclusive disease of the liver (VOD), cardiovascular and
pulmonary problems [1]. Although there is literature on
these complications, little information is available about
renal complications after BMT. In contrast to other
organs, such as the liver that is a primary target organ for
GVHD and chemoradiotherapy toxicity, kidneys are not
directly involved. Renal impairment after BMT is pre­
dominantly secondary to circulatory disturbances associ­
ated with VOD, and to sepsis in conjunction with the
wide use of nephrotoxic agents in these patients.
In an attempt to define the clinical causes and charac­
teristics of renal complications after BMT and to evaluate
their influence on clinical outcome, we have reviewed our
experience in 275 consecutice patients who received a
BMT for different diseases.
Patients and Methods
The medical records of 275 patients who received BMT in our
institution between October 1982 and December 1991 were re­
viewed. Minimum follow-up was 6 months. Patients were divided
into 2 groups according to the presence or absence of acute renal
Gruss et al.
failure (ARF). ARF was defined by two conditions: at least a dou­
bling of baseline creatinine, and also by reaching levels higher than
177 pmol/1 (2 mg/dl) [2]. All patients had a previously normal creati­
nine level (below 1.5 mg/dl). The characteristics of both groups are
presented in table 1.
All patients were isolated either in individual high pressure fil­
tered air or laminar air-flow rooms from day 7 until at least neutro­
phil recovery. The main conditioning regimens are shown in table 1.
Busulfan-cyclosphosphamide and cyclophosphamide-total body irra­
diation were mainly used as previously reported [3] for acute and
chronic leukemia. Other schemes, CBV (cyclosphosphamide,
BCNU. VP 16) and BEAC (BCNU, cytarabinc. VP 16. cyclosphos­
phamide) were used for lymphoma patients.
For allogeneic BMT non-T-cell-depleted bone marrows were used
in all cases and dimethylsulfoxide-cryopreserved bone marrows or
peripheral stem cells were used as a source of hematopoietic progeni­
tors in autologous BMT.
Since 1985 all allogeneic BMT patients received GVHD prophy­
laxis with cyclosporin-A (CsA) and a short course of methotrexate
according to the Seattle protocol [4]. Before 1985 GVHD prophylac­
tic regimens were either CsA or methotrexate alone as previously
described [5]. No autologous BMT patient was treated with CsA.
Serum samples for the determination of CsA levels by the fluores­
cence polarization immunoassay method were drawn twice a week,
immediately before the morning CsA dose. CsA adjustments were
made to try to keep levels between 159 and 300 pg/ml.
The following clinical information was gathered for each patient:
age: sex; underlying disease; conditioning regimen; type of trans­
plant; urea and creatinine levels before BMT and during the trans­
plant admission, and clinical complications. In the group with ARF
we also gathered: day of ARF after BMT; maximum creatinine level;
clinical cause of ARF; hemodialysis (HD) necessity, and outcome of
ARF. We associated ARF with 7 clinical causes: ( 1) nephrotoxicity,
when ARF developed with the use of potential nephrotoxic drugs in
the absence of other putative causes of ARF. Major nephrotoxic
drugs used in BMT are aminoglycosides, vancomycin, amphotericin
B and CsA. (2) VOD, when VOD preceded renal insufficiency. VOD
is a nonthrombotic obliteration of small intrahepatic veins by loose
connective tissue [6]. VOD was diagnosed based on clinical criteria,
statistically associated with the histologic abnormalities [7], when
two of the following events occurring within 20 days of transplanta­
tion were presented: hyperbilirubinemia (total serum bilirubin
>34.2 mmol/I, 2 mg/dl), hepatomegaly or right upper quadrant pain
of liver origin and sudden weight gain (>2% of baseline body weight)
because of fluid accumulation. No other explanation for these signs
and symptoms could be present at the time of diagnosis. (3) Sepsis,
when ARF developed with fever, hypotension, tachycardia and posi­
tive blood cultures. (4) Systemic capillary leak syndrome (SCLS),
when ARF developed according to the criteria previously reported
[8]. (5) Hemolytic uremic syndrome (HUS). ARF developed with
hemolytic microangiopatic anemia, thrombopenia and hypertension.
(6) Hemoglobinuria (HB), ARF developed on the same day of mar­
row infusion due to the presence of freeze-broken red cells on the
cryopreserved product. (7) Multifactorial, ARF was assigned to this
category when more than one of the above causes was present in the
same patient.
ARF was analyzed first in all the patients and a separate analysis
was performed in the allogeneic BMT group because of the special
circumstances that occurred in this group (greater incidence of ARF,
use of cyclosporin and greater incidence of VOD).
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Table 1. Data base and statistical comparison for groups
Statistical A nalysis
Table 2. Characteristics of ARF
The main characteristics of ARF are presented in
table 2. ARF occurred in 72 of 275 patients who under­
went BMT (26.2%) and in most cases appeared during the
first month after transplant (81.9%). The median dura­
tion of ARF was 14.4 days and in 89.7% of the patients
creatinine levels returned to normal.
The major causes of ARF, according to the clinical
classification given above, were as follows: (1) multifacto­
rial, 26 patients (36.1%); (2) nephrotoxicity, 21 patients
(29.1%); (3)VOD, 11 patients (15.3%); (4) sepsis, 6 pa­
tients (8.3%); (5) SCLS, 4 patients (5.5%); (6) HUS, 2
patients (2.7%), and (7) HB, 2 patients (2.7%). All cases in
the multifactorial group had nephrotoxic drugs, other
associated principal causes were: VOD (69%), and sepsis
(50%). CsA was the most common drug responsible for
renal injury in the nephrotoxic group. Higher levels were
found in most of the patients and the mean serum level
was 588 ± 47 ng/dl (79-1,182) for this group of patients.
Table 3 shows clinical data for 17 of the 72 patients
with ARF that required HD. The mean number of ses­
sions was 4.5 and most of them were carried out in the
first 2 weeks. The mean creatinine concentration was
4.6 mg/dl. Seventy percent of the dialyzed patients had
severe VOD preceding ARF.
The type of BMT was an important determinant for
the development of ARF, being more common in allo­
geneic (36%) than in autologous (6.5%) (p< 0.001) BMT.
The differences between both types of transplants are pre­
sented in table 4.
Table 4. Differences between allogeneic
BMT and autologous BMT
Allogeneic BMT
Autologous BMT
Total patients
72 (26.2%)
With ARF
Without ARF
Creatinine level, mg/dl
0.8 ±0.2 (0.4-1.5)
3.19± 1.3 (2-7,2)
1.1 ± 0.3 (0.5-1.8)
Time of ARF after BMT
1st month
2nd month
3rd month
4 (5.5%)
Evolution ARF during transplant hospitalization
Death with ARF
Recovery of total renal function
No recovery of total renal function
14.4 ± 8 (3-39)
Mean duration ARF, days
1 At discharge in surviving patients.
Table 3. Characteristics of hemodialysis
Number of patients
Mean age, years
Underlying disease
Indication for initiating dialysis
Volume overload
Severe azotemia (cr > 6 mg/dl)
Number of sessions
Day after BMT
Mean level of Cr, mg/dl
Associated disease
27.2 ± 8
4.5 ± 3.7 (1-16)
8.7 ± 5.4 ( 1—23)
4.6 ±1.6 (3-72)
Abbreviation are as in table 1.
66 (36%)
51 (27.9%)
6 (6.5%)
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Values are expressed as mean ± standard deviation or percent­
age. Univariate analyses were performed on the data employing '/}
statistics for discrete variables and the Student’s t test was used for
continuous variables.
Using the statistical analysis system package (SAS Institute 1984,
Cary, N.C., USA) in allogeneic transplants a stratified analysis by
Mantel-Haenszel method was conducted. Confidence intervals were
determined by the Cornfield method. After multivariate analysis,
multiple logistic regression was performed in allogeneic transplant.
Actuarial survival was analyzed by the Kaplan-Meier method.
Table 5. Data base and statistical comparison in allogogous
univariate multivariate
Age, years
27.6 ±9.2
p < 0.001
p < 0.0001
odds ratio 3.8
p < 0 .0 5
odds ratio 1.9
22.7 ± 9.9
p < 0.001
Abbreviations are as in table 1.
1 GVHD only in engrafted patients.
The data base and statistical comparison, by univar­
iate analysis, between the patients that developed ARF
and those without ARF are presented in table 1. The sex
distribution, underlying disease, and sepsis did not differ
between both groups. ARF was more common among
patients cyclophosphamide-total body irradiation as the
conditioning regimen (p < 0.01). The main factors associ­
ated with ARF were older ager (over 25 years) and VOD
preceding renal insufficiency. The prevalence of ARF
among patients older than 25 was 33.8% (43 of 127); in
those younger than 25, it was 19.6% (29 of 148; p < 0.01).
VOD was present in 43% (31 of 72) of patients with renal
failure, whereas it was present in only 12.8% (26 of 203)
patients without ARF (p < 0.001).
As ARF was especially prevalent among allogeneic
BMT patients a separate univariate and multivariate
analysis was performed in this group (table 5). Both stud­
ies confirmed the strong association between older age,
VOD and ARF. In this sense the global incidence of ARF
in patients older than 25 was 45.7% (37 of 81) vs. 28.4%
(29 of 102) (p < 0.0 T, odds ratio 1.9). On the other hand
Grusset al.
Fig. 1. Different actuarial survival rates (months) for the ARF
and non-ARF groups.
VOD was present in 47% (31 of 66) of the patients with
ARF vs. only 17% of those without ARF (20 of 177; p <
0.0001; odds ratio 3.8). Conditioning therapy was not sig­
Survival was significantly lower for those patients who
developed ARF because the transplant-related mortality
was 45.8% in the ARF group (33 of 72) vs. 17.7% (36 of
203) in the rest. A higher mortality rate was observed for
those patients who required HD: 88% (15 of 17). Among
those patients with ARF the highest mortality rate was
found in the VOD group (10 of 11) and the lowest in the
nephrotoxicity group (2 of 21).
The overall survival was worse in the ARF group at
1 month (69.4 vs. 88.1%) and 3 months (50 vs. 77.8%).
With a minimum follow-up of 6 months the actuarial
overall projected survival at 10 years was 29.7% for the
ARF group vs. 53.2% in those without ARF (p < 0.001;
fig. 1).
Organ toxicities other than bone marrow are common
side effects in BMT recipients. A lot of information is
available concerning liver, cardiopulmonary, neurologic,
and endocrine toxicities. This study shows that ARF is
also a very common complication of BMT because 26%
of the 275 patients analyzed developed renal damage
(36% in allogeneic transplant and 6% in autologous). This
experience is not unique. A retrospective study from the
Hutchinson Center conducted in 1989 found a 53% inci­
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Underlying disease
Conditioning therapy
(ATN) the incidence was relatively low in our group and
in other series [10]. It has been postulated that this low
incidence is due to the emergency of counter-balancing
cytoprotective pathways that may be the cytoprotectant
heat-shock proteins in relation with common hyperther­
mia following BMT [19]. ATN is also associated with HB
developing on the same day of marrow infusion in autolo­
gous BMT due to the presence of freeze-broken red cells in
the cryopreserved product [20], However, this complica­
tion can usually be avoided with good previous hydration,
and this could explain why only 2 of 92 autologous BMT
patients developed HB. ATN is also associated with
tumor lysis syndrome but we have not found a single case
because most transplanted patients were in remission or
routinely received prophylaxis with volume expansion.
Tubular dysfunction associated with high-dose cyclophos­
phamide and radiotherapy has been proposed [21]. The
influence of a conditioning regimen on renal function is
controversial. We found a higher incidence of ARF by
univariate analysis among patients that were treated with
cyclophosphamide-total body irradiation in the total
number of patients. This was not confirmed by multivar­
iate analysis in the more homogeneous group of allogeneic
BMT. It has been described as a belated impairment of
renal function associated with irradiation in autologous
BMT [22], Also some authors found that total body irra­
diation is the single most important risk factor for renal
damage at 6 months [18], but they conducted the study in
a small group without separately analyzing autologous
and allogeneic BMT.
Some cases of HUS following BMT have been pub­
lished [23] and we observed 2 cases. This syndrome is
associated with the vascular and thrombotic effects of
CsA in early BMT renal dysfunction [24] and with irra­
diation in late renal failure [10].
Another uncommon cause of ARF is SCLS. It is char­
acterized by attacks of a marked increase in capillary per­
meability in relation to liberation of leukotrienes [25] that
can cause intravascular volume depletion and hence
ARF. Four cases with this diagnosis were observed before
1985. Nowadays we consider this syndrome as volume
depletion in severe presentation of GVHD.
The study of HB has identified hepatic dysfunction
and weight gain as risk factors of ARF following BMT [9],
but these factors are included in the definition of VOD.
We have identified several factors that either contributed
to or correlated with the subsequent development of ARF.
In our series the main factor, as assessed by risk factor
analysis, was VOD. Forty-three percent of patients with
ARF had associated VOD versus 12.8% in the group
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dence [9] and recently this center reported a 40% inci­
dence [10]. The Johns Hopkins University School of
Medicine reported a 64% incidence of ARF after BMT
[11]. The lower incidence in our group can be explained
because there were fewer allogeneic BMTs, less mis­
matched grafts, no cases of tumor lysis syndrome, and
because of our more restricted definition of ARF (not only
by doubling the baseline creatinine but also by reaching
levels higher than 2 mg/dl).
Most of the ARFs developed in the first month after
BMT (81%) and nearly all the patients that recovered
renal function did so completely. This experience is simi­
lar to other series [9,11]. The main complications develop
during the first month after transplant: life-threatining
infections and potential use of nephrotoxic drugs; hepatic
toxicity (mainly VOD); acute GVHD, and the necessity of
prophylaxis with CsA (only in allogeneic transplant).
Therefore, it is understandable that ARF mainly develops
in this period, and that the first clinical cause was attribut­
ed to multifactoriality (VOD, sepsis, nephrotoxicity). It
can be extremely difficult to identify the underlying cause
of ARF in some patients. The important role of VOD and
its relationships with ARF will be discussed below. The
second clinical cause of ARF is nephrotoxicity. Of the
diverse nephrotoxic agents commonly employed in BMT,
CsA is one of the most relevant. Nephrotoxicity with CsA
was clearly dose-dependent with improvement after the
dose was lowered. Two forms of CsA nephrotoxicity are
recognized: an acute reversible form, and a chronic irre­
versible one (beyond the scope of this study). There is now
a consensus that acute CsA nephrotoxicity is the result of
alterations in intrarenal hemodynamics [12] due mainly
to an increase in renal vascular resistance associated with
a reduction in the glomerular filtration rate [ 13]. There is
also evidence that acute CsA nephrotoxicity is rapidly
reversible when CsA is stopped [13]. When vascular renal
lesions occur during CsA treatment, they are probably
triggered, enhanced or act with other nephrotoxic drugs
[14-16] or with other causes of endothelial damage
present in BMT as ischemia, infection and VOD [17].
Although other authors have not found this association
between CsA and BMT nephrotoxicity, the final end
point analysis (renal function at 6 months) and the ARF
criteria definition were different [9, 18]. In most cases
ARF caused by nephrotoxicity was reversible, HD was
not necessary, and mortality was low.
Less frequent clinical causes of ARF were sepsis,
SCLS, HUS and HB. Sepsis is very common in immunosuppressed BMT patients. Although BMT patients have
many potential risk factors for acute tubular necrosis
without ARF. By multivariate analysis in allogeneic trans­
plants VOD carried an odds ratio of 3.8. VOD occurs
principally as a complication of chemoradiation particu­
larly following BMT. Although jaundice is a risk factor for
the development of ATN, it probably was not the underly­
ing cause of renal failure. The observed hepatic dysfunc­
tion plays an important pathophysiologic role in the
induction of renal failure by decreasing renal perfusion
and producing prerenal azotemia [9]. Brief renal insuffi­
ciency is mainly hemodynamic and in many ways mimicks the hepatorenal syndrome. Investigators have found
that pretransplant levels of tumor-growth factor-P may
predict subsequent VOD and the probability of ARF [26].
Preventive and newer treatment measures in lessening
VOD and ARF, such as prostaglandins of the El group
[27], recombinant tissue plasminogen factor [28] or block­
ing tumor-necrosis factor-L (pentoxifylline) [29], are espe­
cially interesting but require further evaluation.
An age of more than 25 years was the second strongest
association with ARF. In spite of important advances in
BMT over the last 10 years, age persists as one of the most
important factors related to survival [30]. The higher inci­
dence of ARF in older patients could probably contribute
to this finding. This higher incidence of ARF in the oldest
patients could be explained by a lower renal function
reserve or because of a higher number of medical compli­
ARF was significantly more frequent in allogeneic
transplants than in autologous BMT. The major incidence
of VOD and the use of CsA definitely contributed to this
finding (table 4).
Another observation of our study was that develop­
ment of renal insufficiency had ominous implications for
patient survival. The overall mortality in the ARF group
was 45.8 versus 17% in the non-ARF group. However, in
patients who needed dialysis mortality increased to 88%.
The higher mortality for ARF dialyzed patients is not
related to the dialysis technique. Other authors found
mortality rates in the dialyzed group as high as ours [9]. A
potential explanation exists: 70% of the patients had
severe hepatic VOD preceding ARF, and the substantial
mortality and morbidity from VOD are significantly asso­
ciated with the subsequent onset of multiorgan failure.
This high mortality rate is similar to intensive care unit
multiorgan ARF [31]. Also this high incidence of VOD
could explain why volume overload, not severe azotemia,
is the usual indication for initiating dialysis. Approxi­
mately two thirds of the patients are monoliguric; how­
ever, after dialysis is begun oliguria frequently super­
Although nearly all cases with ARF that survived
recovered renal function completely at 1 month, renal
insufficiency is a bad prognostic marker for up to 3
months because the mortality rate in this group was signif­
icantly worse.
In summary ARF is a common and early complication
following BMT especially in allogeneic BMT and carries a
grave prognosis. Neither sex, nor underlying disease, nor
sepsis, nor GVHD, nor conditioning therapy correlated
with ARF. Both age and VOD are the main risk factors
that can increase the probability of ARF following BMT.
ARF associated with VOD is the main indication of HD.
The authors wish to thank Dr. F. Rodriguez Salvanés from the
Investigation Unit for his statistical assistance.
This work was supported in part by grant number 93/0522
awarded by the Fondo de Investigaciones Sanitarias de la Seguridad
Social o f the National Institute of Health of Spain.
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