Acute renal failure (ARF) is an important complication after stem cell transplantation (SCT). We retrospectively analysed ARF in 363 recipients of allogeneic myeloablative SCT to identify incidence, risk factors, associated post-transplantation complications and mortality of ARF. ARF was graded as grade 0 (no ARF) to grade 3 (need for dialysis) according to creatinine, estimated glomerular filtration rate and need for dialysis. The incidence of severe renal failure (grades 2 and 3 combined) was 49.6% (180 of 363 patients). Hypertension present at SCT was identified as a risk factor for ARF (P=0.003). Despite this, survival of these patients was not different compared to patients without hypertension. Admission to the intensive care unit (ICU) was a post-transplantation complication significantly associated with ARF (P<0.001). Survival rate was highest in patients with ARF grade 0–1 and lowest in patients with grade 3 (P<0.001). However, after correction for complications associated with high mortality (admission to the ICU, thrombotic thrombocytopenic purpura, sinusoidal occlusion syndrome (SOS) and acute graft-versus-host disease) the significant difference in survival disappeared, showing that ARF without co-morbid conditions has a good prognosis, and ARF with co-morbid conditions has a poor prognosis. This poor prognosis is due to the presence of co-morbid conditions rather than development of ARF itself.
Complications limit the success of allogeneic stem cell transplantation (SCT). In the first months after SCT, the major complications seen are sepsis (possibly leading to organ failure and admission to the intensive care unit (ICU)),1 sinusoidal occlusion syndrome (SOS) (also known as veno-occlusive disease),2 thrombotic thrombocytopenic purpura (TTP),3 acute graft-versus-host disease (GVHD)4 and cytomegalovirus (CMV) reactivation.5 Several of these complications can be accompanied by acute renal failure (ARF),2, 3, 6, 7, 8, 9 and are therefore risk factors for ARF. However, ARF can also occur in the absence of these complications, mainly as a result of nephrotoxic medications, such as amphotericin B8 and cyclosporine.10 Several additional risk factors have been described for ARF, including age above 25 years,10 high-risk malignancy, pulmonary toxicity and increased co-morbidity score.8 The major risk factors for ARF are not well defined and understanding these will enable interventions that can reduce incidence and severity of ARF.
Mortality is 2–3 times higher in patients with ARF compared to patients without ARF. When ARF patients need dialysis, mortality rates may rise to more than 80%, attributable to ARF.11 Whether the higher mortality in patients with ARF is directly caused by ARF or reflects pre-existing co-morbid complications, such as SOS and severe sepsis, remains unclear.12
The aim of this retrospective study was to identify major risk factors for ARF at the time of transplantation and to identify post-transplantation complications that are associated with ARF. Second, we investigated whether the increased mortality in ARF patients is primarily due to ARF or is influenced by other associated complications.
Patients and methods
Between January 1993 and January 2004 allogeneic myeloablative SCT was performed on 363 adult patients aged 17–57 years, at the Department of Haematology of the University Medical Centre, Utrecht. Patient data were collected and analysed retrospectively using a database and computerized patient records. Patients gave informed consent and were treated according to clinical protocols approved by the local investigation review board.
Stem cell transplantation procedure
All patients received a myeloablative-conditioning regimen that consisted of cyclophosphamide (60 mg/kg/day for 2 days), total body irradiation (TBI) (600 cGy/day for 2 days) with partial shielding of the lungs (total lung dose 850 cGy) and partial shielding of the kidneys (500 cGy/day for 2 days). After the second TBI fraction on day 0, the graft was infused. The graft was partially T-cell-depleted, as described earlier.13 In recipients of histocompatibility leukocyte antigen (HLA)-matched unrelated donor or a single HLA-antigen mismatched family donor, anti-thymocyte globulin (Rabbit ATG, Thymoglobulin, Sangstat, Amstelveen, the Netherlands) was given before cyclophosphamide was infused. All patients received GVHD prophylaxis with cyclosporine, which started on day −2 at a dose of 3 mg/kg/day by continuous infusion for 3–4 weeks. It was thereafter given orally for 4–6 weeks at a dose that gave comparable trough levels, followed by tapering. Dose adjustments were made to keep cyclosporine trough levels between 200 and 450 ng/ml. Serum creatinine and cyclosporine trough levels were measured at least twice a week during the first month, and at least once a week thereafter until the cyclosporine was stopped. When no active GVHD was present, cyclosporine was discontinued within 3 months after transplantation. GVHD was diagnosed according to the Seattle criteria.4 Acute GVHD grade I was treated with topical corticosteroids. Acute GVHD grade II or higher was treated with high-dose systemic corticosteroids. Limited chronic GVHD was not treated, and extensive chronic GVHD was treated with systemic corticosteroids, in some cases combined with cyclosporine.
Infection prophylaxis consisted of ciprofloxacin, fluconazole and amphotericine B given orally until granulocyte counts exceeded 500 cell/μl. Cephalotin was given intravenously from day +3 until day +13. Co-trimoxazole 480 mg twice daily and valacyclovir 500 mg twice daily were given orally from day +1 until 12 months after transplantation (or longer in cases of active GVHD).
Indication for dialysis in event of ARF was made by nephrologists based on the presence of hyperkalaemia and/or fluid overload. No patients were denied dialysis if an indication existed. Patients on ICU were treated with continuous renal replacement therapy. In other cases, intermittent dialysis was given.
Data on patient characteristics were collected at time of SCT. Hypertension before transplantation, previous autologous transplantation, gender, age, mismatched transplant, underlying disease and presence of high-risk malignancy were noted for all patients. The following complications were recorded (when they occurred within 3 months after transplantation): admission to ICU, acute GVHD, TTP, SOS and CMV reactivation.
Serum creatinine before transplantation as well as the highest serum creatinine within 3 months after transplantation were noted. For these two values, the glomerular filtration rate (GFR) was estimated, using the MDRD formula (GFR=186.3 × (serum creatinine)−1.154 × age−0.203 × (0.742 for women)).14 We also recorded four cyclosporine trough levels before the highest serum creatinine and the trough level at the day of the highest serum creatinine, and calculated the mean cyclosporine trough level.
ARF was defined as the occurrence of renal dysfunction within 3 months after transplantation. ARF was graded, as described earlier,11 as follows: grade 0 (or normal renal function) was equivalent to a decrease in estimated GFR of less than 25% of the value at time of transplantation. Grade 1 corresponded to a maximum of a twofold rise in serum creatinine concentration, with a decrease in estimated GFR of more than 25% of the value at time of transplantation. Grade 2 corresponded to more than a twofold rise in serum creatinine concentration of the value at time of transplantation, without indication for dialysis. Grade 3 corresponded to patients with grade 2 parameters, and requiring dialysis.
Hypertension before transplantation was defined as a documented history of hypertension, the use of antihypertensive drugs or a blood pressure of over 140/90 mm Hg on the day of admission for SCT. The development of hypertension within 3 months after transplantation was not an objective of this study.
Patients with acute leukaemia in first complete remission, chronic myelogenous leukaemia in first chronic phase and untreated severe aplastic anaemia were considered low risk; all other haematological diseases were considered high risk.
TTP was defined as the simultaneous occurrence of thrombocytopenia and haemolytic anaemia with red cell fragmentation, raised lactate dehydrogenase, raised bilirubin and decreased haptoglobin level.
SOS was defined as hyperbilirubinemia, right upper quadrant pain and weight gain within 20 days post-transplantation.
Continuous variables are displayed as the median, with ranges in parentheses. For dichotomous variables the frequency of occurrence is given along with the corresponding percentage.
Differences between groups in characteristics at time of transplantation or in complications within 3 months after transplantation were assessed with the χ2 test or Fisher's exact test (where appropriate). A two-sided Student's t-test was used for continuous variables. The relative contributions of continuous and dichotomous variables on the outcome of ARF were examined using stepwise multiple logistic regressions.
Survival was analysed by the Kaplan–Meier method. Curves were compared with the log-rank test. All P-values were two-sided, and a value of <0.05 was considered statistically significant.
All analyses were performed using SPSS version 12.0 (SPSS Inc., Chicago, IL, USA).
Occurrence of the different grades of ARF among 363 patients that underwent myeloablative SCT is depicted in Table 1. Severe ARF grade 2–3 occurred in 180 of 363 patients (49.6%) at a median of 40 days (range 7–90) after SCT (Figure 1). No difference in time of occurrence of ARF after SCT was found between January 1993 and January 2004. ARF occurred significantly earlier after SCT in patients who suffered from SOS (median of 19 days (range 7–48) (P<0.001)). There was no statistical difference in timing of ARF in patients with other complications.
Univariate analysis of patient characteristics at time of transplantation revealed a significantly higher proportion of patients with hypertension before transplantation in patients with ARF grade 2 and grade 3 compared to grade 0 or grade 1 (P=0.007). There was no statistical difference in age, gender, underlying disease, high-risk disease, type of transplant, mismatch transplant or creatinine and estimated GFR at time of transplantation between the groups (Table 2).
Univariate analysis of complications revealed that patients with grade 2 and grade 3 ARF were more often admitted to the ICU and had a higher incidence of TTP compared to patients with grade 0 or grade 1 ARF (P<0.001 and P<0.017, respectively). There was no difference in the incidence of SOS, acute GVHD grade 0–I, II or III–IV, and CMV reactivation in patients with grade 2 or grade 3 ARF compared to those with grade 0 or grade 1 ARF. The mean cyclosporine trough levels and the trough level at the time of the highest serum creatinine did not differ between patients with grade 0–1 ARF and patients with grade 2–3 ARF (Table 3).
Multivariate analysis of characteristics at time of transplantation as well as complications within 3 months after SCT revealed that hypertension present at transplantation and admission to the ICU were significantly associated with ARF grade 2 and 3 (P=0.003, OR 3.1 95% CI 1.4–6.6 and P<0.001, OR 18.4 95% CI 2.4–141.2, respectively).
After 6 months, 272 patients (74.9%) were still alive and 91 patients (25.1%) had died; 26 patients due to relapse (28.6%) and 65 patients due to complications (71.4%). The mortality rate was significantly higher in patients with grade 2–3 ARF compared to patients with grade 0–1 ARF (P=0.002). There were four patients with grade 3 ARF. Three out of four patients with grade 3 ARF died shortly after start of dialysis on the ICU; one of refractory septic shock due to Aspergillus infection, one of CMV disease, and one of an unknown cause. The one patient who survived grade 3 ARF needed dialysis for 10 days because of ARF induced by non-steroidal anti-inflammatory drug (NSAID). Of the patients with a survival of less than 6 months, those with grade 2–3 ARF died significantly more often from complications than from relapse (P=0.027) compared to patients with ARF grade 0 or grade 1 (Table 3).
There was no significant difference in cause of death between patients with or without hypertension before transplantation (P=1.00). Patients who suffered from the complications with acute GVHD grade III–IV, SOS, TTP or admission to the ICU all had a significantly higher mortality rate compared to patients who suffered from CMV reactivation, or who did not have complications.
Kaplan–Meier survival curves (Figure 2) of the three categories of renal failure (grade 1–3) showed significant difference in 6-month survival, with the best survival in patients with grade 1 ARF and the worst survival in patients with grade 3 ARF (P<0.001). After correction for complications with a high mortality (acute GVHD grade III and IV, SOS, TTP and admission to the ICU), the significant difference in 6-month survival between patients in the three grades of renal failure disappeared (P=0.240).
At 6 months after SCT, creatinine levels were significantly higher in patients with ARF grade 2–3 compared to patients with ARF grade 0–1 (P=0.014). After 12 months after SCT this difference disappeared.
ARF after SCT is a very common complication, occurring in almost all recipients of myeloablative SCT (93.4%) in our study. This high percentage of patients with renal failure was reported in an earlier study.11 In approximately half of the patients (49.6%), there is severe renal failure with at least a doubling of the serum creatinine, and in some cases dialysis is needed (1.1%).
A major objective of our study was to analyse whether patient characteristics at time of transplantation can predict the occurrence of ARF. We found that hypertension present before transplantation was the only predictor for ARF in this cohort. Although hypertension was only seen in 35 patients (9.6%) before SCT, 25 of them (71.4%) developed grade 2 or 3 ARF. There was no difference in 6-month survival or relapse rate of haematological disease between patients with, or without, hypertension at time of transplantation. Hypertension before transplantation as a risk factor for ARF was not identified in previous studies.6, 10, 11, 15, 16, 17, 18, 19 Hypertension is a known risk factor for chronic kidney disease.20 The patients with hypertension before SCT in our cohort did not have lower estimated GFRs (data not shown), so there was no apparent renal dysfunction. However, hypertension may have caused occult renal damage, which made the kidney more vulnerable to toxic medication used during and after SCT (e.g. cyclosporine), resulting in ARF. The underlying mechanism for hypertension as a risk factor for ARF needs further investigation. Treatment with calcium antagonists, lower doses of cyclosporine or use of other alternative immunosuppressants and pre-hydration might be helpful in decreasing the incidence of ARF in patients with hypertension. Although patients with hypertension are at risk for ARF, their prognosis at 6 months after SCT does not differ compared to patients without hypertension. In our cohort, none of the other characteristics present at time of transplantation was associated with ARF. We could not therefore confirm age above 25 years or high-risk malignancy as risk factors for ARF, in contrast to the studies that found these to be risk factors.8, 10
The first months after transplantation are recognized for their association with several complications that can have a relationship with ARF,10 and can cause increased mortality. We investigated several of these complications for their association with ARF and if complications with a high mortality influenced ARF-associated survival. We found that admission to the ICU was significantly associated with the occurrence of ARF. The main reasons for SCT patients to be admitted to the ICU are respiratory failure, cardiac failure, neurological complications, gastrointestinal bleeding and infections with associated sepsis.21 ARF is a very common complication of SCT patients on the ICU and has been reported to be associated with sepsis and/or liver failure.7 It is not therefore surprising that admission to the ICU was associated with ARF in this study. The second complication associated with ARF was TTP. TTP after SCT differs from classic TTP. The pathogenesis of SCT-related TTP is probably dependent on endothelial injury, and ADAMTS-13 is not decreased in contrast to classic TTP.22 There is substantial evidence that cyclosporine plays a role in the development of SCT-related TTP.23 In our patient cohort, 12 patients suffered from TTP, and 10 of them developed ARF grade 2–3 (Table 3). In the majority of these patients, the occurrence of ARF preceded TTP. The association between ARF and TTP may indicate a shared pathophysiological mechanism of endothelial dysfunction, which causes ARF before apparent thrombocytopenia and haemolysis occur. Cyclosporine toxicity may contribute to this endothelial dysfunction.
The median time to occurrence of ARF after SCT in our study was 40 days. This is longer than reported in other studies.9, 10, 24 The one complication that was associated with a significantly shorter time to occurrence of ARF after SCT was SOS. In patients suffering from SOS, ARF developed within a median of 19 days after SCT. In our study a relatively small proportion of patients (4.4%) suffered from SOS compared to other studies.6, 8, 10 This might explain the relatively long median time to occurrence of ARF in our whole cohort compared to other studies, in which a greater number of SOS may have shortened the median time to development of ARF for all patients.
As seen in other studies, as well as ours, mortality rates during the first 6 months post-transplantation were significantly higher for patients with ARF.11 Survival curves of three categories of ARF showed a significant difference in survival between patients with grade 1 ARF versus grade 2 and grade 3 ARF. To analyse whether the lower survival rate of grade 2 and 3 ARF was due to ARF only, or was a reflection of severe complications with a high mortality, we corrected for these complications. After this correction the difference in survival vanished and was comparable for all grades of ARF. The majority of patients with ARF did not experience one of the severe complications and these patients did not have decreased survival rates, even in the event of grade 2 ARF or the one patient with grade 3 ARF induced by use of a NSAID. Together, these data suggest that if no co-morbid conditions are present, survival rates are not influenced by ARF. The differences in survival shown in Figure 2 are thus entirely attributable to the presence of a severe complication, instead of the development of ARF per se. The development of ARF in the absence of complications is most probably due to drug-induced nephrotoxicity. Cyclosporine is known to cause ARF. It is also known that cyclosporine trough levels do not always correlate with the occurrence of ARF.15 There is evidence that acute cyclosporine nephrotoxicity is rapidly reversible when cyclosporine treatment is stopped. This reversibility may explain the low mortality in patients with ARF due to nephrotoxic drugs.10 Adequate monitoring of serum creatinine is crucial in detecting drug-induced nephrotoxicity and a concomitant rise of serum creatinine, to stop or adjust the dose of nephrotoxic drugs where possible.
In summary, we conclude from this retrospective study of 363 recipients of allogeneic myeloablative SCT that ARF is a very common complication. We identified hypertension present at time of SCT to be the only risk factor for occurrence of ARF after SCT. However, the prognosis at 6 months after SCT of patients with hypertension at time of SCT is similar to patients without hypertension.
Complications associated with development of ARF grade 2–3 are admission to the ICU and TTP. At first sight, survival rates seem to be influenced by the degree of ARF. Grade 0 and grade 1 ARF have similar six-month survivals, whereas grade 2 ARF has a significantly lower survival, and grade 3 ARF has the lowest survival. However, after correction for complications with a high mortality (acute GVHD grade III-IV, SOS, TTP or admission to the ICU) survival of all grades of ARF are comparable, showing that ARF without co-morbid conditions has a good prognosis, and ARF with co-morbid conditions has a poor prognosis. This poor prognosis is due to the presence of co-morbid conditions rather than development of ARF itself.
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We thank Dr P Westers, Centre of Biostatistics University Utrecht, for expert statistical assistance. We are also grateful to MI Gerrits, J vd Giessen and Dr E Meijer (Department of Haematology, University Medical Centre Utrecht) for providing data.
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Kersting, S., Koomans, H., Hené, R. et al. Acute renal failure after allogeneic myeloablative stem cell transplantation: retrospective analysis of incidence, risk factors and survival. Bone Marrow Transplant 39, 359–365 (2007). https://doi.org/10.1038/sj.bmt.1705599
- acute renal failure
- stem cell transplantation
- intensive care unit
- thrombotic thrombocytopenic purpura
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