| Abstract|| |
Renal insufficiency is a common complication early after hematopoietic cell transplantation (HCT). We retrospectively examined the incidence, risk factors and associated mortality of acute renal failure (ARF) in a cohort of 101 consecutive allogeneic HCT patients. These patients were reviewed to determine their baseline characteristics, the presence of co-morbid conditions and mortality rates at one year. ARF was defined by the doubling of the baseline serum creatinine (Scr) levels. The mean age of the 101 study patients was 34 ± 11.8 years. Of them, 58 (57.4%) had ARF, yielding an incidence of 2.6% per week during the first year following HCT. The peak frequency of ARF occurred during the second week (29.3%). The need for hemodialysis, a proof of the severity of ARF, was seen in 12 cases (20.7%). On univariate analysis, the Scr at one month greater than 90 μmol/L (P = 0.008), use of aminoglycosides (P < 10 -3 ), the presence of veno-occlusive disease (VOD) (P < 10 -3 ) and the need for admission to the intensive care unit (ICU) (P = 0.003) were associated with a significantly increased risk of ARF. On multivariate analysis, the independent variables associated with an increased risk for ARF were the presence of VOD [P = 0.07, relative risk (RR) = 2.06] and use of aminoglycosides (P < 10 -3 , RR = 11.2). The overall mortality rate among the study patients was 35.6% at the end of the first year. On multivariate analysis, only the use of aminoglycosides (P = 0.02, RR = 0.31), admission to the ICU (P < 10 -3, RR = 7.29) and the development of ARF (P = 0.001, RR = 8.97) were independent predictors of mortality. Our study shows that ARF is highly prevalent during the early period following HCT and increases mortality, particularly if dialysis dependent. It frequently occurs following VOD and aminoglycoside use. As the prognosis is rather grim, it is very important that the associated factors be identified early, for an effective prevention of this disease.
|How to cite this article:|
Helal I, Byzun A, Rerolle JP, Morelon E, Kreis H, Bruneel-Mamzer MF. Acute renal failure following allogeneic hematopoietic cell transplantation: Incidence, outcome and risk factors. Saudi J Kidney Dis Transpl 2011;22:437-43
|How to cite this URL:|
Helal I, Byzun A, Rerolle JP, Morelon E, Kreis H, Bruneel-Mamzer MF. Acute renal failure following allogeneic hematopoietic cell transplantation: Incidence, outcome and risk factors. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2019 Apr 24];22:437-43. Available from: http://www.sjkdt.org/text.asp?2011/22/3/437/80477
| Introduction|| |
Bone marrow transplantation (BMT) has become a widely used therapy for various malignant and non-malignant diseases.  Complications limit the success of allogeneic hematopoietic cell transplantation (HCT). In the first months after HCT, the major complications seen are sepsis [possibly leading to organ failure and admission to the intensive care unit (ICU)],  sinusoidal occlusion syndrome (SOS) [also known as veno-occlusive disease (VOD)],  thrombotic thrombocytopenic purpura (TTP),  acute graft-versus-host disease (GVHD)  and cytomegalovirus (CMV) reactivation.  Several of these complications can be accompanied by acute renal failure (ARF) ,,,,, and are therefore risk factors for ARF. The incidence of ARF in the early period following myelo-ablative HCT varies from 30 to 90% and is higher in patients receiving an allogeneic HCT. ,,,, Mortality is 2-3 times higher in patients with ARF compared to those without ARF. When ARF patients need dialysis, the mortality rates may rise to more than 80%. 
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. 
In an attempt to define the clinical causes and characteristics of renal complications after allogeneic HCT and to evaluate their influence on clinical outcome, we studied 101 consecutive patients who had received allogeneic HCT for different diseases.
| Patients and Methods|| |
One hundred and one patients who had undergone allogeneic HCTs at Necker Hospital between March 1991 and May 2002 were clinically assessed. These patients were reviewed to determine their baseline characteristics including: age, gender, underlying disease, marrow donor, chemotherapy and conditioning regimen, nephrotoxic drug exposure, development of co-morbid conditions and mortality at one year.
ARF was defined by the doubling of the baseline serum creatinine (Scr) concentration within one year after transplantation. TTP was defined as the simultaneous occurrence of thrombocytopenia and hemolytic anemia with red cell fragmentation, raised lactate dehydrogenase, raised bilirubin and decreased haptoglobin level. SOS was defined as hyper-bilirubinemia, right upper quadrant pain and weight gain.
| Statistical Analysis|| |
Continuous variables are reported as mean ± SD. For dichotomous variables, the frequency of positive occurrences is given along with their corresponding percentages. Each factor was contrasted by univariate analysis, using either unpaired Student's "t" test for continuous variables, or by χ2 analysis for non continuous data. Significant factors by univariate analysis were then compared by multiple analyses and the relative risk (RR) for each was calculated. Statistical significance was accepted for P less than 0.05. Comparisons between Kaplan-Maier curve of patients were made using Log-rank test. All analyses used SPSS 11.0 software.
| Results|| |
Patient baseline characteristics
The baseline characteristics of the 101 patients included in the study are shown in [Table 1]. Forty-two women and 59 men, with an average age of 40 ± 11.8 years, were studied. Different treatment protocols were used according to the diagnosis and stage of the underlying disease. A total of 82 patients (81.2%) had received total body irradiation (TBI) in addition to chemotherapy prior to HCT.
|Table 1: Baseline characteristics of patients who received an allogeneic hematopoietic cell transplantation.|
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The majority of patients (95/101: 95%) had received cyclosporine prophylaxis and overall, 67 patients (66.3%) developed acute GVHD. Only 12 of the 101 patients (11.9%) developed VOD. Of the 101 patients, 40 (39.6%) were admitted to the ICU, mainly for septic shock in 14 cases (35%) and acute respiratory failure in 11 (27.5%) cases.
Renal dysfunction and predictive factors
Fifty-eight patients (57.4%) presented with ARF corresponding to an incidence of 2.6% per week during the first year following HCT. The peak frequency of ARF occurred during the second week (29.3%).
The major causes of ARF were as follows: nephrotoxicity in 24 (41.4%), multi-factorial in 19 (32.75%) and associated VOD in 12 patients (20.7%). The need for hemodialysis, a proof of the severity of ARF, was seen in 12 patients (20.7%).
On univariate analysis, the age, sex, type of underlying disease, conditioning regimens (TBI or without TBI), bone marrow donor (related or unrelated), cyclosporine prophylaxis, baseline Scr, use of anti-fungal drugs and the frequency of GVHD were not associated with a significant risk for ARF. On the other hand, Scr level greater than 90 μmol/L at one month (P = 0.008), aminoglycoside use (P < 10 -3 ), the development of VOD (P < 10 -3 ) [Figure 1] and admission to the ICU (P = 0.003) were associated with a significantly increased risk for ARF [Table 2]. On multivariate analysis on logistic regression, the independent variables associated with increased risk for ARF were the development of VOD (P = 0.07, RR = 2.06) and aminoglycoside use (P < 10 -3 , RR = 11.2).
|Table 2: Univariate and multivariate analysis of risk factors for acute renal failure.|
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In addition, analysis of the entire group revealed a significant rise in Scr over time after transplantation. The baseline Scr was 71.99 μmol/L and the value at one month was 115.35 ± 50.53 (P < 10 -3 ), at six months was 101.05 ± 34.51 (P < 10 -3 ), and at one year was 99.91 ± 29.89 (P < 10 -3 ).
Mortality and predictive factors
The overall mortality rate for the 101 allogeneic HCTs was 35.6% at the end of the first year. The mortality rate for the 58 patients who had developed ARF was 43.1% at the end of the first year ([Table 3]; [Figure 1], [Figure 2]). The survival rates for patients who had developed ARF as against those that did not at one month, six months and one year were 87.9% versus 97.7%, 65.5% versus 90.7% and 56.9% versus 81.4%, respectively. Thus, survival was significantly lower for patients who developed ARF [Table 3]. Among the patients with ARF, the highest mortality rate was found in the VOD group (9 out of 12).
|Table 3: Survival of patients with or without acute renal failure (ARF).|
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|Figure 1: Kaplan– Maier survival curve for all patients after hematopoietic cell transplantation (HCT).|
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|Figure 2: Different Kaplan– Maier survival curves for the groups with and without acute renal failure (ARF) (P = 0.001, RR = 8.97).|
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On univariate analysis, the age, sex, type of underlying disease, conditioning regimens (TBI or without TBI), bone marrow donor (related or unrelated), cyclosporine prophylaxis, baseline Scr, use of anti-fungal drugs and the frequency of GVHD were not associated with a significant risk of mortality. Only the Scr level greater than 130 μmol/L at one month (P = 0.029), use of aminoglycosides (P = 0.041), development of VOD (P < 10 -3 ), need for admission to the ICU (P < 10 -3 ) and development of ARF (P = 0.005) were associated with a significantly increased risk of mortality.
On multivariate analysis by cox model regression, only the use of aminoglycosides (P = 0.02, RR = 0.31), need for admission to the ICU (P < 10 -3 , RR = 7.29) and development of ARF (P = 0.001, RR = 8.97) were independent predictors of mortality.
| Discussion|| |
Organ toxicities in recipients of HCT are common and potentially life-threatening. In this study, we have shown that renal dysfunction is a common and potentially life-threatening complication following HCT. In previous studies, the incidence of renal dysfunction ranged between 56 and 92% in cohorts of patients receiving autologous or allogeneic HCT, with 20% requiring dialysis. ,,,, In this study, 57.4% of the patients developed ARF corresponding to an incidence of 2.6% per week during the first year following BMT. The incidence of ARF reported in our study is comparable with that reported in earlier studies. ,
This study shows that ARF is a common complication of HCT, reinforcing the results already published. In our study, the onset of ARF was very early (14 days post-BMT) as compared to the data in literature (21 days);  this may be because of the high frequency of SOS, admission to the ICU and the contribution made by iatrogenic factors. The one complication that was associated with a significantly shorter time to occurrence of ARF after HCT was SOS. In patients suffering from SOS, ARF developed within a median of 19 days after HCT. In our study, a relatively important proportion of patients (11.9%) suffered from SOS compared to other studies. ,,
The initial period after transplantation is recognized for its association with several complications that can have an association with ARF  and can cause increased mortality. We investigated several of these complications for their association with ARF and also if the 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 indications for admission to the ICU in the HCT patients were respiratory failure, cardiac failure, neurological complications, gastrointestinal bleeding and infections with associated septicemia.  ARF is a very common complication of HCT patients in the ICU and has been reported to be associated with sepsis and/or liver failure.  It is therefore not surprising that admission to the ICU was associated with occurrence of ARF in this study. The second complication associated with ARF was TTP. TTP after HCT differs from classic TTP. The pathogenesis of HCT-related TTP is probably dependent on endothelial injury, and ADAMTS-13 is not decreased in contrast to classic TTP.  There is substantial evidence that cyclosporine plays a role in the development of HCT-related TTP.  In our patient cohort, two developed TTP. In these patients, the occurrence of ARF preceded TTP. The association between ARF and TTP may indicate a shared patho-physiological mechanism of endothelial dysfunction, which causes ARF before apparent thrombocytopenia and hemolysis occur. Cyclosporine toxicity may contribute to this endothelial dysfunction.
In our series, the independent variables associated with increased risk of ARF were the development of VOD and use of aminoglycosides. The associated hepatic dysfunction plays an important patho-physiologic role in the causation of renal failure by decreasing renal perfusion and producing pre-renal azotemia.  Renal insufficiency is mainly hemodynamic and in many ways mimics the hepatorenal syndrome. Investigators have found that pre-transplant levels of tumor-growth factor-β may predict subsequent occurrence of VOD and the probability of ARF.  Preventive and newer therapeutic measures in lessening VOD and ARF, such as prostaglandins of the E1 group,  recombinant tissue plasminogen factor  or blocking tumornecrosis factor-L (pentoxifylline),  are especially interesting, but require further evaluation.
Another observation of our study was that the development of renal insufficiency had ominous implications for patient survival. The overall mortality rate among the 101 allogeneic HCTs was 35.6% at the end of the first year, while the mortality rate for the 58 patients who had developed ARF was 43.1% at the end of first year. Among the patients with ARF, the highest mortality rate was found in the VOD group (9 of 12).
The present results also indicate that allogeneic transplants may result in long-term renal dysfunction. The mean Scr in patients surviving at one year was significantly higher compared to the baseline values (P < 10 -3 ). Further studies are needed to better elucidate the long-term effects of allogeneic HCT on renal function.
We conclude that ARF is a common complication of allogeneic HCT. Its onset is early after transplantation, it is of multifactorial origin and is often associated with iatrogenic complications. It frequently occurs following VOD and use of aminoglycosides. As the prognosis is rather grim, it is very important that these associated factors be identified early for an effective prevention of this disease. Their occurrence, although life-threatening, offers nephrologists unique opportunities to study prospectively the pathogenesis of these diseases and their treatment.
| Acknowledgment|| |
The authors would like to acknowledge Prof. Bechir Zouari for his help in the statistical analysis of the study.
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Department of Internal Medicine A and Laboratory of Kidney Pathology 02, Charles Nicolle Hospital, Boulevard 9 Avril, 1006 Tunis, Tunisia
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]