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Incidence and predictors of delayed chronic kidney disease in long-term survivors of hematopoietic cell transplantation
Version of Record online: 14 AUG 2008
Copyright © 2008 American Cancer Society
Volume 113, Issue 7, pages 1580–1587, 1 October 2008
How to Cite
Choi, M., Sun, C.-L., Kurian, S., Carter, A., Francisco, L., Forman, S. J. and Bhatia, S. (2008), Incidence and predictors of delayed chronic kidney disease in long-term survivors of hematopoietic cell transplantation. Cancer, 113: 1580–1587. doi: 10.1002/cncr.23773
- Issue online: 17 SEP 2008
- Version of Record online: 14 AUG 2008
- Manuscript Accepted: 6 MAY 2008
- Manuscript Revised: 5 MAY 2008
- Manuscript Received: 28 FEB 2008
- National Institutes of Health. Grant Numbers: R01 CA078938, P01 CA30206
- Lymphoma/Leukemia Society Scholar Award for Clinical Research. Grant Number: 2191-02
- calcineurin inhibitors;
- cyclosporine A;
- graft-versus-host disease;
- primary multiple myeloma;
- hematopoietic cell transplantation
The authors investigated the risk of delayed chronic kidney disease (CKD) in 1190 adult hematopoietic cell transplantation (HCT) survivors who underwent HCT for hematologic malignancies or aplastic anemia between 1976 and 1997 and survived for at least 1 year.
CKD was defined as a sustained elevation of serum creatinine that indicated a glomerular filtration rate of <60 mL per minute per 1.73 m2 for ≥3 months. The median age at HCT was 35 years (range, 18.1-68.6 years), and the median length of follow-up was 7.1 years after HCT (range, 1-24.3 years).
Sixty patients with CKD were identified, resulting in a cumulative incidence of 4.4% at 5 years (autologous HCT, 3.8%; matched-sibling HCT, 4.5%; unrelated donor HCT, 10%; P = .09 compared with autologous HCT). Older age at HCT (relative risk [RR] per 5-year increment, 1.33; 95% confidence interval [CI], 1.2-1.5), exposure to cyclosporine without tacrolimus (RR, 1.90; 95% CI, 1.1-3.4) or with tacrolimus (RR, 4.59; 95% CI, 1.8-11.5), and a primary diagnosis of multiple myeloma (RR, 2.51; 95% CI, 1.1-5.6) were associated with an increased risk of delayed CKD.
In this study, the authors identified a subpopulation of patients who underwent HCT and remained at increased risk for CKD. The current findings set the stage for appropriate long-term follow-up of vulnerable patients. Cancer 2008. © 2008 American Cancer Society.
Hematopoietic cell transplantation (HCT) is an established, effective therapeutic modality for a variety of malignant and nonmalignant disorders. The number of patients undergoing this procedure has increased steadily over the last decade.1 Improved transplantation techniques and supportive care strategies have resulted in a growing population of long-term survivors who potentially may be at risk for treatment-related complications that adversely affect their long-term survival along with their health and well being. One such late complication of HCT is chronic kidney disease (CKD), which may lead to progressive loss of renal function and potentially could terminate in end-stage renal disease.2 Previously reported risk factors for developing renal insufficiency within the first year after HCT include exposure to a variety of nephrotoxic agents, such as pre-HCT conditioning with high-dose chemotherapy and total body irradiation (TBI)3–9; post-HCT use of aminoglycoside antibiotics and antifungal agents for the management of sepsis9–11; exposure to calcineurin inhibitors for graft-versus-host disease (GvHD) prophylaxis and treatment9, 12–20; and the development of chronic GvHD.21 Although delayed CKD after HCT (defined as CKD that develops ≥1 year after HCT) was recognized 15 years ago, inconsistent reporting of the magnitude of risk and associated risk factors stemmed from widely differing definitions used for describing CKD,22 various periods of post-HCT follow-up of the cohort at risk,4, 6, 21, 23 and limited sample sizes.3, 8, 14, 17, 18, 20, 21
By using a standardized definition of CKD,24 we followed 1190 patients who underwent HCT at age ≥18 years at the City of Hope National Medical Center (COH) and survived for at least 1 year. The objective of this study was to gain a better understanding of the incidence and risk factors associated with the development of delayed CKD in long-term survivors of HCT.
MATERIALS AND METHODS
A retrospective cohort study design was used. Eligible participants had undergone autologous or allogeneic HCT at COH between 1976 and 1997 for a hematologic malignancy or severe aplastic anemia; all patients were aged ≥18 years at the time of transplantation; they had survived for at least 1 year after HCT; and they had not developed CKD during the first year after HCT. The COH Long-term Follow-up (LTFU) Program actively follows patients who have undergone HCT at COH and survived at least 1 year. An LTFU data-collection form is completed for all patients who meet eligibility criteria. The form captures information beginning 1 year after transplantation through the date of last contact. Medical records maintained at COH are the primary source of data for completion of the LTFU form. If the date of last hospital/clinic visit recorded in the medical records is not recent (exceeds 18 months from the date of data abstraction) or if there are any unexpected gaps in the patients' history within the time window of interest (exceeding a period of 18 months), then a standard protocol is used to identify and contact physicians who are taking care of patients outside COH to obtain the pertinent information. If the physician is not available or is unable to provide recent information, then the patient is called directly. The Human Subjects Committee at City of Hope approved the protocol. Informed consent was provided according to the Declaration of Helsinki.
Information collected on the LTFU form included demographics, disease status, medication, hospitalization, vaccination history, and post-HCT complications, including new malignancies, cardiopulmonary dysfunction, renal compromise, neurologic toxicity, avascular necrosis, gastrointestinal complications, cataracts, and details regarding GvHD. Data from the LTFU form were merged with data from an institutional database on HCT that contained information on conditioning for HCT and GvHD prophylaxis/treatment.
By using this combined dataset, we identified patients who had renal insufficiency diagnosed by a healthcare provider. Medical records were reviewed again to confirm the presence of CKD using the following definition: CKD was defined as a sustained decrease in the glomerular filtration rate (GFR) to levels <60 mL per minute per 1.73 m2 for a period ≥3 months.24 Direct measurement of the GFR is complex, expensive, and difficult to do in routine clinical practice and, thus, was not logistically possible in this retrospective study. Therefore, the endogenous filtration marker creatinine was used to assess GFR. We used the Modification of Diet in Renal Disease (MDRD) Study equation endorsed by the National Kidney Foundation24 to calculate GFR based on serum creatinine value according to the following equation:
where Pcr is the serum creatinine value in mg/dL.25
By using this definition, the cumulative incidence of delayed CKD after HCT was calculated taking into consideration the competing risk from death, as described by Gray.26 The time at risk was computed from 1 year post-HCT to the date of onset of CKD, the date of last contact, or the date of death, whichever came first. Cox proportional hazards regression techniques were used to calculate relative risk (RR) estimates and their 95% confidence intervals (CIs).27 Univariate analyses for all pertinent variables were performed first to estimate the RR individually. Stepwise regression was used to separate important variables from those that approached statistical significance in the univariate analysis, and a P value <.10 was used as the selection criterion.
Variables that were examined in the regression model included age at transplantation, sex, primary diagnosis, type of transplantation (autologous, allogeneic [related and unrelated]), chemotherapeutic agents and radiation used as part of conditioning, presence or history of chronic GvHD, and exposure to immunosuppressive agents used for GvHD prophylaxis and/or treatment. Age at HCT was analyzed both as a continuous variable and as a categorical variable (≤45 years vs >45 years). Six major drugs were used for GvHD prophylaxis/treatment in the study cohort: methotrexate, systemic steroids (prednisone), cyclosporine, tacrolimus (FK506), thalidomide, and mycophenolate mofetil (MMF). On the basis of prior knowledge about the nephrotoxic potential of these immunosuppressive agents,28 we combined these agents into the following composite variables: use of methotrexate alone for prophylaxis and no agents for GvHD treatment; exposure to cyclosporine with or without other agents listed above, except tacrolimus; and exposure to cyclosporine and tacrolimus along with the other agents listed above. All tests of statistical significance were 2-sided, and P values ≤.05 were considered statistically significant. Data were analyzed using SAS version 9.1 (SAS Institute, Cary, NC).
Table 1 describes the characteristics of the patient population. Of the 1190 patients in the cohort, 700 were men (59%). The median age at transplantation was 35 years (range, 18.1-68.6 years). The follow-up for this study extended to May 31, 2005. Thus, as of May 2005, 67% of the cohort was alive at last contact, and the median length of follow-up for these patients was 7.1 years from HCT (range, 1-24.3 years). For patients who remained alive without CKD, the median time from date of last contact to May 31, 2005 was 3.3 years (range, 0.02-17 years). Overall, 75% of the cohort had been followed up within 5 years from May 31, 2005.
|Characteristic||Total (n=1190)||Patients With CKD (n=60)|
|No. of Patients||%||No. of Patients||%|
|Year of HCT|
|Age at HCT, y|
|Acute myeloid leukemia||294||25||16||27|
|Chronic myeloid leukemia||213||18||14||23|
|Acute lymphoblastic leukemia||131||11||3||5|
|Type of HCT|
|Agents used for conditioning*|
|Total body irradiation||899||76||46||77|
|GvHD prophylaxis treatment†|
|No agents/methotrexate alone||637||54||27||45|
|Cyclosporine without tacrolimus‡||500||42||27||45|
|Cyclosporine and tacrolimus‡||48||4||6||10|
|Status at last contact|
|Presence of chronic GvHD§|
Allogeneic HCT from human leukemic antigen (HLA)-matched or partially matched family member donors was performed in 561 patients (47%); 67 patients (6%) received grafts from unrelated donors who were matched for HLA phenotype, and 562 patients (47%) underwent autologous HCT. The major indications for transplantation were non-Hodgkin lymphoma (24%), Hodgkin disease (14%), acute myeloid leukemia (25%), chronic myeloid leukemia (18%), acute lymphoblastic leukemia (11%), multiple myeloma (MM) (5%), and severe aplastic anemia (3%). The main chemotherapeutic agents used for conditioning were cyclophosphamide (74%), etoposide (72%), TBI (76%), carmustine (12%), busulfan (10%), and melphalan (3%). Multiple drugs were used for GvHD prophylaxis or treatment, including cyclosporine A, methotrexate (prophylaxis), systemic steroids, thalidomide, tacrolimus, and MMF (primarily treatment).
Sixty patients (5% of the entire cohort) developed CKD. These included 31 patients (5.5%) who received HCT from related family members, 6 patients (9%) who received HCT from unrelated donors, and 23 patients (4.1%) autologous HCT survivors. Figure 1 illustrates the cumulative incidence of CKD, which was 4.4% (95% CI, 3.2%-5.6%) at 5 years post-HCT and 5.7% (95% CI, 4.2%-7.2%) at 10 years. Twenty-two events (37%) occurred within 2 years post-HCT. The large majority of events occurred within the first 10 years, followed by a plateau. Compared with autologous HCT recipients (cumulative incidence, 3.8% at 5 years after HCT), the cumulative incidence was comparable for matched-sibling HCT recipients (4.5% at 5 years; P > .5) and was higher with borderline significance for patients who had undergone a matched unrelated donor HCT (10%; P = .09 compared with autologous HCT recipients).
Patients with MM can be at an increased risk of CKD because of infiltration of the kidneys with primary disease. To examine the risk of CKD because of transplantation-related exposures, we repeated the analyses described above after excluding patients with MM. The cumulative incidence of delayed CKD by donor source was as follows: autologous HCT recipients, 3.5% at 5 years post-HCT; matched-sibling HCT recipients, 4.2% at 5 years (P = .54 compared with autologous HCT recipients); matched unrelated donor HCT recipients, 10% at 5 years (P = .05 compared with autologous HCT recipients).
Table 2 presents the results of the univariate analyses of the associations between delayed CKD and demographic factors, chemotherapeutic agents used for conditioning, and drugs used for prophylaxis and/or treatment of GvHD. Stepwise regression (Table 3) revealed that older age at HCT (RR per increase of 5 years, 1.33; 95% CI, 1.17-1.51) and prophylaxis/treatment of GvHD using cyclosporine without tacrolimus (RR, 1.90; 95% CI, 1.07-3.41) or with tacrolimus (RR, 4.59; 95% CI, 1.84-11.46) were associated significantly with an increased risk of CKD. A primary diagnosis of MM (RR, 2.51; 95% CI, 1.12-5.60) also was associated with an increased risk of CKD. It is noteworthy that exposure to TBI did not increase the risk of CKD (RR, 0.92; 95% CI, 0.51-1.68).
|Risk Factor||Entire Cohort (n=1190)|
|No. With/Without CKD||RR (95% CI)|
|Year of HCT|
|Age at HCT, y|
|Other than myeloma||52/1079||1.00|
|Multiple myeloma||8/51||3.68 (1.74-7.79)|
|Total body irradiation|
|Drugs used for GvHD prophylaxis/treatment*|
|Cyclosporine, no tacrolimus||27/473||1.22 (0.72-2.08)|
|Cyclosporine and tacrolimus||6/42||2.77 (1.14-6.70)|
|Source of hematopoietic cells|
|Allogeneic, related||31/530||1.16 (0.72-2.09)|
|Matched, unrelated||6/61||2.70 (1.21-6.01)|
|Risk Factor||Overall RR (95% CI)|
|Age at HCT in 5-y increments||1.33 (1.17-1.51)|
|Drug combinations for prophylaxis/treatment of GvHD|
|Cyclosporine without tacrolimus*||1.90 (1.07-3.41)|
|Cyclosporine with tacrolimus*||4.59 (1.84-11.46)|
|Primary diagnosis other than myeloma||1.00|
|Multiple myeloma||2.51 (1.12-5.60)|
Restricting the analysis to allogeneic HCT recipients, the cumulative incidence of CKD among those aged <45 years at the time of HCT who were not exposed to calcineurin inhibitors for GvHD prophylaxis/treatment was substantially lower than the cumulative incidence of delayed CKD for those aged >45 years at the time of HCT who had been exposed to calcineurin inhibitors (2.7% vs 19.5% at 10 years post-HCT; P < .01) (Fig. 2).
Comparison With Published Results in the General Population
According to National Health Interview data published in 2004,29 the prevalence of CKD (defined by asking whether the patient had been informed in the past 12 months by a physician or other healthcare professional that they had weak or failing kidneys, excluding kidney stones, bladder infections, or incontinence) was lower in the general population (0.9% at ages 18-44 years, 1.8% at ages 45-64 years, and 3.4% at ages 65-74 years) than in our HCT survivors (the comparable rates were 3.5%, 9.5%, and 15%, respectively; P < .01).
Outcome after CKD
A detailed review of the 60 patients with CKD was conducted in terms of the need for dialysis. Four patients had gaps in data in the medical records that precluded a detailed evaluation of this outcome. Of the 56 patients who could be evaluated in detail, in total, 4 patients required dialysis. Twenty of the 60 patients (33.3%) who had CKD died. The median survival after CKD was 121 months (range, 0-159 months). Causes of death included primary disease (9 patients), secondary malignancy (3 patients), GvHD (1 patient), organ failure (liver in 1 patient and respiratory system in 1 patient), restrictive lung disease (2 patients), infection (2 patients), and unknown cause (1 patient).
Renal dysfunction has been recognized as a complication of HCT for the past 15 years; however, the initial studies were in the form of case reports and case series that were unable to assess the magnitude of risk or identify risk factors.3, 6, 8, 30–35 The analytical studies4, 5, 7, 9–11, 13, 17, 18, 36–43 have been limited by small sample sizes and relatively short follow-up after HCT,44 thus limiting their ability to describe the magnitude of risk with precision and to assess the contribution of various nephrotoxic exposures as well as host and demographic factors in the development of delayed CKD. The current study overcomes these limitations by evaluating the risk of delayed CKD in a large cohort of HCT survivors who were followed for a median of 7 years and describes subpopulations at increased risk.
Among the 1190 adult patients who underwent HCT for hematologic malignancies or severe aplastic anemia at COH between 1976 and 1997 and who survived for at least 1 year after HCT, the estimated cumulative incidence of CKD was 4.4% at 5 years and increased to 5.7% at 10 years after transplantation. Autologous and allogeneic matched-sibling HCT recipients were at a comparable risk of developing CKD, and their 5-year cumulative incidence rates were 3.8% and 4.5%, respectively; unrelated donor HCT recipients, conversely, were at a higher risk of developing delayed CKD (10%) compared with autologous HCT recipients. The large majority of events occurred within the first 10 years after HCT, followed by a plateau. Compared with published, age-matched general population rates, the prevalence of CKD was significantly higher in HCT survivors.
It has been reported that, among long-term HCT survivors, approximately 5% to 20% will develop CKD.45 The variability in the magnitude of risk of CKD may be attributed in part to the finding that no standard definition for chronic renal dysfunction has been used in previous reports.22 Accurate estimation of kidney function is central to the detection, evaluation, and treatment of CKD; and the GFR is widely accepted as the best overall measure of kidney function.46 The National Kidney Foundation Kidney Disease Outcomes Quality Initiative defines CKD as a GFR <60 mL per minute per 1.73 m2 for ≥3 months with or without kidney damage.24 Our study used the MDRD Study equation endorsed by the National Kidney Foundation24 to calculate GFR based on serum creatinine and included the variables age, sex, and race. Currently, the MDRD equation is recommended for routine clinical use by the National Kidney Foundation, the American Society of Nephrology, and the National Kidney Disease Education Program of the National Institutes of Health.
Renal dysfunction after HCT can be caused by several nephrotoxic agents that are used in the early phases of disease (chemotherapy before transplantation), during conditioning (high-dose chemotherapy and TBI), and subsequently in the early period after transplantation (sepsis and its treatment with antifungal agents and antibiotics, immunosuppressive agents used to prevent and treat GvHD, and the development of chronic GvHD itself). Previous studies have reported that the presence or history of GvHD and exposure to cyclosporine A, tacrolimus, ifosfamide, and TBI are associated with an increased risk of CKD.3–21 The results from the current multivariate analyses indicated that older age at HCT increases the risk of delayed CKD, consistent with 2 recent studies.4, 37 This may be explained by a higher prevalence of comorbid conditions that increase the vulnerability of the kidney or by the finding that renal function decreases with age.24 The results also indicated that patients with MM who undergo HCT are at a 2.5-fold increased risk of developing CKD. Renal impairment is a common complication of MM and has a multifactorial pathogenesis.47 Nephrotoxic manifestations of monoclonal immunoglobulin overexpression include the ‘myeloma kidney,’ light-chain deposition disease, amyloidosis, plasma cell infiltration, and glomerulonephritis. Other factors, such as hypercalcemia, hyperuricemia, infection, hyperviscosity, and the use of nephrotoxic drugs, can precipitate or exacerbate acute and chronic renal failure in patients with MM.
The association between CKD and TBI has been recognized for over a decade22 and was confirmed in a study that indicated a direct dose-response relation, in which patients who were conditioned with 13.5 grays (Gy), 12 Gy, or 10 Gy had an estimated probability of CKD at 18 months after transplantation of 45%, 26%, and 5%, respectively.21 Conversely, other studies have failed to demonstrate an association between TBI and CKD.39, 42, 44 The large majority of the our cohort who had TBI received 1320 centigrays (cGy) of fractionated TBI for allogeneic HCT and 1200 cGy for autologous HCT. It also should be noted that radiation-related nephropathy reportedly occurs relatively early after HCT—usually between 8 months and 12 months after post-HCT48—a timeframe we did not investigate in the current study. Therefore, the delayed CKD that developed 1 year after transplantation in our cohort probably represented nonradiation-related insult to the kidney.
Antifungal agents and aminoglycoside antibiotics are known nephrotoxins, but they are tubular rather than glomerular toxins. We did not demonstrate any association between fungal infections (used as a surrogate for exposure to potentially nephrotoxic agents) and CKD. Again, use of antifungals and aminoglycosides decreases after the first year post-HCT, perhaps explaining in part the lack of association in the current study.
Nephrotoxicity has been among the most serious complications of calcineurin inhibitors.49 Cyclosporine and tacrolimus are associated with renal impairment in patients who undergo HCT.12–16, 19, 50, 51 Cyclosporine causes glomerular thrombosis and tubular injury in the early months after HCT20 that is reversible with dose modification or withdrawal of the drug. A longer term syndrome of cyclosporine toxicity involves both arteriolar and tubular lesions accompanied by interstitial fibrosis.52, 53 It is known that the use of tacrolimus potentially can cause chronic nephrotoxicity, because it causes structural lesions in the kidney, and it also has been reported previously as a risk factor for kidney disease post-HCT.54 In the current study, exposure to calcineurin inhibitors (cyclosporine and tacrolimus) was associated with a significantly increased risk of delayed CKD after adjustment for age at transplantation and primary diagnosis. Furthermore, the effect appeared to be additive, as demonstrated by the increase in the magnitude of risk by the addition of tacrolimus to a cyclosporine-exposed setting. We were limited in our ability to collect details regarding the dose or duration of exposure to immunosuppressive agents used for prophylaxis/treatment of GvHD and, thus, could not explore a detailed dose-response association.
Chronic GvHD reportedly plays a role in the development of CKD after HCT.21 We did not demonstrate an independent association between chronic GvHD and CKD, probably because the strong correlation between the use of nephrotoxic drugs to prevent and/or treat chronic GvHD and the presence of chronic GvHD would make it impossible to identify the role of chronic GvHD independent of the use of these agents in the development of CKD.
By using rigorous, standardized definitions for identifying patients with CKD, this report describes the magnitude of risk of CKD in a large cohort of long-term survivors of autologous and allogeneic HCT. It demonstrates that the risk of CKD is elevated for the first 10 years after HCT and plateaus after that. Furthermore, in this study, we identified high-risk subgroups in this population, in particular, older patients, patients with a diagnosis of MM, and patients with exposure to calcineurin inhibitors. Findings from this study may guide clinicians in monitoring high-risk subpopulations and may help to establish guidelines for the appropriate follow-up of these survivors.
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- 24National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002; 39(2 suppl 1 ): S1–S266.
- 25[No authors listed] Effects of diet and antihypertensive therapy on creatinine clearance and serum creatinine concentration in the Modification of Diet in Renal Disease Study. J Am Soc Nephrol. 1996; 7: 556–566.
- 27Regression models and life tables. J R Stat Soc B. 1972; 34: 187–220..
- 29Summary Health Statistics for US Adults: National Health Interview Survey, 2004. Vital Health Statistics, Volume 10, Issue 228. Hyattsville, Md: National Center for Health Statistics; 2006., , .