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Hematopoietic cell transplantation–related nephropathy in Japan
Hematopoietic Cell Transplantation–Related Nephropathy in Japan Hirokazu Imai, MD, Yuhta Oyama, MD, Akira B. Miura, MD, Masayuki Endoh, MD, and Hideto Sakai, MD ● To clarify the incidence and characteristics of hematopoietic cell transplantation (HCT)-related nephropathy (HCT-N) in Japan, we sent questionnaire letters to 188 hematologic divisions of 91 hospitals and analyzed the responses. Of 2,136 Japanese hematopoietic cell transplant recipients, 51 patients (2.4%) had HCT-N. The early-onset (<30 days after HCT), middle-onset (31 to 120 days after HCT), and late-onset (>180 days after HCT) groups included 20, 16, and 15 patients, respectively. The early-onset group mainly consisted of patients with acute renal failure (ARF) and hemolytic uremic syndrome and/or thrombotic thrombocytopenic purpura. ARF was the dominant type in the middle-onset group. The main phenotype of the late-onset group was nephrotic syndrome, which correlated with chronic graft-versus-host disease (P ⴝ 0.008). The total amounts of irradiation for patients with chronic renal failure and urinary abnormality were significantly greater than those for patients with ARF (P ⴝ 0.004). The survival rate of the early-onset and middle-onset groups was 47.2%, whereas 87% of patients in the late-onset group survived (P ⴝ 0.002). HCT-N is expected to become a serious and important problem in Japan because of the increasing number of HCTs from unrelated donors. © 2000 by the National Kidney Foundation, Inc. INDEX WORDS: Bone marrow transplantation (BMT); hematopoietic cell transplantation (HCT); nephropathy; acute renal failure (ARF); hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP); nephrotic syndrome (NS); chronic renal failure (CRF).
I
N THE LATE 1960s E. Donnall Thomas introduced bone marrow transplantation (BMT) to save patients with such refractory hematologic disorders as aplastic anemia and leukemia. Recently, the addition of peripheral-blood and umbilical-cord blood cell transplantation has conceptually changed BMT into hematopoietic cell transplantation (HCT). The indicative diseases have also expanded to include malignant lymphoma, solid tumors, and such hereditary hematologic disorders as sickle cell anemia and thalassemia. Recently, HCT has been performed on patients with moderate or severe autoimmune diseases in Western countries. Although HCT in Japan started 10 years later than in the United States, the total case registry of HCTs exceeded 8,000 in 1996, and the number of hematopoietic cell transplant recipients increased to more than
From the Third Department of Internal Medicine, Akita University School of Medicine, Akita City; and the Division of Nephrology and Metabolism, Tokai University School of Medicine, Isehara City, Japan. Received August 27, 1999; accepted in revised form April 7, 2000. Supported in part by a grant for Progressive Renal Disease from the Ministry of Health and Welfare Research Project for Specially Selected Disease. Address reprint requests to Hirokazu Imai, MD, Third Department of Internal Medicine, Akita University School of Medicine, Hondo 1-1-1, Akita City, 010-8543, Japan. Email: [email protected] © 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3603-0003$3.00/0 doi:10.1053/ajkd.2000.9787 474
1,700 in 1 year.1 The cumulative number of hematopoietic cell transplants from unrelated donors was 978 in December 1996, with an annual number of approximately 500 HCTs. HCT-related nephropathy (HCT-N) has been a serious problem since the early days of HCT treatment. Acute renal failure (ARF) is a major complication, as is late-onset nephropathy, which occurs in 20% to 25% of the long-term survivors in Western countries.2,3 In this study, we attempt to analyze and review Japanese cases of HCT-N to clarify its incidence and characteristics in Japan. METHODS We sent questionnaires to 188 hematologic divisions of 91 hospitals that performed BMT or peripheral-blood stem-cell transplantation, using data from the Japanese BMT (HCT) registry. Data collected were as follows: (1) total number of HCTs performed until September 1, 1997; (2) initials, sex, and birth date of patients with HCT-N (nephropathy was defined as the presence of such urinary abnormalities as proteinuria or hematuria and serum creatinine levels greater than 1.5 mg/dL); (3) original hematologic disorders of patients with HCT-N; (4) type of HCT (autogenic or allogeneic, related/sibling or unrelated); (5) preparatory regimen of HCT (chemotherapy, total-body irradiation); (6) posttreatment of HCT (total amount of cyclosporine A and use of antibiotics); (7) time of onset of HCT-N; (8) phenotype of HCT-N, classified into five groups: urinary abnormalities, nephrotic syndrome (NS), ARF, hemolytic uremic syndrome and/or thrombotic thrombocytopenic purpura (HUS/TTP), and chronic renal failure (CRF); (9) renal biopsy; (10) laboratory data of patients with HCT-N; (11) observation
American Journal of Kidney Diseases, Vol 36, No 3 (September), 2000: pp 474-480
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period after HCT; (12) suspected causes of nephropathy; and (13) patient outcomes. We analyzed the responses. Statistical analysis was performed using Student’s t-test, Welch’s t-test, Mann-Whitney test, chi-square test for independence, and log-rank (MantelCox) test for survival rate using Microsoft Excel version 5.0 (Microsoft Corp, Redmond, WA) and Statview version 4.0 (Abacus Concepts Inc, Berkeley, CA). P less than 0.05 is considered statistically significant. In addition to the cited analysis, we extensively reviewed case reports in English and Japanese and oral case presentations from Japanese meetings.
RESULTS
Replies were obtained from 32 divisions of 32 hospitals, a recovery rate of 27.1%. The total number of HCTs performed in the present study was 2,136, corresponding to one fourth of all Japanese HCTs (almost 8,000 patients). Nephropathy occurred in 51 of the 2,136 patients, for an incidence rate of 2.4% in hematopoietic cell transplant recipients. Renal biopsy or necropsy was performed in 10 of 51 patients with HCT-N. Of the 2,136 patients, 450 patients (21.1%) were from the pediatric department (⬍15 years of age); the remaining 1,686 patients (78.9%) were from the internal medicine department (⬎15 years of age). HCT-N was found in 6 of 450 pediatric patients (1.3%) and 45 of 1,686 adult patients (2.6%). However, all adult transplant recipients were aged younger than 40 years, according to the consensus of the Japanese BMT (HCT) study group. There was no significant difference in the incidence of HCT-N between children and adults (P ⫽ 0.097). Table 1 shows that 45 of 51 patients (88%) had hematologic malignancies (leukemia, 40 patients; malignant lymphoma, 5 patients). Fortyseven of 51 patients (92%) were allogeneic HLAmatched siblings (Table 2), which reflects the data that almost 90% of HCTs performed in Japan (⬃8,000 cases) were either between allogeneic HLA-matched siblings or autogenic, beTable 1.
Types of Disease in Transplant Recipients
Acute nonlymphocytic leukemia Acute lymphocytic leukemia Chronic myelogenous leukemia Malignant lymphoma Aplastic anemia Others Total
10 13 17 5 1 5 51
Table 2.
Types of Transplantations Performed Onset of Nephropathy
Type
Autologous Allogeneic Matched sibling Related partial match Unrelated Total
⬍120 Days
⬎180 Days
Total
1
0
1
32 1 2 36
15 0 0 15
47 1 2 51
cause the total number of unrelated allogeneic HCTs was 978 as of December 1996. Figure 1 shows the relation between the time of onset of nephropathy and number of patients. Based on evidence that transplanted stem cells recover 1 month after HCT and that no HCT-N occurred in patients between 120 and 180 days after HCT in this study, we divided patients into three groups: early-onset (ⱕ30 days after HCT), middle-onset (between 31 and 120 days after HCT), and late-onset (⬎180 days after HCT), including 20, 16, and 15 patients, respectively. Table 3 shows the relation between onset time and nephropathy phenotype. The early-onset group mainly included cases of ARF and HUS/ TTP. NS was not found in this group. Although the middle-onset group showed almost the same pattern as the early-onset group, ARF was more dominant in the middle-onset group. Conversely, the main phenotype of the late-onset group was NS (P ⫽ 0.0008). Regarding the influence of irradiation on the phenotype of nephropathy, the amount of irradiation in patients with urinary abnormalities and CRF was significantly greater than that in patients with ARF (P ⫽ 0.0035; Table 4). Table 5 lists the suspected causes of nephropathy, judged by the physician. Drugs were dominant causative factors in both the early-onset and middle-onset groups. However, graft-versushost disease (GVHD) and irradiation were the main causes in the late-onset group. These results suggest that the causes of late-onset nephropathy significantly differ from those of the earlyonset and middle-onset groups. Although the survival rate of the early-onset and middle-onset groups was 47.2% (17 of 36 patients), 13 of 15 patients (87%) in the lateonset group are still alive (P ⬍ 0.002; Fig 2). Ten of 30 surviving patients from all groups showed
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Fig 1. The relation between time of onset of nephropathy and number of patients. There were no patients with nephropathy between 120 and 180 days after HCT in this study.
renal dysfunction (serum creatinine level ⬎ 1.5 mg/dL), and 1 patient had undergone continuous ambulatory peritoneal dialysis (CAPD)4 (Table 6). Table 7 lists pathological findings of the biopsies and necropsy in this study. Nine patients in the late-onset group underwent renal biopsy, and necropsy was performed on one patient with HUS/TTP in the early-onset group. Six of nine patients who underwent biopsy had NS; three of these had membranous nephropathy. Tubulointerstitial nephritis and fibrosis was found in three of the nine patients who underwent biopsy. All patients with NS responded to steroid therapy (40 to 60 mg/d of prednisolone, with additional methylprednisolone pulse therapy in some pa-
tients) and retained normal renal function. However, patients with HUS/TTP, CRF, or urinary abnormality progressed to renal failure, and one patient was started on CAPD therapy. DISCUSSION
The present study showed 51 patients with HCT-N of 2,136 Japanese hematopoietic cell transplant recipients, which is approximately one fourth of the 8,000 HCT patients registered in Japan until 1996. The total number of cases of HCT-N in Japan is estimated to exceed 200, calculated by multiplying the 51 cases by four. Table 4. Relationship Between Radiation and Nephropathy Phenotypes
Table 3. Relationship Between Onset and Nephropathy Phenotypes ARF
Days after HCT 1-30 31-120 ⬎180
11 11 2
HUS/TTP
6 2 3
UA
2 1 1
CRF
1 2 1
NS
0 0 8
Total
20 16 15
NOTE. Chi-square test for independence, P ⫽ 0.0008. Abbreviation: UA, urinary abnormality.
Total irradiation (Gy) No. Mean SD
ARF
HUS/TTP
UA
CRF
NS
24 7.4 5.9
11 9.5 4.7
4 13.3 2.2
4 13.3 2.2
8 9.2 5.7
NOTE. Welch’s t-test, ARF versus UA, P ⫽ 0.0035; HUS/TTP versus UA, P ⫽ 0.056; ARF versus CRF, P ⫽ 0.0035; HUS/TTP versus CRF, P ⫽ 0.056. Abbreviation: UA, urinary abnormality.
HCT-RELATED NEPHROPATHY IN JAPAN Table 5.
477 Table 6.
Suspected Causes of Nephropathy
Prognosis of Renal Function
Onset of Nephropathy Causes
Cys A FK506 AMPH-B Drugs Sepsis Adenovirus VOD GVHD Radiation Unknown Total
Onset of Nephropathy
⬍120 Days
⬎180 Days
Total
17 5 3 3 1 2 1 5 3 2 42
2 1 0 0 0 0 0 7 4 2 16
19 6 3 3 1 2 1 12 7 4 58
NOTE. Less than 120 days, Cys A, FK506, AMPH-B, and other drugs; more than 180 days, GVHD and radiation. Abbreviations: Cys A, cyclosporine A; AMPH-B, amphotericin B; VOD, veno-occlusive disease.
We also reviewed 19 additional cases reported in journals or scientific meetings5-17 (Table 8). Nine patients underwent allogeneic HCT, and 10 patients underwent autogenic HCT. Eleven of 19 patients showed HUS/TTP, and there were two cases each of ARF, NS, CRF, and urinary abnormality. Although we could not calculate an accu-
Fig 2. Survival rate for patients with HCT-N after diagnosis. There is a significant difference between the late-onset group and earlyonset and middle-onset groups (Mantel-Cox log-rank test, P ⴝ 0.002).
⬍120 Days Renal Function
SCr ⬍1.5 mg/dL SCr ⱖ1.5 mg/dL Dialysis Total
⬎180 Days
Alive
Dead
Alive
Dead
11 6 0 17
5 12 2 19
9 3 1 13
0 1 1 2
Abbreviation: SCr, serum creatinine.
rate incidence rate, the incidence of HCT-N in Japan is significantly less than that in the United States. Zager et al18 reported in 1986 that 64 of 272 HCT patients (24%) had ARF requiring hemodialysis, and 79 patients (29%) had renal dysfunction. Lawton et al19 showed that 14 of 103 patients undergoing HCT (13.6%) had late renal failure. The cumulative probability of having late renal dysfunction is 20% at 1 year. Several possibilities can be considered to explain the difference in incidence between the United States and Japan. First, the donors of HCT were mainly HLA-matched siblings in the
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IMAI ET AL Table 7.
Onset (mo)
Phenotype of GN
Type of Study
0.5 6 10 12 17 19 28
HUS/TTP HUS NS NS NS NS NS
Necropsy Biopsy Biopsy Biopsy Biopsy Biopsy Biopsy
34
NS
Biopsy
54
UA
Biopsy
93
CRF
Biopsy
Pathological Findings
Pathological Findings
Outcome
Renal Function at Presentation
HUS, microthrombosis HUS, double contour Minor glomerular change with focal TIN Details unknown Membranous nephropathy Chronic GVHD Focal segmental glomerulosclerosis and membranous nephropathy Membranous nephropathy with interstitial fibrosis Segmental mesangial proliferative GN and left kidney atrophy Mesangial proliferative GN with mesangiolysis and TIN
Dead Alive Alive Alive Alive Alive Alive
ND CRF SCr ⬍1.5 mg/dL SCr ⬍1.5 mg/dL SCr ⬍1.5 mg/dL SCr ⬍1.5 mg/dL SCr ⬍1.5 mg/dL
Alive
SCr ⬍1.5 mg/dL
Alive
CRF
Alive
CRF-CAPD
Abbreviations: GN, glomerulonephritis; TIN, tubulointerstitial nepritis; SCr, serum creatinine; ND, not determined; UA, urinary abnormality.
present study, whereas unrelated allogeneic HCT is predominant in the United States. Second, the total amounts of antitumor drugs, immunosuppressants, and irradiation in Japan are less than those used in the United States. Third, there is a racial difference. Fourth, there is a short observation time since the start of HCT in Japan. Further Table 8. Case No.
Year
Author
Reference
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
1993 1993 1994 1995 1995 1995 1997 1997 1998 1998 1998 1998 1998 1988 1988 1998 1998 1998 1999
Ohmoto et al Yuzawa et al Maruyama et al Tamura et al Ujiie et al Kawai et al Ohno et al Yabana et al Togitani et al Takeuchi et al Yorioka et al Arai et al Arai et al Arai et al Arai et al Arai et al Arai et al Arai et al Oguni et al
5 6 7 8 9 10 11 12 13 14 15 16 16 16 16 16 16 16 17
study will show whether the lower incidence of HCT-N in Japan is a temporary phenomenon. The present study suggests that HCT-N is a rare complication after autogenic transplantation because only 1 of 51 cases of HCT-N was autogenic. However, review of other Japanese cases showed that 9 of 19 cases were autogenic. This
Case Reports Other Than Present Study
Disease
ALL AML ML ML CML ALL ML CML ML ML CML AML ALL ALL ALL ALL ML ALL CML
Type of HCT
Irradiation
Onset (d)
Phenotype
Outcome
Allo BMT Allo BMT PBSCT Auto BMT Allo BMT Auto BMT Auto PBSCT Allo BMT Auto PBSCT Auto PBSCT Allo PBSCT Allo BMT Auto BMT Allo BMT Auto BMT Auto BMT Auto BMT Allo BMT Allo BMT
(⫹) 10 Gy 12 Gy (⫺) 12 Gy 12 Gy (⫺) 2.5 Gy (⫺) (⫺) ? (⫺) (⫹) (⫹) (⫹) (⫹) (⫹) (⫹) 12 Gy
175 43 24 120 150 730 110 365 2 90 335 36 196 182 108 181 78 91 50
HUS/TTP ARF ARF CRF/UP UA UA HUS/TTP NS HUS/TTP CRF NS HUS/TTP HUS/TTP HUS/TTP HUS/TTP HUS/TTP HUS/TTP HUS/TTP HUS/TTP
Dead Dead Alive Alive, CRF Alive, CRF Alive Alive Alive Alive, CRF Alive, CRF Alive Dead Dead Alive Dead Dead Alive, CRF Alive Dead
Abbreviations: ALL, acute lymphocytic leukemia; Allo, allogeneic; AML, acute myelogenous leukemia; ML, malignant lymphoma; UA, urinary abnormality; PBSCT, peripheral-blood stem-cell transplantation; CML, chronic myelogenous leukemia; Auto, autologous.
HCT-RELATED NEPHROPATHY IN JAPAN
incidence is relatively high because the dominant type of HCT (⬎90%) is allogeneic. Further study should clarify whether type of HCT is a risk factor for nephropathy. Regarding the relation between the onset and pattern of nephropathy, the main patterns of HCT-N in the early-onset group were ARF and HUS/TTP. Conversely, NS and CRF were the dominant types in the late-onset group. Cohen et al20 reported that ARF occurs within the first 100 days after HCT, related to sepsis and the use of nephrotoxic antibiotics. Recently, Noel et al21 classified HCT-N into four groups according to time of onset: a very early-onset group, within 2 weeks; an early-onset group, between 2 weeks and 3 months; a middle-onset group, between 3 and 6 months; and a late-onset group, more than 6 months. In the very early-onset group, 75% of patients with mainly ARF and veno-occlusive diseases died. The causes of death in the earlyonset group were acute GVHD, infection, drug reactions, and HUS/TTP. In the middle-onset group, chronic GVHD was the predominant cause of death. However, patients in the late-onset group were affected by irradiation. Our results were similar to those of Noel et al.20 It is a characteristic pattern that only 3 of 70 patients (the sum of 51 present cases and 19 reviewed cases) were found to have HCT-N between 120 and 180 days after HCT. Further study should clarify why there is a low incidence of HCT-N between 120 and 180 days after HCT. Many physicians in the present study suspect that primary causative factors of ARF and HUS/ TTP are several drugs, such as cyclosporine, FK506, and amphotericin B in early-onset cases. Conversely, NS is strongly suspected to be caused by chronic GVHD. The total amount of irradiation in the CRF and urinary abnormality groups was significantly greater than that in the ARF group. In this respect, Moulder et al22 noted that late-onset nephropathy occurs in 20% of longterm survivors after HCT and is related to irradiation nephropathy. Also, they suggested that angiotensin-converting enzyme inhibitor is effective in the prophylaxis of HCT-N related to irradiation. Lawton et al23 showed that renal shielding reduces the incidence of HCT-N from 29% ⫾ 7% to 14% ⫾ 5% (P ⫽ 0.012). Selective renal shielding when undergoing total-body irradia-
479
tion was recommended to reduce the incidence of late-onset nephropathy. Pathological analysis of the kidney showed that three of six patients with NS had membranous nephropathy. This membranous nephropathy, depending on the abnormal immune response after HCT, responded to steroid therapy. Other nonspecific findings, such as mesangiolysis, tubulointerstitial nephritis, and focal segmental glomerulosclerosis, were observed. The present study showed a survival rate in the early-onset and middle-onset groups of 47.2%, whereas 87% of the patients in the late-onset group survived (P ⬍ 0.002). Thirty of 51 patients with HCT-N from all groups are alive. However, 10 of 30 patients progressed to CRF, and 1 patient underwent CAPD.4 Reports from Western countries showed that 5 of 125 patients (4%) surviving 5 years underwent dialysis therapy because of CRF.24 Butcher et al25 reported their experience with renal transplantation in six patients with end-stage renal disease after HCT. We need to continue the survey of HCT-N because of the increasing number of unrelated-donor HCTs, which may induce severe acute and chronic GVHD and may require greater dosages of immunosuppressive drugs. ACKNOWLEDGMENT The authors thank the doctors in the Department of Pediatrics, Sapporo Medical University; Second Department of Internal Medicine, Tohoku University School of Medicine; Division of Haematology and Blood Transfusion, Jichi Medical University; Department of Internal Medicine, Saiseikai-Maebashi Hospital; Ibaraki Prefectural Children’s Hospital; First Department of Internal Medicine, Nihon University School of Medicine; Department of Haematology/ Oncology, The Institute of Medical Science, University of Tokyo; Third Department of Internal Medicine, Jikei Medical University; Division of Haematology/Oncology, Kanagawa Prefectural Cancer Hospital; Division of Haematology/ Oncology, Niigata University School of Medicine; Department of Internal Medicine, Saku General Hospital; First Department of Internal Medicine, Shizuoka Prefectural General Hospital; Third Department of Internal Medicine, Hamamatsu Medical University; Division of Hematology and Immunology, Department of Internal Medicine, Kanazawa Medical University; Division of Haematology, Nagoya University School of Medicine, Branch Hospital; Department of Clinical Immunology and Pediatrics, Mie University School of Medicine; Second Department of Internal Medicine, Kyoto Prefectural Medical University; Division of Immunology and Haematology, Kobe Central Hospital; Department of Pediatrics, Hiroshima Red Cross Hospital; Division of Hematology, Ehime Prefectural Central Hospi-
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tal; and the Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University School of Medicine.
REFERENCES 1. Kodera Y: Hematopoietic stem cell transplantation in Japan [Japanese]. Jpn J Intern Med 87:1457-1463, 1998 2. Zager RA: Acute renal failure in the setting of bone marrow transplantation. Kidney Int 46:1443-1458, 1994 3. Cohen EP, Lawton CA, Moulder JE, Becker CG, Ash RC: Clinical course of late-onset bone marrow transplant nephropathy. Nephron 64:626-635, 1993 4. Oyama Y, Komatsuda A, Imai H, Ohtani H, Hamai K, Wakui H, Miura AB, Nakamoto Y: Late-onset bone marrow transplant nephropathy. Intern Med 35:489-493, 1996 5. Ohmoto A, Kohno M, Matsuyama R: An autopsy case report of hemolytic uremic syndrome after allogeneic bone marrow transplantation [Japanese with English abstract]. Jpn J Clin Hematol 34:229-231, 1993 6. Yuzawa Y, Aoki N, Fukatsu A, Ichida S, Yoshida F, Akatsuka Y, Minami S, Kodera Y, Matsuo S: Acute renal failure and degenerative tubular lesions associated with in situ formation of adenovirus immune complexes in a patient with allogeneic bone marrow transplantation. Transplantation 55:67-72, 1993 7. Maruyama F, Miyazaki H, Ezaki K, Sobue R, Tsuzuki M, Hirano M: Severe rhabdomyolysis as a complication of peripheral blood stem cell transplantation. Bone Marrow Transplant 14:481-482, 1994 8. Tamura H, Mitarai T, Niimi Y, Kato H, Matsubara O, Isoda K: Late-onset renal dysfunction in a patient with non-Hodgkin’s lymphoma following an autologous bone marrow transplantation. Jpn J Nephrol 37:474-480, 1995 9. Ujiie K, Tanigawa S, Kaneko T, Utsumi K, Nagai T, Sakamaki H, Onozawa Y, Saito H, Koike M: A case of massive proteinuria associated with bone marrow transplantation [Japanese]. Nippon Jinzo Gakkai Shi 37:699A, 1995 (abstr) 10. Kawai S, Watanabe M, Nishimoto Y, Ito I, Naruse T, Ookura Y, Takeo T: A case of acute lymphoblastic leukemia revealed proteinuria, hematuria and mesangiolysis following 24 months after bone marrow transplantation [Japanese]. Nippon Jinzo Gakkai Shi 37:742A, 1995 (abstr) 11. Ohno E, Ohtsuka E, Iwashita T, Uno N, Ogata M, Kikuchi H, Nasu M: Hemolytic uremic syndrome following autologous peripheral blood stem cell transplantation in a patient with malignant lymphoma. Bone Marrow Transplant 19:1045-1047, 1997 12. Yabana M, Takagi N, Kihara M, Muto R, Tamura K, Maemoto S, Minamisawa M, Nakatani Y, Ishii M: A case of nephrotic syndrome after bone marrow transplantation [Japanese with English abstract]. Nippon Jinzo Gakkai Shi 39:414420, 1997 13. Togitani K, Takeyama K, Yokozawa T, Andoh M, Narabayashi M, Kobayashi Y, Takenaka T, Tobinai K: Thrombotic microangiopathy of hyperacute onset after autologous
peripheral blood stem cell transplantation in malignant lymphoma. Bone Marrow Transplant 21:1263-1266, 1998 14. Takeuchi M, Tamaoki A, Tada A, Jyo Y, Nomura S, Takahashi K, Ohsawa G, Kibata M: Crescentic glomerulonephritis developing 3 months after autologous peripheral blood stem cell transplantation for non-Hodgkin’s lymphoma. Bone Marrow Transplant 22:725-727, 1998 15. Yorioka N, Taniguchi Y, Shimote K, Komo T, Yamakido M, Hyodo H, Kimura A, Taguchi T: Membranous nephropathy with chronic graft-versus-host disease in a bone marrow transplant recipient. Nephron 80:371-372, 1998 16. Arai A, Sakamaki H, Tanikawa S, Akiyama H, Onozawa Y, Okamoto R, Maeda Y, Sasaki T, Kaku H, Tsuzuki S, Takamoto S: Hemolytic uremic syndrome after bone marrow transplantation [Japanese with English abstract]. Jpn J Clin Haematol 39:422-426, 1998 17. Oguni T, Hino N, Waki M, Sasaki N, Taniyama K: Thrombotic thrombocytopenic purpura following allogeneic bone marrow transplantation for chronic myeloid leukemia [Japanese]. Naika 83:586-689, 1999 18. Zager RA, O’Quigley J, Zager BK, Alpers CE, Shulman HM, Gamelin LM, Stewart P, Thomas ED: Acute renal failure following bone marrow transplantation: A retrospective study of 272 patients. Am J Kidney Dis 13:210-216, 1989 19. Lawton CA, Cohen EP, Barber-Derus W, Murray KJ, Ash RC, Casper JT, Moulder JE: Late renal dysfunction in adult survivors of bone marrow transplantation. Cancer 67:2795-2800, 1991 20. Cohen EP, Lawton CA, Moulder JE: Bone marrow transplant nephropathy: Radiation nephritis revisited. Nephron 70:217-222, 1995 21. Noel C, Hazzan M, Noel-Walter MP, Jouet JP: Renal failure and bone marrow transplantation. Nephrol Dial Transplant 13:2464-2466, 1998 22. Moulder JE, Cohen EP, Fish BL, Hill P: Prophylaxis of bone marrow transplant nephropathy with captopril, and inhibitor of angiotensin-converting enzyme. Radiat Res 136: 404-407, 1993 23. Lawton CA, Cohen EP, Murray KJ, Derus SW, Casper JT, Drobyski WR, Horowitz M, Moulder JE: Long-term results of selective renal shielding in patients undergoing total body irradiation in preparation for bone marrow transplantation. Bone Marrow Transplant 20:1069-1074, 1997 24. Duell T, Teresa van Lint M, Ljungman P, Tichelli A, Socie G, Apperley JF, Weiss M, Cohen A, Nekolla E, Kolb H-J, for the EBMT Working Party on Late Effects and EULEP Study Group on Late Effects: Health and functional status of long-term survivors of bone marrow transplantation. Ann Intern Med 126:184-192, 1997 25. Butcher JA, Hariharan S, Adams MB, Johnson CP, Roza AM, Cohen EP: Renal transplantation for end-stage renal disease following bone marrow transplantation: A report of six cases, with and without immunosuppression. Clin Transplant 13:330-335, 1999
I
N THE LATE 1960s E. Donnall Thomas introduced bone marrow transplantation (BMT) to save patients with such refractory hematologic disorders as aplastic anemia and leukemia. Recently, the addition of peripheral-blood and umbilical-cord blood cell transplantation has conceptually changed BMT into hematopoietic cell transplantation (HCT). The indicative diseases have also expanded to include malignant lymphoma, solid tumors, and such hereditary hematologic disorders as sickle cell anemia and thalassemia. Recently, HCT has been performed on patients with moderate or severe autoimmune diseases in Western countries. Although HCT in Japan started 10 years later than in the United States, the total case registry of HCTs exceeded 8,000 in 1996, and the number of hematopoietic cell transplant recipients increased to more than
From the Third Department of Internal Medicine, Akita University School of Medicine, Akita City; and the Division of Nephrology and Metabolism, Tokai University School of Medicine, Isehara City, Japan. Received August 27, 1999; accepted in revised form April 7, 2000. Supported in part by a grant for Progressive Renal Disease from the Ministry of Health and Welfare Research Project for Specially Selected Disease. Address reprint requests to Hirokazu Imai, MD, Third Department of Internal Medicine, Akita University School of Medicine, Hondo 1-1-1, Akita City, 010-8543, Japan. Email: [email protected] © 2000 by the National Kidney Foundation, Inc. 0272-6386/00/3603-0003$3.00/0 doi:10.1053/ajkd.2000.9787 474
1,700 in 1 year.1 The cumulative number of hematopoietic cell transplants from unrelated donors was 978 in December 1996, with an annual number of approximately 500 HCTs. HCT-related nephropathy (HCT-N) has been a serious problem since the early days of HCT treatment. Acute renal failure (ARF) is a major complication, as is late-onset nephropathy, which occurs in 20% to 25% of the long-term survivors in Western countries.2,3 In this study, we attempt to analyze and review Japanese cases of HCT-N to clarify its incidence and characteristics in Japan. METHODS We sent questionnaires to 188 hematologic divisions of 91 hospitals that performed BMT or peripheral-blood stem-cell transplantation, using data from the Japanese BMT (HCT) registry. Data collected were as follows: (1) total number of HCTs performed until September 1, 1997; (2) initials, sex, and birth date of patients with HCT-N (nephropathy was defined as the presence of such urinary abnormalities as proteinuria or hematuria and serum creatinine levels greater than 1.5 mg/dL); (3) original hematologic disorders of patients with HCT-N; (4) type of HCT (autogenic or allogeneic, related/sibling or unrelated); (5) preparatory regimen of HCT (chemotherapy, total-body irradiation); (6) posttreatment of HCT (total amount of cyclosporine A and use of antibiotics); (7) time of onset of HCT-N; (8) phenotype of HCT-N, classified into five groups: urinary abnormalities, nephrotic syndrome (NS), ARF, hemolytic uremic syndrome and/or thrombotic thrombocytopenic purpura (HUS/TTP), and chronic renal failure (CRF); (9) renal biopsy; (10) laboratory data of patients with HCT-N; (11) observation
American Journal of Kidney Diseases, Vol 36, No 3 (September), 2000: pp 474-480
HCT-RELATED NEPHROPATHY IN JAPAN
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period after HCT; (12) suspected causes of nephropathy; and (13) patient outcomes. We analyzed the responses. Statistical analysis was performed using Student’s t-test, Welch’s t-test, Mann-Whitney test, chi-square test for independence, and log-rank (MantelCox) test for survival rate using Microsoft Excel version 5.0 (Microsoft Corp, Redmond, WA) and Statview version 4.0 (Abacus Concepts Inc, Berkeley, CA). P less than 0.05 is considered statistically significant. In addition to the cited analysis, we extensively reviewed case reports in English and Japanese and oral case presentations from Japanese meetings.
RESULTS
Replies were obtained from 32 divisions of 32 hospitals, a recovery rate of 27.1%. The total number of HCTs performed in the present study was 2,136, corresponding to one fourth of all Japanese HCTs (almost 8,000 patients). Nephropathy occurred in 51 of the 2,136 patients, for an incidence rate of 2.4% in hematopoietic cell transplant recipients. Renal biopsy or necropsy was performed in 10 of 51 patients with HCT-N. Of the 2,136 patients, 450 patients (21.1%) were from the pediatric department (⬍15 years of age); the remaining 1,686 patients (78.9%) were from the internal medicine department (⬎15 years of age). HCT-N was found in 6 of 450 pediatric patients (1.3%) and 45 of 1,686 adult patients (2.6%). However, all adult transplant recipients were aged younger than 40 years, according to the consensus of the Japanese BMT (HCT) study group. There was no significant difference in the incidence of HCT-N between children and adults (P ⫽ 0.097). Table 1 shows that 45 of 51 patients (88%) had hematologic malignancies (leukemia, 40 patients; malignant lymphoma, 5 patients). Fortyseven of 51 patients (92%) were allogeneic HLAmatched siblings (Table 2), which reflects the data that almost 90% of HCTs performed in Japan (⬃8,000 cases) were either between allogeneic HLA-matched siblings or autogenic, beTable 1.
Types of Disease in Transplant Recipients
Acute nonlymphocytic leukemia Acute lymphocytic leukemia Chronic myelogenous leukemia Malignant lymphoma Aplastic anemia Others Total
10 13 17 5 1 5 51
Table 2.
Types of Transplantations Performed Onset of Nephropathy
Type
Autologous Allogeneic Matched sibling Related partial match Unrelated Total
⬍120 Days
⬎180 Days
Total
1
0
1
32 1 2 36
15 0 0 15
47 1 2 51
cause the total number of unrelated allogeneic HCTs was 978 as of December 1996. Figure 1 shows the relation between the time of onset of nephropathy and number of patients. Based on evidence that transplanted stem cells recover 1 month after HCT and that no HCT-N occurred in patients between 120 and 180 days after HCT in this study, we divided patients into three groups: early-onset (ⱕ30 days after HCT), middle-onset (between 31 and 120 days after HCT), and late-onset (⬎180 days after HCT), including 20, 16, and 15 patients, respectively. Table 3 shows the relation between onset time and nephropathy phenotype. The early-onset group mainly included cases of ARF and HUS/ TTP. NS was not found in this group. Although the middle-onset group showed almost the same pattern as the early-onset group, ARF was more dominant in the middle-onset group. Conversely, the main phenotype of the late-onset group was NS (P ⫽ 0.0008). Regarding the influence of irradiation on the phenotype of nephropathy, the amount of irradiation in patients with urinary abnormalities and CRF was significantly greater than that in patients with ARF (P ⫽ 0.0035; Table 4). Table 5 lists the suspected causes of nephropathy, judged by the physician. Drugs were dominant causative factors in both the early-onset and middle-onset groups. However, graft-versushost disease (GVHD) and irradiation were the main causes in the late-onset group. These results suggest that the causes of late-onset nephropathy significantly differ from those of the earlyonset and middle-onset groups. Although the survival rate of the early-onset and middle-onset groups was 47.2% (17 of 36 patients), 13 of 15 patients (87%) in the lateonset group are still alive (P ⬍ 0.002; Fig 2). Ten of 30 surviving patients from all groups showed
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Fig 1. The relation between time of onset of nephropathy and number of patients. There were no patients with nephropathy between 120 and 180 days after HCT in this study.
renal dysfunction (serum creatinine level ⬎ 1.5 mg/dL), and 1 patient had undergone continuous ambulatory peritoneal dialysis (CAPD)4 (Table 6). Table 7 lists pathological findings of the biopsies and necropsy in this study. Nine patients in the late-onset group underwent renal biopsy, and necropsy was performed on one patient with HUS/TTP in the early-onset group. Six of nine patients who underwent biopsy had NS; three of these had membranous nephropathy. Tubulointerstitial nephritis and fibrosis was found in three of the nine patients who underwent biopsy. All patients with NS responded to steroid therapy (40 to 60 mg/d of prednisolone, with additional methylprednisolone pulse therapy in some pa-
tients) and retained normal renal function. However, patients with HUS/TTP, CRF, or urinary abnormality progressed to renal failure, and one patient was started on CAPD therapy. DISCUSSION
The present study showed 51 patients with HCT-N of 2,136 Japanese hematopoietic cell transplant recipients, which is approximately one fourth of the 8,000 HCT patients registered in Japan until 1996. The total number of cases of HCT-N in Japan is estimated to exceed 200, calculated by multiplying the 51 cases by four. Table 4. Relationship Between Radiation and Nephropathy Phenotypes
Table 3. Relationship Between Onset and Nephropathy Phenotypes ARF
Days after HCT 1-30 31-120 ⬎180
11 11 2
HUS/TTP
6 2 3
UA
2 1 1
CRF
1 2 1
NS
0 0 8
Total
20 16 15
NOTE. Chi-square test for independence, P ⫽ 0.0008. Abbreviation: UA, urinary abnormality.
Total irradiation (Gy) No. Mean SD
ARF
HUS/TTP
UA
CRF
NS
24 7.4 5.9
11 9.5 4.7
4 13.3 2.2
4 13.3 2.2
8 9.2 5.7
NOTE. Welch’s t-test, ARF versus UA, P ⫽ 0.0035; HUS/TTP versus UA, P ⫽ 0.056; ARF versus CRF, P ⫽ 0.0035; HUS/TTP versus CRF, P ⫽ 0.056. Abbreviation: UA, urinary abnormality.
HCT-RELATED NEPHROPATHY IN JAPAN Table 5.
477 Table 6.
Suspected Causes of Nephropathy
Prognosis of Renal Function
Onset of Nephropathy Causes
Cys A FK506 AMPH-B Drugs Sepsis Adenovirus VOD GVHD Radiation Unknown Total
Onset of Nephropathy
⬍120 Days
⬎180 Days
Total
17 5 3 3 1 2 1 5 3 2 42
2 1 0 0 0 0 0 7 4 2 16
19 6 3 3 1 2 1 12 7 4 58
NOTE. Less than 120 days, Cys A, FK506, AMPH-B, and other drugs; more than 180 days, GVHD and radiation. Abbreviations: Cys A, cyclosporine A; AMPH-B, amphotericin B; VOD, veno-occlusive disease.
We also reviewed 19 additional cases reported in journals or scientific meetings5-17 (Table 8). Nine patients underwent allogeneic HCT, and 10 patients underwent autogenic HCT. Eleven of 19 patients showed HUS/TTP, and there were two cases each of ARF, NS, CRF, and urinary abnormality. Although we could not calculate an accu-
Fig 2. Survival rate for patients with HCT-N after diagnosis. There is a significant difference between the late-onset group and earlyonset and middle-onset groups (Mantel-Cox log-rank test, P ⴝ 0.002).
⬍120 Days Renal Function
SCr ⬍1.5 mg/dL SCr ⱖ1.5 mg/dL Dialysis Total
⬎180 Days
Alive
Dead
Alive
Dead
11 6 0 17
5 12 2 19
9 3 1 13
0 1 1 2
Abbreviation: SCr, serum creatinine.
rate incidence rate, the incidence of HCT-N in Japan is significantly less than that in the United States. Zager et al18 reported in 1986 that 64 of 272 HCT patients (24%) had ARF requiring hemodialysis, and 79 patients (29%) had renal dysfunction. Lawton et al19 showed that 14 of 103 patients undergoing HCT (13.6%) had late renal failure. The cumulative probability of having late renal dysfunction is 20% at 1 year. Several possibilities can be considered to explain the difference in incidence between the United States and Japan. First, the donors of HCT were mainly HLA-matched siblings in the
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Onset (mo)
Phenotype of GN
Type of Study
0.5 6 10 12 17 19 28
HUS/TTP HUS NS NS NS NS NS
Necropsy Biopsy Biopsy Biopsy Biopsy Biopsy Biopsy
34
NS
Biopsy
54
UA
Biopsy
93
CRF
Biopsy
Pathological Findings
Pathological Findings
Outcome
Renal Function at Presentation
HUS, microthrombosis HUS, double contour Minor glomerular change with focal TIN Details unknown Membranous nephropathy Chronic GVHD Focal segmental glomerulosclerosis and membranous nephropathy Membranous nephropathy with interstitial fibrosis Segmental mesangial proliferative GN and left kidney atrophy Mesangial proliferative GN with mesangiolysis and TIN
Dead Alive Alive Alive Alive Alive Alive
ND CRF SCr ⬍1.5 mg/dL SCr ⬍1.5 mg/dL SCr ⬍1.5 mg/dL SCr ⬍1.5 mg/dL SCr ⬍1.5 mg/dL
Alive
SCr ⬍1.5 mg/dL
Alive
CRF
Alive
CRF-CAPD
Abbreviations: GN, glomerulonephritis; TIN, tubulointerstitial nepritis; SCr, serum creatinine; ND, not determined; UA, urinary abnormality.
present study, whereas unrelated allogeneic HCT is predominant in the United States. Second, the total amounts of antitumor drugs, immunosuppressants, and irradiation in Japan are less than those used in the United States. Third, there is a racial difference. Fourth, there is a short observation time since the start of HCT in Japan. Further Table 8. Case No.
Year
Author
Reference
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
1993 1993 1994 1995 1995 1995 1997 1997 1998 1998 1998 1998 1998 1988 1988 1998 1998 1998 1999
Ohmoto et al Yuzawa et al Maruyama et al Tamura et al Ujiie et al Kawai et al Ohno et al Yabana et al Togitani et al Takeuchi et al Yorioka et al Arai et al Arai et al Arai et al Arai et al Arai et al Arai et al Arai et al Oguni et al
5 6 7 8 9 10 11 12 13 14 15 16 16 16 16 16 16 16 17
study will show whether the lower incidence of HCT-N in Japan is a temporary phenomenon. The present study suggests that HCT-N is a rare complication after autogenic transplantation because only 1 of 51 cases of HCT-N was autogenic. However, review of other Japanese cases showed that 9 of 19 cases were autogenic. This
Case Reports Other Than Present Study
Disease
ALL AML ML ML CML ALL ML CML ML ML CML AML ALL ALL ALL ALL ML ALL CML
Type of HCT
Irradiation
Onset (d)
Phenotype
Outcome
Allo BMT Allo BMT PBSCT Auto BMT Allo BMT Auto BMT Auto PBSCT Allo BMT Auto PBSCT Auto PBSCT Allo PBSCT Allo BMT Auto BMT Allo BMT Auto BMT Auto BMT Auto BMT Allo BMT Allo BMT
(⫹) 10 Gy 12 Gy (⫺) 12 Gy 12 Gy (⫺) 2.5 Gy (⫺) (⫺) ? (⫺) (⫹) (⫹) (⫹) (⫹) (⫹) (⫹) 12 Gy
175 43 24 120 150 730 110 365 2 90 335 36 196 182 108 181 78 91 50
HUS/TTP ARF ARF CRF/UP UA UA HUS/TTP NS HUS/TTP CRF NS HUS/TTP HUS/TTP HUS/TTP HUS/TTP HUS/TTP HUS/TTP HUS/TTP HUS/TTP
Dead Dead Alive Alive, CRF Alive, CRF Alive Alive Alive Alive, CRF Alive, CRF Alive Dead Dead Alive Dead Dead Alive, CRF Alive Dead
Abbreviations: ALL, acute lymphocytic leukemia; Allo, allogeneic; AML, acute myelogenous leukemia; ML, malignant lymphoma; UA, urinary abnormality; PBSCT, peripheral-blood stem-cell transplantation; CML, chronic myelogenous leukemia; Auto, autologous.
HCT-RELATED NEPHROPATHY IN JAPAN
incidence is relatively high because the dominant type of HCT (⬎90%) is allogeneic. Further study should clarify whether type of HCT is a risk factor for nephropathy. Regarding the relation between the onset and pattern of nephropathy, the main patterns of HCT-N in the early-onset group were ARF and HUS/TTP. Conversely, NS and CRF were the dominant types in the late-onset group. Cohen et al20 reported that ARF occurs within the first 100 days after HCT, related to sepsis and the use of nephrotoxic antibiotics. Recently, Noel et al21 classified HCT-N into four groups according to time of onset: a very early-onset group, within 2 weeks; an early-onset group, between 2 weeks and 3 months; a middle-onset group, between 3 and 6 months; and a late-onset group, more than 6 months. In the very early-onset group, 75% of patients with mainly ARF and veno-occlusive diseases died. The causes of death in the earlyonset group were acute GVHD, infection, drug reactions, and HUS/TTP. In the middle-onset group, chronic GVHD was the predominant cause of death. However, patients in the late-onset group were affected by irradiation. Our results were similar to those of Noel et al.20 It is a characteristic pattern that only 3 of 70 patients (the sum of 51 present cases and 19 reviewed cases) were found to have HCT-N between 120 and 180 days after HCT. Further study should clarify why there is a low incidence of HCT-N between 120 and 180 days after HCT. Many physicians in the present study suspect that primary causative factors of ARF and HUS/ TTP are several drugs, such as cyclosporine, FK506, and amphotericin B in early-onset cases. Conversely, NS is strongly suspected to be caused by chronic GVHD. The total amount of irradiation in the CRF and urinary abnormality groups was significantly greater than that in the ARF group. In this respect, Moulder et al22 noted that late-onset nephropathy occurs in 20% of longterm survivors after HCT and is related to irradiation nephropathy. Also, they suggested that angiotensin-converting enzyme inhibitor is effective in the prophylaxis of HCT-N related to irradiation. Lawton et al23 showed that renal shielding reduces the incidence of HCT-N from 29% ⫾ 7% to 14% ⫾ 5% (P ⫽ 0.012). Selective renal shielding when undergoing total-body irradia-
479
tion was recommended to reduce the incidence of late-onset nephropathy. Pathological analysis of the kidney showed that three of six patients with NS had membranous nephropathy. This membranous nephropathy, depending on the abnormal immune response after HCT, responded to steroid therapy. Other nonspecific findings, such as mesangiolysis, tubulointerstitial nephritis, and focal segmental glomerulosclerosis, were observed. The present study showed a survival rate in the early-onset and middle-onset groups of 47.2%, whereas 87% of the patients in the late-onset group survived (P ⬍ 0.002). Thirty of 51 patients with HCT-N from all groups are alive. However, 10 of 30 patients progressed to CRF, and 1 patient underwent CAPD.4 Reports from Western countries showed that 5 of 125 patients (4%) surviving 5 years underwent dialysis therapy because of CRF.24 Butcher et al25 reported their experience with renal transplantation in six patients with end-stage renal disease after HCT. We need to continue the survey of HCT-N because of the increasing number of unrelated-donor HCTs, which may induce severe acute and chronic GVHD and may require greater dosages of immunosuppressive drugs. ACKNOWLEDGMENT The authors thank the doctors in the Department of Pediatrics, Sapporo Medical University; Second Department of Internal Medicine, Tohoku University School of Medicine; Division of Haematology and Blood Transfusion, Jichi Medical University; Department of Internal Medicine, Saiseikai-Maebashi Hospital; Ibaraki Prefectural Children’s Hospital; First Department of Internal Medicine, Nihon University School of Medicine; Department of Haematology/ Oncology, The Institute of Medical Science, University of Tokyo; Third Department of Internal Medicine, Jikei Medical University; Division of Haematology/Oncology, Kanagawa Prefectural Cancer Hospital; Division of Haematology/ Oncology, Niigata University School of Medicine; Department of Internal Medicine, Saku General Hospital; First Department of Internal Medicine, Shizuoka Prefectural General Hospital; Third Department of Internal Medicine, Hamamatsu Medical University; Division of Hematology and Immunology, Department of Internal Medicine, Kanazawa Medical University; Division of Haematology, Nagoya University School of Medicine, Branch Hospital; Department of Clinical Immunology and Pediatrics, Mie University School of Medicine; Second Department of Internal Medicine, Kyoto Prefectural Medical University; Division of Immunology and Haematology, Kobe Central Hospital; Department of Pediatrics, Hiroshima Red Cross Hospital; Division of Hematology, Ehime Prefectural Central Hospi-
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tal; and the Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University School of Medicine.
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peripheral blood stem cell transplantation in malignant lymphoma. Bone Marrow Transplant 21:1263-1266, 1998 14. Takeuchi M, Tamaoki A, Tada A, Jyo Y, Nomura S, Takahashi K, Ohsawa G, Kibata M: Crescentic glomerulonephritis developing 3 months after autologous peripheral blood stem cell transplantation for non-Hodgkin’s lymphoma. Bone Marrow Transplant 22:725-727, 1998 15. Yorioka N, Taniguchi Y, Shimote K, Komo T, Yamakido M, Hyodo H, Kimura A, Taguchi T: Membranous nephropathy with chronic graft-versus-host disease in a bone marrow transplant recipient. Nephron 80:371-372, 1998 16. Arai A, Sakamaki H, Tanikawa S, Akiyama H, Onozawa Y, Okamoto R, Maeda Y, Sasaki T, Kaku H, Tsuzuki S, Takamoto S: Hemolytic uremic syndrome after bone marrow transplantation [Japanese with English abstract]. Jpn J Clin Haematol 39:422-426, 1998 17. Oguni T, Hino N, Waki M, Sasaki N, Taniyama K: Thrombotic thrombocytopenic purpura following allogeneic bone marrow transplantation for chronic myeloid leukemia [Japanese]. Naika 83:586-689, 1999 18. Zager RA, O’Quigley J, Zager BK, Alpers CE, Shulman HM, Gamelin LM, Stewart P, Thomas ED: Acute renal failure following bone marrow transplantation: A retrospective study of 272 patients. Am J Kidney Dis 13:210-216, 1989 19. Lawton CA, Cohen EP, Barber-Derus W, Murray KJ, Ash RC, Casper JT, Moulder JE: Late renal dysfunction in adult survivors of bone marrow transplantation. Cancer 67:2795-2800, 1991 20. Cohen EP, Lawton CA, Moulder JE: Bone marrow transplant nephropathy: Radiation nephritis revisited. Nephron 70:217-222, 1995 21. Noel C, Hazzan M, Noel-Walter MP, Jouet JP: Renal failure and bone marrow transplantation. Nephrol Dial Transplant 13:2464-2466, 1998 22. Moulder JE, Cohen EP, Fish BL, Hill P: Prophylaxis of bone marrow transplant nephropathy with captopril, and inhibitor of angiotensin-converting enzyme. Radiat Res 136: 404-407, 1993 23. Lawton CA, Cohen EP, Murray KJ, Derus SW, Casper JT, Drobyski WR, Horowitz M, Moulder JE: Long-term results of selective renal shielding in patients undergoing total body irradiation in preparation for bone marrow transplantation. Bone Marrow Transplant 20:1069-1074, 1997 24. Duell T, Teresa van Lint M, Ljungman P, Tichelli A, Socie G, Apperley JF, Weiss M, Cohen A, Nekolla E, Kolb H-J, for the EBMT Working Party on Late Effects and EULEP Study Group on Late Effects: Health and functional status of long-term survivors of bone marrow transplantation. Ann Intern Med 126:184-192, 1997 25. Butcher JA, Hariharan S, Adams MB, Johnson CP, Roza AM, Cohen EP: Renal transplantation for end-stage renal disease following bone marrow transplantation: A report of six cases, with and without immunosuppression. Clin Transplant 13:330-335, 1999