Renal insufficiency after bone marrow transplantation in children

Between 1975 and 1988, 92 pediatric patients have undergone bone marrow transplantation (BMT) at our institution for malignant or immune deficiency disease. We evaluated in a retrospective fashion 64 of these patients who survived beyond the first 60 days post-BMT. The clinical course was divided into: less than 60 days post-BMT (early) and greater than 60 days post-BMT (late). The presence or absence of renal insufficiency was noted as well as all known potential factors predisposing to insufficiency. Step-wise regression analysis was then performed to determine which of the factors were most significantly associated with renal dysfunction during the two periods. The follow-up period was 2 months to 11 years (mean 17.5 months). The mean age of the patients was 7.6 years (1 month-18 years). Fifty percent of the patients had renal insufficiency during the early period and 28% of the patients had insufficiency after the initial 60 days. Three major predictors of renal insufficiency were discovered. Cyclosporin A or amphotericin B early or late post-BMT was independently predictive of developing insufficiency during the same period. Conditioning with total body irradiation was a predictor for insufficiency in both periods. Early insufficiency was not predictive of late insufficiency. Hypertension was present in 31% of patients during the early period and in 16% during the late period. Hypertension was strongly associated with cyclosporin use and renal insufficiency. Renal insufficiency is a frequent sequela in children following BMT and likely results from a combination of radiation injury and drug toxicity.     

Donor-derived red blood cell antibodies and immune hemolysis after allogeneic bone marrow transplantation

Six cases of immune hemolytic anemia attributed to donor-derived red cell antibodies after allogeneic bone marrow transplantation (BMT) are reported. In 2/6 cases, severe intravascular hemolysis was seen, 6/6 required increased red cell transfusion, and 1/6 was treated by plasma exchange. All recipients were receiving cyclosporine to prevent graft-v- host disease. Investigations showed that in each case, the donor lacked ABO or Rho(D) red cell antigens present in the recipient. The direct antiglobulin test was positive in 6/6. Relevant serum antibody (anti-A, four cases; anti-B, one case; anti-D, one case) was first detected one to three weeks after BMT. Eluates made from recipient red cells showed the same specificity as serum antibody. Maximum hemolysis occurred nine to 16 days after BMT, suggesting that active production of antibody by "passenger" donor lymphocytes was the likely mechanism of hemolysis, rather than passive transfer of antibody in the marrow infusion. Retrospective analysis of 21 consecutive cyclosporine-treated BMT patients receiving marrow lacking ABO or D antigens present in the recipient showed that (1) 15/18 patients tested had red cell antibody production against recipient red cell antigens; (2) despite the frequent presence of antibody specific for recipient red cell antigens, only 3/21 patients developed clinically significant hemolysis; (3) clinical hemolysis could not be predicted by donor or recipient red cell antibody titers. We conclude that although red cell antibody against recipient antigens is frequently produced after minor ABO and D mismatched BMT in cyclosporine-treated recipients, only 10% to 15% of cases develop clinically significant immune hemolysis. The data presented show that the most likely source of antibody is "passenger" donor lymphoid cells.     

Long-term renal function following bone marrow transplantation

Renal function, evaluated as glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), was investigated in 187 pediatric patients who underwent allogeneic (n=169) or autologous bone marrow transplantation (BMT). Allogeneic BMT patients were divided into three groups: hematological malignancies, aplastic anemia and non-malignant diseases, whereas autologous patients constituted a fourth group. A total of 64% received total body irradiation (TBI) as conditioning therapy, and 50 healthy children served as controls. GFR and ERPF were normal before transplantation. After 1 year, both GFR and ERPF were significantly reduced. GFR had recovered slightly after 3 years and remained stable thereafter. Recovery in ERPF was not apparent. Renal impairment was found in 41% of patients at 1 year, in 31% at 3 years and in 11% 7 years after BMT. Patients with hematological malignancies had lower GFRs than patients with non-malignant diseases at all time points. The most important risk factor as regards chronic renal impairment was TBI. Type of donor, cyclophosphamide (CY), or acute graft-versus-host disease (GVHD) did not seem to contribute to the development of chronic renal impairment. We suggest that tests of renal function should be included in long-term followup after BMT.     

Antibody-mediated marrow failure after allogeneic bone marrow transplantation

Marrow graft failure observed in association with histocompatibility differences between donor and recipient is often attributed to rejection mediated by host-derived cytolytic T lymphocytes. The data presented in this report indicate that persistent host antibodies specific for donor antigen may also mediate graft failure, either by antibody-dependent cell-mediated cytotoxicity (ADCC), or complement- mediated cytotoxicity. In the case of HLA Class I disparity, where all donor cells express the target antigen, the presence of alpha-donor antibody was associated with complete graft failure and death. In the case of ABO blood group antigen disparity, the presence of alpha-donor antibody resulted in erythroid hypoplasia. The latter cases proved informative insofar as they established that host antibodies could persist for more than 18 months after chemoradiotherapy and impair marrow function.     

Cytomegalovirus infection after autologous bone marrow transplantation with comparison to infection after allogeneic bone marrow transplantation

Cytomegalovirus (CMV) infection was detected in 65 of 143 (45%) autologous bone marrow transplant (BMT) patients. CMV pneumonitis occurred in only 2% of the patients and CMV retinitis occurred in none. Infection occurred in half of the 40 initially seronegative patients and 47% of the 94 initially seropositive patients. Among initially seropositive patients, platelet recovery was slower in infected patients than in those not infected (97 v 35 days median, P = .003), and neutrophil recovery was slightly delayed in infected patients (31 days v 24 days, P = .02). Although the incidence of CMV infection was comparable in autologous and allogeneic BMT patients, CMV pneumonitis was less frequent in autologous BMT patients (2% v 12%, P less than .001). The risk for CMV pneumonitis in autologous BMT patients was comparable with that in allogeneic BMT patients without graft-v-host disease (GVHD) (2% v 6%), but significantly lower than the risk in allogeneic BMT patients with GVHD (2% v 23%, P less than .001).     

Bronchiolitis obliterans after bone marrow transplantation

Bronchiolitis obliterans occurred in the setting of chronic graft-versus-host disease 1 year after allogeneic bone marrow transplantation for chronic myelogenous leukemia. The severe obstructive pulmonary disease followed an episode of interstitial pneumonitis. The etiology and possible relationship to graft-versus-host disease of this rare pulmonary lesion following bone marrow transplantation are discussed.     

Autoimmune thyroiditis after bone marrow transplantation

We describe the transfer of autoimmune thyroiditis by bone marrow transplantation. The male recipient developed compensated hypothyroidism 3 years after transplantation, and progressed to thyroid failure 1 year later. The female sibling had compensated hypothyroidism when screened 4 years after marrow donation. The donor, the recipient, and an older male sibling were HLA DR4, 5; the father was presumed homozygous for DR4 and the mother for DR5. Only the donor and recipient had abnormal thyroid function and positive antithyroid antimicrosomal antibodies. The most probable mechanism for the organ specific autoimmune dysfunction is the transfer of abnormal B and T cell clones from the donor. Radiation damage to the thyroid prior to transplantation, the mild graft-versus-host disease immediately following transplantation, and the general immune dysregulation seen in the first several years after marrow engraftment may have contributed to an acceleration of the autoimmune destruction of the recipient's thyroid.     

Immunotherapy after bone marrow transplantation.

Residual disease after bone marrow transplantation (BMT) can either cause relapse or persist in a balanced state in which immune mechanisms keep control over malignant cell proliferation. After allogeneic BMT the latter mechanism [summarized as graft-versus-leukemia (GVL)] is probably supported by cellular (e.g. T lymphocytes, natural killer cells) and humoral (e.g. cytokines) effectors and often linked to clinical manifestations of GVHD. Preclinical and clinical studies are now emerging in which cytokines, such as interleukin-2 or interferons, are given after BMT to support cellular immune function particularly in situations in which GVL does not occur. We summarize here results from both pre-clinical and clinical studies that are relevant to the design of protocols seeking to improve elimination of residual malignant disease in BMT patients by modulation of the immune system.     

Legionnaires' disease after bone marrow transplantation

Four patients developed legionnaires' disease after bone marrow transplantation. Two cases occurred early after transplant and were considered as part of a hospital epidemic due to contamination of water supply. The other two cases were considered to be sporadic because they occurred 3-4 weeks after hospital discharge. The outcome was good in two patients. In the third patient, recurrent disease was probably due to acquired resistance to macrolides, and complete cure was achieved after treatment with pefloxacin and rifampicin. The fourth patient died of overwhelming infection despite early treatment with erythromycin and pefloxacin. During the same period we treated 14 patients with pefloxacin for prevention of bacterial infection, of whom none developed Legionella pneumophila infection, while three of the patients reported here were in a group of 11 patients who received only oral non-absorbable antibiotics for gut decontamination. The fourth patient in this report was receiving no antibiotics. Thus pefloxacin seems to be effective as prophylaxis against L. pneumophila infection. When the hospital water supply was heated to 60 degrees C and chlorinated, the nosocomial cases in the hospital completely disappeared.     

HTLV-III infection after bone marrow transplantation

We prospectively documented the development of a fatal, secondarily acquired severe immunodeficiency in a 19-year-old man who underwent uncomplicated bone marrow transplantation. He had no graft v host disease (GVHD) and had normal recovery of his immune system as determined by lymphocyte phenotyping, mitogenic responses of his peripheral blood lymphocytes, and his ability to secrete immunoglobulin. This alteration in immunity was associated with the acquisition of antibody to HTLV-III. His only risk factor for the development of HTLV-III infection was the transfusions he had received during the transplant and recovery period. Two of his 54 transfusions were from an asymptomatic individual at high risk for acquired immunodeficiency syndrome (AIDS), who was subsequently found to be seropositive for anti-HTLV-III and from whom HTLV-III was isolated. The loss of immunocompetence in patients without chronic GVHD disease is unusual, and our data support the view that this patient's immunodeficiency was due to HTLV-III. When bone marrow transplant recipients without chronic GVHD develop late opportunistic infections, consideration should be given to transfusion-associated AIDS.     

Extramedullary haemopoiesis after bone marrow transplantation

44 patients underwent bone marrow transplantation (BMT) for treatment of severe aplastic anaemia or haematological malignancies. During their post-transplant phase all patients had erythroblasts and granulocytic precursors in their peripheral blood. 15 patients died between day +6 and +346 after BMT and autopsies were performed. The sections of all 15 patients revealed extramedullary haemopoiesis in the spleen. Extramedullary haemopoiesis in the liver was found only in those patients who died early (between d +6 and d +21 after BMT). Medullary haemopoiesis, normally only occurring in the vertebral body, was also observed in the shaft of the femur. The present data show that after BMT all tissues with a haemopoietic matrix in ontogenesis can be repopulated with haemopoiesis in the early phase of reconstitution, possibly to compensate for the haemopoietic insufficiency after conditioning therapy. The expansion of haemopoiesis in the later period of up to 1 year after BMT, remains to be explained.     

Pseudoparasitic pneumonia after bone marrow transplantation

We present a female patient from Somalia with an acute lymphoblastic leukemia, who received an allogeneic bone marrow transplantation (BMT) and developed several periods of moderate to severe pulmonary symptoms that were accompanied by pulmonary infiltrates and peripheral blood eosinophilia. After several recurrences an open lung biopsy was performed, which initially gave rise to the diagnosis parasitic infection. Later on this diagnosis was questioned and it was suggested that the structures were artifacts that might have been aspirated. Nevertheless, after the immediately given antihelminthic treatment no peripheral blood eosinophilia occurred anymore, but at that point of time pulmonary function was already severely hampered and eventually led to a lethal complication. With the worldwide increasing migration from Third World countries with a high prevalence of parasitic infections, more patients will receive immunosuppressive therapies in countries less familiar with parasites. This may complicate diagnostic procedures, prevent early recognition and delay adequate treatment. Specific screening for opportunistic parasitic infections of the population at risk before BMT and a great awareness for these infections is strongly recommended.     

Hemopoietic reconstitution after bone marrow transplantation

Forty-one patients underwent bone marrow transplantation (BMT) for treatment of severe aplastic anemia or hematologic malignancies. Hemopoietic reconstitution after BMT was monitored by peripheral blood counts, counts of bone marrow cellularity, and clonal assays for hemopoietic progenitors (CFUc, CFUe, and BFUe), along with bone marrow morphology. The number of transplanted nucleated cells and the number of transplanted progenitors (CFUc, CFUe, and BFUe) correlated significantly with the time of reticulocyte recovery. The number of transplanted CFUc correlated significantly with the time of granulocyte recovery. Platelet recovery occurred late and showed large variations. No correlation between the transplanted cells and the recovery of nucleated cells or hemopoietic progenitors (CFUc, CFUe, and BFUe) in the bone marrow was found. Bone marrow cellularity and hemopoietic progenitors showed a rapid, but incomplete, recovery during the first 56 days after BMT. Hematologic studies on seven long-term survivors with an uncomplicated posttransplantation course revealed subnormal bone marrow cellularity and hemopoietic progenitor incidence up to three years after BMT, despite normal peripheral blood counts. The low progenitor incidence could be explained by a proliferative defect of the stem cells, compensated for by an amplification in the more differentiated compartment of hemopoiesis.     

Association of renal failure with Lewis incompatibility after allogeneic bone marrow transplantation

The cause of the renal failure that occurs in approximately 20 percent of patients following allogeneic bone marrow transplantation is poorly understood. A patient is described in whom acute renal failure occurred one week after allogeneic bone marrow transplantation. The onset of the renal failure was associated with the demonstration of anti-Lewis antibodies in the patient's serum, which could only have been derived from donor lymphocytes. Recovery of renal function coincided with the disappearance of the Lewis antibody. It is postulated that Lewis incompatibility between graft and host tissue may have contributed to the renal failure in this patient and that incompatibility associated with determinants present on renal cells may account for other instances of acute renal failure following allogeneic bone marrow transplantation.     

Graft-versus-leukemia reactions after bone marrow transplantation

To determine whether graft-versus-leukemia (GVL) reactions are important in preventing leukemia recurrence after bone marrow transplantation, we studied 2,254 persons receiving HLA-identical sibling bone marrow transplants for acute myelogenous leukemia (AML) in first remission, acute lymphoblastic leukemia (ALL) in first remission, and chronic myelogenous leukemia (CML) in first chronic phase. Four groups were investigated in detail: recipients of non--T-cell depleted allografts without graft-versus-host disease (GVHD), recipients of non-- T-cell depleted allografts with GVHD, recipients of T-cell depleted allografts, and recipients of genetically identical twin transplants. Decreased relapse was observed in recipients of non--T-cell depleted allografts with acute (relative risk 0.68, P = .03), chronic (relative risk 0.43, P = .01), and both acute and chronic GVDH (relative risk 0.33, P = .0001) as compared with recipients of non--T-cell depleted allografts without GVHD. These data support an antileukemia effect of GVHD. AML patients who received identical twin transplants had an increased probability of relapse (relative risk 2.58, P = .008) compared with allograft recipients without GVHD. These data support an antileukemia effect of allogeneic grafts independent of GVHD. CML patients who received T-cell depleted transplants with or without GVHD had higher probabilities of relapse (relative risks 4.45 and 6.91, respectively, P = .0001) than recipients of non--T-cell depleted allografts without GVHD. These data support an antileukemia effect independent of GVHD that is altered by T-cell depletion. These results explain the efficacy of allogeneic bone marrow transplantation in eradicating leukemia, provide evidence for a role of the immune system in controlling human cancers, and suggest future directions to improve leukemia therapy.