Objectives: Renal transplant may be complicated by cytopenia, fever of unknown etiology, or hematolymphoid malignancies. Bone marrow biopsy may be indicated to evaluate these complications. However, to the best of our knowledge, no previous study has systematically documented the characteristics of bone marrow biopsy in these patients. The present study reports the range of bone marrow findings in renal transplant recipients.

Materials and Methods: We selected 85 patients who underwent bone marrow biopsy among 1745 renal transplant recipients who had transplant at Başkent University from January 1990 to December 2013. The files of these patients were reviewed for age, sex, age at renal transplant, underlying renal disease, donor type, immunosuppressive therapy, presence or absence of acute humoral or cellular rejection, duration between transplant and bone marrow biopsy, indication for bone marrow biopsy, and histopathologic diagnoses of bone marrow biopsies.

Results: The most common cause of renal insufficiency leading to transplant in this patient group was unknown etiology, observed in 24 patients (28.2%). The most common indication for bone marrow biopsy was blood cytopenia, detected in 56 patients (65.9%). Neoplastic involvement of the bone marrow was detected in 6 patients (7.1%), all of which were hematolymphoid malignancies. Corticosteroids were the most commonly used immunosuppressive agents, administered to all patients.

Conclusions: Bone marrow biopsy provides important information in renal transplant recipients, especially in cases of neoplastic bone marrow involvement, specific inflammation, and amyloidosis, which are uncommon in this patient group. The overall diagnostic use is related to the individual situation of each patient.

Key words : Anemia, Cytopenia, Kidney transplant

Introduction

Renal transplant may be complicated by persistent fever or cytopenia. Renal transplant recipients also are susceptible to the development of hemato­lymphoid malignancies, and bone marrow biopsy may be indicated for malignancy staging. Therefore, bone marrow biopsy is not infrequently performed in this patient group. However, to the best of our knowledge, no previous study has systematically documented the characteristics of bone marrow biopsy in these patients. The present study reports the range of bone marrow findings in renal transplant recipients.

Materials and Methods

Patients
Patients who underwent bone marrow biopsy were selected among 1745 kidney transplant recipients from January 1990 to December 2013 in Başkent University. Clinical findings of these patients were reviewed from patient files, including age, sex, age at renal transplant, underlying renal disease, donor type, immunosuppressive therapy, presence or absence of acute humoral or cellular rejection, duration between transplant and bone marrow biopsy, indication for bone marrow biopsy, and histopathologic diagnoses of bone marrow biopsies.

Statistical analyses
Descriptive and comparative statistical analyses were conducted with statistical software (SPSS for Windows, Version 16.0, SPSS Inc., Chicago, IL, USA).

Results

There were 85 patients who underwent bone marrow biopsy after kidney transplant. In the 85 patients, 57 patients (67.1%) were male and 28 patients (32.9%) were female. The mean age at renal transplant was 32.0 ± 12.3 years. The graft source was a living-related donor in 54 patients (63.5%) and deceased donor in 31 patients (36.47%). The mean age at bone marrow biopsy was 36.5 ± 13.1 years (range, 4-65 y), and 7 patients (8.2%) were aged < 19 years at bone marrow biopsy. The mean duration between transplant and the requirement for bone marrow biopsy was 59.1 ± 57.8 months (range, 1-250 mo).

The most common cause of renal insufficiency leading to transplant in this patient group was unknown, observed in 24 patients (28.2%). The most common known underlying disease was primary glomerulopathy (19 patients [22.4%]). The other underlying diseases, in order of decreasing fre­quency, were pyelonephritis (6 patients [7.0%]), diabetes mellitus (6 patients [7.0%]), polycystic kidney disease (5 patients [5.9%]), Alport syndrome (4 patients [4.7%]), systemic hypertension (4 patients [4.7%]), familial Mediterranean fever (4 patients [4.7%]), nephrolithiasis (4 patients [4.7%]), vesico­ureteral reflux (3 patients [3.5%]), cystinosis (2 patients [2.4%]), tubulointerstitial nephritis (2 patients [2.4%]), systemic lupus erythematosus (1 patient [1.2%]), and renal agenesis (1 patient [1.2%]) (Table 1).

Indications for bone marrow biopsy were fever of unknown origin in 18 patients (21.2%), cytopenia in 56 patients (65.9%), and staging evaluation for posttransplant lymphoproliferative disorder (PTLD) in 11 patients (12.9%).

In the 85 bone marrow biopsies, 6 biopsies (7.1%) showed neoplastic infiltration, including 3 biopsies performed for staging of PTLD (Table 2). There were 2 bone marrow biopsies that were characterized by diffuse blast infiltration; and bone marrow was infiltrated with diffuse large-B-cell lymphoma in 1 patient. The frequency of bone marrow involvement by PTLD in our series of renal transplant recipients was 3 of 11 patients (27.3%), and no neoplastic involvement of bone marrow other than hemato­lymphoid malignancies was observed. All 4 patients (4.7%) who underwent renal transplant due to familial Mediterranean fever had amyloidosis in their bone marrow biopsies. Granulomatous inflammation was observed in 3 bone marrow biopsies (3.5%); in these patients, 1 patient had systemic lupus erythematosus and 1 patient had nephrolithiasis as the underlying etiology (both patients were investigated for fever of unknown origin), and 1 patient had cryptogenic origin of renal insufficiency and was biopsied for pancytopenia. In the other bone marrow biopsies, 34 biopsies (40.0%) were normocellular for patient age, 23 biopsies (27.1%) were hypocellular, and 9 biopsies (10.6%) were hypercellular (Table 2). In 1 patient, there was infiltration of bone marrow histiocytes with foreign material secondary to ingestion of a traditional herbal medication in a renal transplant recipient of unknown underlying cause.

The most common immunosuppressive drugs were corticosteroids, which were used in all patients. Additionally, 41 patients (48.23%) used cyclosporine and 14 patients (16.47%) used tacrolimus. There were 30 patients (35.29%) who received triple immunosuppressive therapy (calcineurin inhibitor, antimetabolite, and corticosteroids).

There were 2 of 85 patients (2.6%) who experienced acute humoral rejection, 20 patients (23.5%) who had acute cellular rejection, and 3 patients (3.5%) who had both acute humoral and cellular rejection.

When cases were grouped as neoplastic (6 patients [7.1%]), nonneoplastic (75 patients [88.2%]), and amyloidosis (4 patients [4.7%]) according to bone marrow biopsy histology, there were no significant differences in mean duration between transplant and bone marrow sampling; presence or absence of acute humoral and cellular rejection; presence of interfering cytomegalovirus, hepatitis C virus, or Epstein-Barr virus infections; use of cyclosporine, tacrolimus, or sirolimus as immunosuppressive medication; or indication of bone marrow biopsy grouped as investigation of cytopenia, fever of unknown origin, or staging for hematolymphoid malignances (all relevant P values were above .05).

Discussion

Anemia is a common complication of renal transplant and may occur due to a variety of causes including impaired renal function, immuno­suppressive medication, donor and recipient age, and impaired iron homeostasis.^1,2 Immuno­suppressive drugs, especially azathioprine and mycophenolate mofetil, frequently cause bone marrow suppression resulting in anemia, leuko­penia, and thrombocytopenia.³ Bone marrow biopsy may be required in renal transplant patients to rule out neoplastic infiltration in the bone marrow or primary bone marrow pathology, diagnose specific infections involving the bone marrow, and determine the extent of myelosuppression. However, we have not encountered any systematic studies on findings of bone marrow biopsies from renal transplant recipients. Therefore, the present study is a preliminary report which outlines the features of bone marrow biopsies in renal transplant recipients.

Cryptogenic renal insufficiency and primary glomerulopathies were the leading underlying etiologic factors in renal transplant recipients who required bone marrow sampling. Bone marrow biopsies were most commonly taken from patients who were being investigated for cytopenia, and the most frequent histopathologic finding was normocellular bone marrow. Involvement of bone marrow by neoplastic processes was infrequent, and no neoplasms resulted from a solid-organ primary neoplasm.

Bone marrow biopsy provided useful information for renal transplant recipients, and diagnostic utility was related to the individual situation of each patient. Further studies are needed to specify the histologic characteristics and utility of bone marrow biopsy in this patient group.

References:

1. Einollahi B, Lessan-Pezeshki M, Rostami Z, Kalantar E, Afshar R, Beiraghdar F. Anemia after kidney transplantation in adult recipients: prevalence and risk factors. Transplant Proc. 2011;43(2):578-580.
2. Vanrenterghem Y. Anemia after kidney transplantation. Transplantation. 2009;87(9):1265-1267.
3. Danesi R, Del Tacca M. Hematologic toxicity of immunosuppressive treatment. Transplant Proc. 2004;36(3):703-704.