A 27-year-old man had a known history of chronic myeloid leukemia with positive Philadelphia chromosome. He presented with blurred vision secondary to hyperviscosity syndrome, which had been present for 2 years. After a course of chemotherapy, he received allogenic bone marrow transplantation (BMT) from his sister, with 1 antigen mismatch. No total body irradiation was used in pre-BMT conditioning. Cyclophosphamide and busulfan were given. The patient received cyclosporin A and mycophenolate mofetil for control of graft-versus-host disease after bone marrow transplantation.

One year later, the patient experienced deterioration of liver and renal functions. His blood pressure was 130/76 mm Hg. Urine protein level was 0.1 g/dL/d. The patient's hemoglobin level was 8.4 g/dL (normal, 13.0–18.0 g/dL), and his platelet count was low, 83 × 103/μL (normal, 150–400 × 103/μL). Lactate dehydrogenase was elevated to 839 U/L (normal, 197–401 U/L). The serum creatinine level was 2.83 mg/dL (normal, 0.92–1.42 mg/dL). Ultrasound-guided percutaneous renal biopsy was performed because of the proteinuria and persistent impaired renal function.

Microscopically, the glomeruli showed accentuation of lobularity. Diffuse narrowing and obliteration of capillary lumens was evident. Focal aneurysmal capillary dilatation was noted (Figure 1). Prominent mesangiolysis and extreme widening of the space between the endothelium and glomerular basement membrane were easily discernible (Figure 2, periodic acid-Schiff–methenamine silver stain), giving a double-contour appearance. Tubular atrophy, interstitial fibrosis, and chronic inflammatory infiltrate were mild. Immunofluorescence studies revealed nonspecific, mild, granular deposits of immunoglobulin (Ig) M and C3 in the mesangium.

On ultrastructural examination (Figure 3), endothelial cell injury was evident. Separation of the endothelial lining from the basement membrane was prominent, giving rise to a greatly expanded subendothelial space (Figure 3, arrowheads). No immune complex–type electron-dense deposits were apparent.

What is your diagnosis?

Renal impairment may occur after BMT. In the early posttransplant period, impairment is mainly related to acute tubular necrosis, infection, nephrotoxic medications, graft-versus-host disease, tumor lysis syndrome, marrow infusion toxicity, hepatic veno-occlusive disease, and interstitial nephritis. Cyclosporin A renal toxicity can occur as an early and/or late event. A distinct syndrome of late renal toxicity, defined as nephrotoxicity developing more than 3 months after BMT, is also being reported more frequently.1–4 Cohen applied the term bone marrow transplant nephropathy to this syndrome.5 

Pathologic features of bone marrow transplant nephropathy are distinct.1,3,6 It is characterized by prominent mesangiolysis and focal aneurysmal capillary dilatation. Variable degrees of mesangial matrix increase may be observed. The endothelial cells are swollen, and the subendothelial space is considerably widened. The glomerular basement membrane appears duplicated (“double contour”). Focal fibrin thrombi may be identified within the capillary loops. Immunofluorescence studies may show deposits of fibrin and IgM in some glomeruli. Electron microscopy reveals endothelial injury. The subendothelial space is greatly expanded and filled with loose, amorphous, granular material consistent with fibrin and newly laid basement membrane material. Red cell fragments may also be identified.

Endothelial cell injury is the hallmark of bone marrow transplant nephropathy, most probably related to irradiation used for pre-BMT conditioning.3 However, bone marrow transplant nephropathy has also been described in patients with no previous history of irradiation, as demonstrated in our case and others.7–9 The effects of ionizing radiation might be potentiated by cytotoxic chemotherapy imposed before BMT.3,10 

Bone marrow transplant nephropathy is an uncommon but significant late complication of BMT. The patients usually present with delayed renal insufficiency, hypertension, and anemia out of proportion to the level of azotemia, 8 to 12 months after BMT. The more severe cases may present much like hemolytic uremic syndrome. Even with less impressive initial presentations, monitoring of renal function is needed because progressive renal deterioration with need for chronic dialysis or renal transplantation may result. Supportive therapy is the mainstay of treatment.1,3,5 

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Author notes

Corresponding author: Gavin Shueng-wai Chan, FRCPA, Department of Pathology, Queen Mary Hospital, Hong Kong ([email protected])