Dialysis independence following radiotherapy of renal extramedullary haemopoeisis
David Semple,
Edward Kingdon and
Steve Holt
Sussex Renal Centre, Brighton and Sussex University Hospitals, Royal Sussex County Hospital, Brighton, UK
Correspondence and offprint requests to: Steve Holt, Sussex Renal Centre, Brighton and Sussex University Hospitals, Royal Sussex County Hospital, Eastern Road, Brighton, East Sussex BN2 5BE, UK. Email: Steve.Holt{at}bsuh.nhs.uk
Keywords: acute renal failure; extramedullary haemopoeisis
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Introduction
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Myelofibrosis is a clonal haemopoietic stem cell disorder that results in chronic myeloproliferation and atypical megakaryocytic hyperplasia. The abnormal production of growth factors by these megakaryocytes leads to the non-clonal proliferation and hyperactivity of fibroblasts, and subsequent bone marrow fibrosis. Additional characteristic features of myelofibrosis include splenomegaly, extramedullary haemopoiesis (EMH) and severe constitutional symptoms.
Although EMH has been observed in many organs, it usually occurs in the liver and spleen. However, there are cases of EMH occurring within the renal parenchyma. We describe only the third case of acute renal failure secondary to EMH in myelofibrosis, and the first to be treated successfully with radiotherapy alone.
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Case
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This patient, a 77-year-old man with a past history of ischaemic heart disease, was treated at a local hospital with hydroxyurea for myelofibrosis. Two months after commencing treatment, he developed pneumonia complicated by septic shock, acute respiratory distress syndrome and acute renal failure. He required intensive care for several weeks, with ventilation, inotropic support and renal replacement therapy (veno-venous haemofiltration). Eventually, he made a good recovery, but was left with a degree of persistent chronic renal impairment, with his serum creatinine at 250 µmol/l (
2.8 mg/dl). He received no further chemotherapy for his myelofibrosis.
He presented a year later with a 3-week history of vomiting, cough and hiccoughs. His physical examination revealed hepatosplenomegaly and intravascular volume depletion. Blood tests showed acute-on-chronic renal impairment (creatinine of 1000 µmol/l), hypercalcaemia (corrected calcium 3.58 mmol/l), anaemia (haemoglobin 8 g/dl), leukocytosis (neutrophils 27.5 x 109/l) and thrombocytosis (platelets 554 x 109/l). C-reactive protein (CRP), serology (antineutrophilic, antineutrophilic cytoplasmic and anti-glomerular basement membrane antibodies), complement and protein electrophoresis were unremarkable, and BenceJones protein was not detected in his urine. Dipstick urinalysis was positive for blood, protein and leukocytes. Phase contrast microscopy of urinary sediments showed numerous nucleated cells, thought to be mainly leukocytes, but no casts (Figure 1). Some interesting small round cells, thought perhaps to be platelets, were also seen. No organisms were seen on urine microscopy or culture. A peripheral blood film showed immature white cells without evidence of leukaemic transformation. A renal ultrasound scan showed echogenically normal looking kidneys, with bipolar diameters of
10 cm bilaterally and no hydronephrosis.

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Fig. 1. Urine microscopy showed numerous nucleated cells, interpreted as immature white cells of leukocyte lineage (A), and small round cells in chains, perhaps abnormal platelets (B).
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Despite vigorous fluid replacement, empirically chosen broad spectrum antibiotics, and the correction of his serum calcium with a saline diuresis and bisphosphonate therapy, his renal failure did not improve. The patient commenced regular haemodialysis, and a renal biopsy was performed. The biopsy revealed a cellular infiltrate composed of myeloid and red cell precursors and megakaryocytes, as well as inflammatory cells. Staining with appropriate sera did not detect immunoglobulin G, IgM, c3 or fibrinogen. Megakaryocytes stained positive for CD31, myeloid cells positive for CD15 and immature red cells positive for glycophorin. The proliferation marker MIB1 was positive in all these cells. The appearance was in keeping with EMH within the renal parenchyma (Figure 2). In some areas, these cells were also seen within the tubules. Glomeruli were normal by light and electron microscopy.

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Fig. 2. Sections of the first renal biopsy revealed an interstitium heavily infiltrated by large cells of the myeloid (CD15-positive) and red cell lineages (glycophorin-positive) as well as megakaryocytes (CD31-positive). These cells also stained positive for the MIB1 proliferation marker, strongly suggesting that these were bone marrow-derived cells. (H&E x400.)
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Radiotherapy was commenced on day 70, with 10 Gy administered to the kidneys in five divided doses. Following this therapy, serial pre-dialysis creatinines and 24-h urine collections confirmed the gradual improvement of his renal function (Figure 3). He became dialysis independent 12 weeks after radiotherapy, with a creatinine of
250 µmol/l. A repeat renal biopsy was performed in order to assess the effect of radiotherapy on the EMH and to determine if continuing it might be of further benefit. This showed no evidence of EMH and some residual atrophic and fibrotic interstitial areas. The patient's myelofibrosis subsequently was treated with busulfan. The patient remains well and off dialysis >12 months after diagnosis.

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Fig. 3. Graph showing improvement in renal function following radiotherapy. Creatinine clearance measurements (crosses) were performed on urine collected the day prior to a scheduled dialysis. Pre-dialysis creatinines (diamonds) were sampled just before dialysis.
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Discussion
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We have described a case of acute-on-chronic renal impairment secondary to EMH in a patient with primary myelofibrosis. It is postulated that EMH in myelofibrosis is driven by the transformation of heterotopic totipotential cells into haemopoietic cells, or involves the displacement and migration of marrow stem cells into the circulation, with eventual colonization of one organ or other [1]. There is some evidence to suggest that splenectomy, often indicated for local pain or refractory anaemia, may either contribute to the development of EMH, or at least lead to the enlargement and progression of existing lesions [2]. We have described a case of acute-on-chronic renal impairment secondary to EMH in a patient who had primary myelofibrosis, but not splenectomy.
EMH occurring in myelofibrosis has been reported at many sites. Most commonly it involves the liver and spleen; but its occurrence in the renal parenchyma, para-renal spaces, brain, meninges, epidural region, gastrointestinal tract, lung, pleura, pericardium and synovium has also been reported [3]. Typically, EMH is an incidental finding, discovered by computed tomography (CT) or ultrasound scanning [4], or at autopsy [3,5]. EMH appears to be a more prominent feature of myelofibrosis when patients have had a splenectomy.
Para-renal involvement has been described [3,6], and on occasion this may cause renal impairment secondary to the obstruction of the ureter or renal pelvis [7]. Although renal parenchymal EMH is uncommon, it has been described in patients with myelofibrosis and thalassaemia. Occasionally, this mimics solid tumours on imaging, and only biopsy has prevented unnecessary surgical intervention [6].
The English language literature describes only three other cases of renal impairment due to renal parenchymal EMH. Schnuelle et al. [8] report a case of chronic renal failure in a patient with myelofibrosis. Renal biopsy in this case revealed a diffuse fibrosing and infiltrating process rich in immature granulocytes, erythroblasts and abnormal megakaryocytes. Treatment with hydroxyurea prevented further decline in renal function, and the patient remained dialysis independent until death from cerebral haemorrhage. In the two remaining case reports, the patients presented with haemodialysis-dependent renal failure. In both cases, the patients responded favourably to treatment. Holt et al. [9] describe using radiotherapy, steroids and busulphan for their patients, while the patient reported by Woodward et al. [10] was given FLAG [fludarabine, cytarabine, arabinoside and granulocyte colony-stimulating factor (G-CSF)] chemotherapy without radiotherapy.
EMH in a wide variety of tissues appears to be exquisitely sensitive to radiotherapy [2]. It is clear from our case that radiotherapy is effective in some circumstances without chemotherapy; however, some interstitial scarring was present on the second biopsy. It is not clear if this was caused by the radiotherapy or if the scarring is related to the EMH.
EMH in the renal parenchyma is found at autopsy far more frequently than is clinically predictablein up to 34% of patients with myeloproliferative and lymphoproliferative conditions according to one study [5]. While there have been few cases of renal failure directly attributable to it, EMH should be considered in the differential diagnosis of deteriorating renal function in any patient with such conditions, particularly myelofibrosis.
Conflict of interest statement. None declared.
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Received for publication: 13. 6.03
Accepted in revised form: 20.11.03