Departments of 1 Nephrology, 2 Pathology and 3 Haematology, Evangelismos General Hospital, Athens, Greece
Keywords: atheroembolic renal disease; atherosclerosis; membranous nephropathy; myelodysplastic syndrome; trisomy 8
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Introduction |
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A 61-year-old patient is described and discussed thoroughly. The patient had ARD, membranous nephropathy and MDS with eosinophilia, and trisomy 8 of bone marrow cells coexisted.
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Case |
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The laboratory findings were as follows: Ht 24%, Hb 8 g/dl, leukocyte count 5500 µl (polymorphonucleates 21%, lymphocytes 27%, eosinophils 51%, and monocytes 1%), platelets 175 000 µl, blood urea 105 mg%, serum creatinine 2 mg%, and ESR 101 mm/1 h. Urinalysis revealed rare leukocytes and red cells, protein 30 mg%, with 24 h urine protein 1 and 2 g (two samples). Ferritin levels were 112 ng/ml, PTH 97 pg/dl, serum cholesterol 173 mg%, triglycerides 197 mg%, HDL 23 mg%, LDL 111 mg%, fibrinogen 465 mg%, and serum uric acid 8.1 mg%. Serum B12 and folic acid levels were normal. T and B lymphocyte population was also normal. Renal ultrasonography revealed two normal sized kidneys with a mild increase of their cortical echogenicity. A CT scan of the lungs and abdomen revealed a 4 cm aneurismatic dilatation of the ascending aorta, and an aneurysm of the abdominal aorta with a diameter of 4 cm, beginning under the origin of the renal arteries. Serum protein immune-electrophoresis was normal with normal values of IgE. Stool examination for parasites was negative. Search for anti-nuclear, anti-DNA, and ENA antibodies, complement levels, cANCA and pANCA (anti-MPO3 and -PR3) antibodies, HbsAg, and HCV were also negative. A percutaneous kidney biopsy was performed. Light microscopic examination showed ARD and membranous nephropathy stage I-I accompanied by mild mesangial hyperplasia. No evidence of tissue eosinophilic infiltration was noticed. Cholesterol emboli in small sized renal arteries and ischaemic lesions as well as chronic medullary tubular lesions were present. Immunofluorescence was positive for IgG, IgA, IgM, C3, C1q, and anti-nuclear antibody (ANA) deposition, a pattern of full house immune-deposition (Figure 1ac
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During the patient's hospital stay, two blood transfusions and high doses of erythropoietin (40 000 IUx3/week) were needed to increase and maintain Hb levels to 910 g%. Corticosteroid treatment led to the suppression of eosinophilia, while renal function and proteinuria remained stable 1 year after the diagnosis of his disease, under small doses of corticosteroids.
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Discussion |
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MDSs comprise a heterogeneous group of clonal disorders affecting haematopoietic cells, which are considered pre-leukaemic conditions, because of their possibility of transformation in acute leukaemia. They are frequently accompanied by chromosomal disorders where leukaemic transformation is most likely to appear [7,8]. The presence of abnormal eosinophils in bone marrow and/or eosinophilia is a rare expression of MDS. In a large report of cases with MDS, only eight out of 114 patients presented with MDS with eosinophilia. Five of these cases were accompanied by chromosomal disorders [2]. In another report of 179 cases with MDS there is no any reference to MDS and eosinophilia [7]. Thus, MDS and eosinophilia is a rare manifestation of haematological disorder. On the other hand, the presence of chromosomal disorders in MDS is common (3379% of the cases) and is considered a dismal prognostic factor for their clinical outcome, increasing the risk for leukaemic transformation [7,8]. Karyotype instability of bone marrow cells seems to be implicated in these chromosomal disorders, mainly partial deletions (5q, 7q, 20q), or trisomies (+7, 8) [79]. The causes of karyotype instability can be multifactorial in the individual patient. Candidate mechanisms are defects in DNA repair and/or cell cycle control. A mutagen environmental exposition might have a role to MDS pathogenesis as well [8,9]. In a recent report of patients with MDS, history of a chronic exposition to environmental or occupational mutagens was associated with a higher possibility for development of chromosomal disorders [9].
Paraneoplastic autoimmune phenomena have been associated with MDSs [3]. Clinical disorders include an acute systemic vasculitic syndrome, autoimmune disorders, and classical connective tissue diseases, most frequently relapsing polychondritis. Renal involvement in MDS as a paraneoplastic autoimmune phenomenon is rare [3,1012]. There are only sporadic references of association of MDS and glomerulonephritis, like crescentic glomerulonephritis [10], and membranous nephropathy [11,12]. Moreover, in a second large series of patients with MDS in (i) 221 and (ii) 125 patients, renal involvement was found in only 4 and 2% of the MDS patients, respectively [3,12]. Renal findings were variable and presented mainly as a manifestation of vasculitic syndrome or less frequently as membranous or IgA nephropathy. The pathogenesis for the development of these autoimmune disorders in patients with MDS remains unknown. Abnormalities of T- and B-cell function and number have been implicated for their development [3,8,9]. Aggressive therapy with immunosuppressive agents in selected patients often controls autoimmune phenomena associated with MDS and may lead to haematological response in some patients [3,8,12].
Our patient, an ex-heavy smoker, was suffering from generalized atherosclerosis, (aneurysm of thoracic and abdominal aorta, ischaemic heart disease and claudicatio intermittentis). He presented mild renal impairment and proteinuria. Refractory anaemia, disproportional to his renal insufficiency, and eosinophilia, were the characteristics that led to his further investigation, apart from renal biopsy, to bone marrow aspiration and biopsy. These biopsies confirmed the ARD diagnosis and the clonal disorder of haematopoietic cells accompanied by trisomy 8. Renal biopsy showed the characteristic clefts of cholesterol crystals seen in ARD, but also membranous nephropathy stage I-II, together with intense deposits of immunoglobulins in the mesangium, as in secondary forms of membranous nephropathy [13]. Evaluation of the kidney specimens, for the presence of cholesterol crystals to confirm the ARD diagnosis, demands skilful experience. Moreover, clinical manifestations of ARD are not specific and may mimic a variety of syndromes or may even be silent leading to a post-mortem diagnosis. It is believed that many patients have spontaneous embolization of cholesterol crystals in many small arteries that lead to progressive organ impairment. For this reason some investigators used the term Cinderella of Nephrology for ARD in that often Cinderella (the patient and their clinical findings) and her shoe (the final diagnosis of ARD) are not matched in life, to emphasize the difficulty to diagnose the disease [14]. Our patient, apart from the angiography in 1988, had not had any other manipulations or surgery procedures of arteries to incriminate ARD, which was manifested in a silent and spontaneous pattern. Membranous nephropathy cannot be assigned to ARD, but to the presence of MDS, as autoimmune phenomena may be present in these syndromes. There are some references of ARD cases with nephrotic syndrome, but these are attributed to chronic ischaemic lesions and glomerulosclerosis, which at most times take the histological form of secondary FSGS [15]. From the review of the literature there were no cases of membranous nephropathy that occurred with ARD, except from a series of 82 patients with membranous nephropathy where in one patient these two histological findings co-existed, probably because of coincidence [15]. Thus, from established atherosclerosis in our patient, cholesterol embolization led to the development of ARD. At the same time MDS occurred progressively, accompanied by the autoimmune phenomenon of membranous nephropathy.
In conclusion, in cases of severe atherosclerosis, spontaneous and silent development of renal impairment is highly suggestive for ARD. However, permanent eosinophilia combined with refractory anaemia, must point out to further investigation for exclusion of a haematological disease that could induce autoimmune disorder, i.e. membranous nephropathy.
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Notes |
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References |
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