1 Institute for Pathology, University of Basel, Kantonsspital, Switzerland, and 2 Third Department of Internal Medicine, Humboldt Krankenhaus, Berlin, Germany
Correspondence and offprint requests to: Prof. Dr M. J. Mihatsch, Institute for Pathology, University of Basel, Kantonsspital, Schoenbeinstrasse 40, CH-4003 Basel, Switzerland.
Keywords: chronic nephropathy; irradiation; kidney; outcome; pathology; thrombotic microangiopathy
Introduction
Thrombotic microangiopathy (TMA) following irradiation is a rare cause of renal insufficiency, often neglected in the differential diagnosis nowadays. We report the case of a lady with a remote history of ovarian malignancy, treated years ago by irradiation. The patient now presented with moderate renal insufficiency caused by biopsy-proven thrombotic microangiopathy. We wish to draw the attention of the nephrologists to an unusual cause of TMA in the setting of chronic irradiation nephropathy.
Case report
A 46-year-old woman was admitted to the hospital for evaluation of impaired renal function. At age 36, the patient had been surgically treated for a malignant ovarian tumor. Surgery was accompanied by chemotherapy with cisplatin, epirubucin and cyclophosphamid (six cycles) and irradiation of the pelvic region (four fields) in fractioned doses over 8 weeks (total dose of 45 Gray). On admission the patient presented with signs of moderate renal insufficiency (serum creatinine: 2.2 mg/dl; proteinuria: 0.34 g/24 h; unremarkable urinary sediment). The blood pressure was elevated (150/90 mmHg and 140/85 mmHg on repeat controls). Peripheral oedemata were not present. Laboratory data showed normochromic anaemia (Hb 10.2 g/dl), normal platelet count, normal LDH levels and unremarkable reticulocyte counts. Fragmentocytes were not noted. All other laboratory findings were within normal limits. An ultrasound examination of the abdomen revealed small kidneys (9.3 cm and 8.3 cm in length) without evidence of hydronephrosis. Clinical and laboratory findings were stable and essentially unchanged from observations made 1 year prior to admission.
In order to establish a definitive diagnosis of the underlying renal disorder, a percutaneous needle biopsy was performed.
Histological findings
The renal biopsy included 18 glomeruli, six of them were globally sclerosed. Glomeruli and vessels showed signs of remote thrombotic microangiopathy. In glomeruli mesangiolysis was seen with massive `bubbly' expansion and sclerosis of mesangial areas and glomerular tufts (Figure 1). In arterioles and small arteries hyaline deposits segmentally replaced entire vascular walls causing stenosis (Figure 2a
). Interlobular arteries revealed typical subendothelial foam cells, calcifications and small protein deposits (Figure 2b
), whereas, only mild to moderate non-specific intimal fibrosis was found in larger arteries. Interstitial fibrosis and tubular atrophy were mild (Figure 3
). Immunofluorescence microscopy did not reveal any pathognomonic glomerular deposition of immunoglobulins or complement factors (employing a standard panel of antibodies directed against IgG, IgM, IgA, C3, C4, C5b-9, C1q, fibrin).
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This patient had developed renal insufficiency from thrombotic microangiopathy. She had a history of irradiation to the pelvis and abdomen with a total dose of 45 Gray. Such a clinical presentation is typical for chronic radiation nephropathy, which was frequently seen during the first decades of this century. With increasing knowledge about possible renal complications and introduction of better techniques, this complication has become rare. In experimental studies a dosage of 1000 rads (10 Gray) produced irradiation nephropathy [1]. The critical dose may even be higher (approximately 20 Gray) if the application is fractioned and extended over several weeks [2].
Why should radiation damage cause recurrent thrombotic microangiopathy? Very cogent reasons have been put forward that endothelial damage is the primary insult triggering TMA [3]. Irradiation mainly affects endothelial cells of small vessels and glomeruli [1] by formation of toxic oxygen intermediates and by impairing endothelial cell proliferation. In contrast to other forms of TMA in which exposure to the toxin (such as Shiga-like toxin) and functional deterioration are timely linked, renal irradiation and symptomatic disease are typically separated by months to years. Sublethally injured endothelial cells often do not recover and do not divide; a possible explanation for `smoldering' TMA.
Radiation nephropathy can occur in five clinical settings which vastly overlap [4]:
Acute radiation nephropathy follows a latent period of 612 months after abdominal irradiation [4,5]. The onset may be abrupt. Most patients present with uraemia and peripheral oedema. Hypertension is common, often in the malignant range (40% of patients [4]), accompanied by microangiopathic haemolytic anaemia. Chronic radiation nephropathy usually becomes clinically apparent years after therapy, often without a preceding acute episode. It has been suggested that patients primarily presenting with `chronic' nephropathy received less radiation (<2000 rad) in comparison to those with an acute onset (>2000 rad) [6]. The onset of chronic nephropathy is more insidious than in the acute form [4]. In most patients with chronic radiation injury, renal function is impaired. Normally, hypertension and proteinuria are only mild or moderate. Malignant hypertension is seen in acute and chronic radiation nephropathy (18 months to 11 years after irradiation) and indicates poor prognosis [4]. There is convincing evidence that vascular damage and TMA are caused by irradiation [7]; thus, malignant hypertension is secondary to arterial injury. However, as observed in the current case, not all patients develop malignant hypertension. This is possibly due to differences in the severity and extent of endothelial injury.
More recently, new forms of radiation-induced TMA have attracted considerable interest. TMA and HUS are seen after total body irradiation (in combination with various drugs) preparing patients for bone marrow transplantation [8,9]. Radiation induced TMA has also been observed with a new drug (Yttrium-90-DOTATOC) administered to treat somatostatin receptor-positive neuroendocrine tumours (personal observation). Drug-induced TMA is a well known side-effect of mytomycin C [10], 5-fluorouracil [11] deoxycoformycin [12] and cyclosporin [13] or tacrolimus. Although the patient under discussion had originally received cytotoxic drugs to treat her ovarian carcinoma, neither the drugs administered nor the time course suggest a causal relationship between drug application and TMA.
Teaching point
References