Acute renal cortical necrosis due to acquired antiprotein S antibodies
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- Larakeb, A.S., Evrard, S., Louillet, F. et al. Pediatr Nephrol (2009) 24: 207. doi:10.1007/s00467-008-0967-y
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Although varicella is a common disease of childhood, renal complications are quite rare. We report here the interesting case of a-22 month-old boy exhibiting renal cortical necrosis related to an acquired protein S deficiency following varicella. Ten days after the vesicle eruption appearance, he presented with ecchymosed heels, oligoanuric kidney failure, anemia [hemoglobin (Hb) 78 g/L], schizocytosis (2.5%), but normal platelet count. Kidney sonography and magnetic resonance imaging evoked renal cortical necrosis. All together, these features suggested acquired protein S deficiency secondary to varicella. Strikingly, it was confirmed by a dramatic decrease in protein S plasma activity and a huge increase in immunoglobulin (Ig)G antibodies against protein S in the plasma. Anticoagulation therapy in addition with plasmapheresis and steroid pulses allowed a dramatic decrease in the antibodies against protein S and recovery of normal protein S activity. Undelayed diagnosis and treatment did not avoid kidney insufficiency but prevented life-threatening complications. In the light of this case report, protein S deficiency due to antibody inhibition should be carefully monitored anytime in the context of varicella when kidney insufficiency or necrosis occurs.
KeywordsAcute renal failureAntiprotein S antibodyPlasma exchangeProtein S deficiencyVaricella
Kidney failure occurs in varicella as a rare complication of rhabdomyolysis, tubular ischemia, cardiovascular shock, or therapeutic complications such as the very well-known kidney complication due to nonsteroid anti-inflammatory drugs (NSAIDs). Here we report the case of a child presenting renal cortical necrosis due to an acquired protein S deficiency following varicella.
Ten days after varicella occurrence, a 22-month-old boy was admitted for fever, vomiting, and asthenia. Medical history did not note treatment with nonsteroidal anti-inflammatory drugs. Clinical examination showed stuporous state without other neurological symptoms, pallor, and painful ecchymosed heels with necrotizing vesicles on the right foot. Anuric renal failure was diagnosed [serum creatinine 407 μmol/L and blood urea nitrogen (BUN) 22.7 mmol/L] associated with a normochromic anemia [hemoglobin (Hb) 78 g/L], elevated lactic dehydrogenase :(LDH) (4,640 UI/L; normal value 380–760 UI/l)] and schizocytosis (2.5%). Platelet (302 × 109/L) and reticulocyte (38.3 × 109/L) counts were normal. The leukocyte count was elevated (26.6 × 109/L), and C-reactive protein was 250 mg/l. Standard coagulation tests were all normal except the D-dimer levels, which were increased up to 39.361 ng/ml [enzyme-linked immunosorbent assay (ELISA) assay; normal value <500 ng/ml]. Kidney sonography showed bilateral cortical hypoechogenicity with a normal Doppler flow in the main renal arteries and veins. Importantly, no Doppler flow could be detected in the cortex. Magnetic resonance imaging (MRI) showed a hypoechogenic signal in the cortex of the kidney, evoking a cortical necrosis. Chest radiography and cerebral MRI were normal. Blood-sample culture remained sterile.
All together, with a recent history of varicella and ecchymosis, the presence of elevated D dimers and anemia with schizocytosis suggested acquired protein S deficiency. Plasma protein S activity was measured by a clotting assay (Staclot Protein S, Stago, Asnières, France). Free protein S antigen was measured by ELISA (Asserachrom Free Protein S, Stago, Asnières, France). The child presented dramatically low levels of plasma protein S activity (3%; normal value >60%) and free protein S antigen (7%, normal value >60%). Elevated titers of immunoglobulin (Ig)G antibodies against protein S (11,080 AU/ml; Hyphen BioMed, Neuville-sur-Oise, France), along with mild titers of anticardiolipin antibodies (IgG 30 U/ml; normal value <15 U/ml; ELISA assay) were detected in the plasma and confirmed the diagnosis. The IgG anti-beta-2 glycoprotein I antibodies were 5 U/ml (normal value <6 U/ml, ELISA assay). A genetic risk of thrombophilia was discarded: absence of factor V Leiden, nor prothrombin G20210A mutation, nor polymorphism C677T of methylene tetrahydrofolate reductase, and both parents had a normal plasma level of protein S, protein C, and antithrombin. Complement fraction (C3 and C4) were in the normal range, and antinuclear factors were undetectable.
Varicella is a benign viral disease, and complications occur in <1% of children. The most serious complication is multiorgan failure, including reversible acute kidney failure, mostly after a tubular injury due to hemodynamic failure and rhabdomyolysis. Here we report a case of isolated kidney damage, likely a consequence of microvascular clotting related to acquired autoimmune protein S deficiency. Following varicella, autoimmune diseases, including myasthenia gravis , hemolytic anemia , and thrombocytopenic purpura  has been reported. Acquired severe protein S deficiency was first reported in varicella, and the autoimmune origin was further demonstrated in a patient exhibiting multiple thrombosis [4, 5]. Since this report, about 40 additional cases with severe protein S deficiency and transient presence of IgG antibodies against protein S have been reported [6–9]. The epitopes on protein S of these antibodies was reported by one study . Their pathogenic role is identified by (1) the decrease in both total and free protein S concentrations of a normal plasma sample in combination with the putative plasma-containing antibodies against protein S, and (2) the recovery of protein S activity when antibodies against protein S are removed from the plasma . The mechanism for understanding antiprotein S antibody generation is still to be defined, but one study suggests a structure homology between some varicella zoster virus (VZV) antigene peptides and protein S sequences generating cross-reactive antibodies . By contrast, others suggest that a nonspecific immune response following varicella is involved [5–7]. Strikingly, lupus anticoagulant, antiphospholipid, and anticardiolipin antibodies, as well as antiprotein S antibodies, have been evidenced in children with uncomplicated varicella. However, in children with varicella accompanied with purpura fulminans or thromboembolism events, the mean protein S IgG antibody levels were higher and mean protein S levels lower compared with children with uncomplicated varicella . Severe protein S deficiency induced in vitro strong thrombin generation due to functional impairment of the protein C anticoagulant pathway . The simultaneous presence of anticardiolipin antibodies may increase the hypercoagulability.
Undelayed and efficient anticoagulation therapy is based on prompt diagnosis to prevent thrombosis extension and life-threatening complications, including purpura fulminans. In our case, early heparin therapy, plasma exchange, and immunosuppression led to partial recovery of the kidney function. Despite residual and minimal detection of protein S IgG antibodies, protein S level rapidly returned to normal value, corroborating the fact that the antibody titer against protein S was the major factor leading to protein S acquired deficiency.
In conclusion, we report a new complication following varicella infection due to a hypercoagulable state in the context of acquired autoimmune protein S deficiency. During treatment, decrease in IgG antibodies against protein S reversibly correlated to the increase in protein S activity, and should be carefully monitored. Protein S deficiency should be evoked as a reliable diagnosis when a thrombotic event occurs, whatever it is, following varicella. Undelayed diagnosis and treatment did not avoid kidney dysfunction in our case but prevented life-threatening complications.
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