Pediatric Nephrology

, 24:207

Acute renal cortical necrosis due to acquired antiprotein S antibodies


  • Anis Skander Larakeb
    • Department of Pediatric NephrologyAssistance Publique-Hôpitaux de Paris, Hôpital Robert Debré
  • Solène Evrard
    • Department of Biological HemobiologyAssistance Publique-Hôpitaux de Paris, Hôpital Robert Debré
  • Férielle Louillet
    • Department of Pediatric NephrologyAssistance Publique-Hôpitaux de Paris, Hôpital Robert Debré
  • Thérésa Kwon
    • Department of Pediatric NephrologyAssistance Publique-Hôpitaux de Paris, Hôpital Robert Debré
  • Hadji Djaffar
    • Department of PediatricsHôpital Saint Camille
  • Brigitte Llanas
    • Department of PediatricsHôpital Pellegrin
  • Georges Deschênes
    • Department of Pediatric NephrologyAssistance Publique-Hôpitaux de Paris, Hôpital Robert Debré
    • University Paris VII-Denis Diderot
  • Marie-Françoise Hurtaud-Roux
    • Department of Biological HemobiologyAssistance Publique-Hôpitaux de Paris, Hôpital Robert Debré
    • Department of Pediatric NephrologyAssistance Publique-Hôpitaux de Paris, Hôpital Robert Debré
Brief Report

DOI: 10.1007/s00467-008-0967-y

Cite this article as:
Larakeb, A.S., Evrard, S., Louillet, F. et al. Pediatr Nephrol (2009) 24: 207. doi:10.1007/s00467-008-0967-y


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.


Acute 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.

Case report

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.

Anticoagulation therapy based on low molecular weight heparin (enoxaparin) was performed to prevent extension of the thrombosis. In addition, plasma exchange therapy in order to clear the antiprotein S antibodies (50 ml/kg per day with fresh frozen plasma, every day for 12 days then every other day for 1 week) were associated with steroid pulses (1 g/1.73 m2 for 3 following days). Antiprotein S antibodies decreased dramatically (<10% of the initial titer) after the second plasma exchange but remained detectable 6 months later (Fig. 1). As expected and hoped for, protein S activity dramatically increased following the second plasma exchange and returned to sustained normal level (>60%) by day 9. Anticardiolipin antibodies disappeared by day 15, and plasma therapy was discontinued by day 16. Normal neurologic state recovered in a week; diuresis resumed by day 23 but dialysis was required for 6 weeks. After 6 months, the child remained hypertensive, and serum creatinine was 250 μmol/L. Skin lesions recovered without sequelae.
Fig. 1

Protein S activity and antiprotein S immunoglobulin (Ig)G kinetics: antiprotein S antibodies decreased dramatically after the second plasma exchange, and protein S activity returned to sustained normal value of 60% by day 9. IgG antiprotein S remained slightly detectable 6 months later (5 AU/ml). Continuous line represents the level of IgG antiprotein S, and dashed line the level of protein S activity. Each plasmapheresis is labeled with a vertical arrow


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 [1], hemolytic anemia [2], and thrombocytopenic purpura [3] 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 [69]. The epitopes on protein S of these antibodies was reported by one study [10]. 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 [6]. 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 [7]. By contrast, others suggest that a nonspecific immune response following varicella is involved [57]. 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 [8]. Severe protein S deficiency induced in vitro strong thrombin generation due to functional impairment of the protein C anticoagulant pathway [9]. 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.

Conflict of interest statement


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