Toxicon 84 (2014) 36–40
Contents lists available at ScienceDirect
Toxicon journal homepage: www.elsevier.com/locate/toxicon
Clinical report
Bilateral renal cortical necrosis with end-stage renal failure following envenoming by Proatheris superciliaris: A case report François Pourreau a, Michel Pinsard b, Max Goyffon c, Florent Plasse a, Estelle Desport a, Antoine Thierry a, Guy Touchard a, Frank Bridoux a, * a b c
Department of Nephrology and Renal Transplantation, University Hospital and University of Poitiers, France Department of Intensive Care Unit, University Hospital and University of Poitiers, France Museum National d’Histoire Naturelle, Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 January 2014 Received in revised form 10 March 2014 Accepted 25 March 2014 Available online 5 April 2014
Acute bilateral renal cortical necrosis (BRCN) has been reported following envenoming by exotic venomous snakes. Proatheris superciliaris is a rare viper with restricted distribution in east Africa. Very little information is available on envenoming by this species. We herein describe the case of a 60-year-old professional wildlife photographer who was bitten on his thumb while photographing an adult specimen of P. superciliaris that he held at home in France. On admission, physical examination revealed severe hypertension and bruising with edema at the bite site. Within the following 24 h, he developed vomiting, diarrhea, acute lumbar pain and anuria. Laboratory tests showed acute kidney injury (serum creatinine 4.6 mg/dL), with thrombocytopenia, anemia and severe coagulopathy. Contrastenhanced computed tomography scan revealed hypodense areas in the cortex of both kidneys consistent with diffuse BRCN. As no appropriate antivenom existed, only symptomatic care was given to the patient. Coagulation tests returned to normal within 48 h. The patient was placed on chronic hemodialysis, until he underwent successful kidney transplantation 18 months later. In developed countries, severe complications provoked by snake bites tend to be more frequent with the number of trendy exotic pets. Acute kidney injury, including BRCN, is a classic complication of viper bites. The present case of endstage renal failure related to diffuse BRCN illustrates the potentially devastating effects of envenoming by P. superciliaris. Clinicians in developed countries should be informed about renal disorders and other potentially fatal complications of venomous snake bites and seek urgent expert advice for optimizing clinical management. Education and coaching of envenomed patients and exotic snake owners is mandatory to prevent dramatic accidents. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: Snakebite Bilateral cortical renal necrosis Acute kidney injury Proatheris superciliaris
1. Introduction
* Corresponding author. Department of Nephrology and Renal Transplantation, CHU Poitiers, 2 rue de la Milétrie, BP 577, 86021 Poitiers Cedex, France. Tel.: þ33 5 49 44 41 59; fax: þ33 5 49 44 42 36. E-mail address: [email protected] (F. Bridoux). http://dx.doi.org/10.1016/j.toxicon.2014.03.008 0041-0101/Ó 2014 Elsevier Ltd. All rights reserved.
Over the past decade, the fashion of breeding exotic reptiles or spiders has led to the emergence of diseases poorly known in Western countries. A wide range of snake species can be responsible for severe complications, which management is challenging as the medical community is
F. Pourreau et al. / Toxicon 84 (2014) 36–40
not prepared to confront these disorders (Warrell, 2009; Sitprija, 2006). Proatheris superciliaris, also referred to as the swamp viper or domino viper, is native to flood plains and swamps in south-western Tanzania and coastal plain of Mozambique. It is a small snake, 40–50 cm in length, which feeds preferentially on toads and frogs. Due to the rarity of this species and because of its remarkable appearance, it is an increasingly popular snake among amateurs in western countries. Bites have been extremely rarely reported and scarce information on envenoming by P. superciliaris is available (Warrell, 2008). We herein report a case of endstage renal disease secondary to acute bilateral renal cortical necrosis (BRCN) that occurred in France, following bite by P. Superciliaris. 2. Case report A 60-year-old professional wildlife photographer was hospitalized four hours after having been bitten in the left thumb by an adult specimen of P. superciliaris, that he held at home in France among various exotic reptiles (Fig. 1A). His past medical history was marked by tropical diseases (malaria, dengue fever, leishmaniasis and amoebiasis) and 39 previous bites by different species of snakes, most of which had occurred during past expeditions to foreign countries. Of these, two had been associated with lifethreatening complications, including cardiac arrest after envenoming by a rattlesnake and severe anaphylactic reaction after an injection of equine antivenom for a viper bite. On admission, body temperature was 36.8 C, with
37
blood pressure of 190/80 mmHg and pulse rate of 71 bpm. No episode of collapse or hypotension was recorded in the interval between bite and admission. Physical examination was unremarkable, except for bruising at the bite site and edema of the left upper limb with lymphadenopathy. Laboratory tests showed normal full blood count and coagulation profile. Liver enzymes, serum lactate, creatine kinase (CK) and troponin T levels were normal. Serum creatinine was 0.67 mg/dL [59 mmol/L]. Expert advice was required from the National Museum of Natural History (Dr M. Goyffon). Given the past history of allergic reaction, and because a specific antidote did not exist, only prophylactic treatment with amoxicillin and clavulanic acid was introduced. Over the following 24 h, he developed fever, nausea, vomiting, violent bilateral lumbar pain and anuria with persistent severe hypertension. Laboratory investigations showed raised serum transaminases and lactate deshydrogenase level, acute kidney injury (AKI) (serum creatinine 4.6 mg/dL [408 mmol/L]), and coagulopathy with hypofibrinogenemia, decreased prothrombin time, low levels of factor II and factor V, thrombocytopenia, positive D-dimers and fibrin degradation products (Table 1). Blood cultures were negative. Cerebral computed tomography (CT) scan carried out because of headaches and severe hypertension, did not show intra-cranial bleeding. Fundus examination was normal. By Doppler echography, kidneys appeared normal, but with poor and highly resistive arterial flow. Contrast-enhanced CT scan showed hypodense areas in the cortex of both kidneys, consistent with BRCN.
Fig. 1. A. Proatheris supercilaris, also referred to as the “swamp” viper or domino snake. Captive specimen that inflicted the wound (courtesy from D. Heuclin). B. Tc-99m MAG3 scintigraphy. Both kidneys showed very low TC-99m MAG3 uptake, without detectable excretion of the tracer after 30 min. C, D. Contrastenhanced abdominal CT scan. Bilateral lack of enhancement of the renal cortex after contrast infusion on arterial phase (C), contrasting with spared medulla on portal venous phase (D).
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F. Pourreau et al. / Toxicon 84 (2014) 36–40
Table 1 Main clinical and biological parameters over the first 10 days. Day Clinical parameters SBP/DBP (mmHg) Body temperature ( C) Diuresis (ml/day) Biological parameters sCr (mg/dl) Urea (mg/dl) Creatine kinase (UI/l) Hb (g/dl) WBC (103/mL) Platelets (103/mL) Schistocytes PT APTT D-dimers (mg/l) Fibrinogen (g/dl) Soluble fibrin complexes LDH (U/L) SGOT (U/L) SGPT (U/L) Haptoglobin (g/L) hs-CRP (mg/l)
0
1
2
3
4
5
6
7
8
9
187/71 36.3
169/62 35.8 0
114/64 36.4 0
126/67 37.9 50
140/71 37.3 0
152/71 37.1 0
147/57 37.7 0
145/72 37.6 0
150/65 37.8 0
143/65 37.6 0
0.7 13.1
1.5 16.8 62 15.2 17.8 142 Neg 63 0.9 100,000 1.6 þ 3358 138 61 0.1
4.6* 44.8* 74 12.5 39.1 101 Neg 48 4.28 144,700 1.7 þ
5.5 39.2
5 44.8
5 39.2
5.4 50.4
5.9 50.4
5.5 50.4
6.2 53.2
11.1 36.3 110 Neg 63 2.33 10,000 7.3 þ 7018 314 213 0.89 468
10.2 28.2 123 Neg 84 1.75
9.4 21 148
9.3 17.3 160
9 16.6 185
9 19 257
9.2 18.6 303
94 1.42 8534 6.9 – 3808 101 169
96 1.07
97 1.16
1.3
1.2
6
6.8
57 143
54 113 1.85
63 119
47 102
15 9.8 223 81 0.84
20 24 8
0.15 256
8 5199 131 190 1.35
198
Abbreviations: SBP ¼ systolic blood pressure; DBP ¼ diastolic blood pressure; sCr ¼ serum creatinine; Hb ¼ hemoglobin; WBC ¼ white blood cell count; PT ¼ prothrombin time; APTT ¼ activated partial thromboplastin time; hs-CRP ¼ high sensitivity C-reactive protein; neg ¼ negative; * maintenance hemodialysis was started on day 2.
Technetium-99m mercaptoacetyltriglycine (Tc-99m MAG3) scintigraphy confirmed the absence of renal cortical vascularization (Fig. 1B–D). Despite heparin and antiplatelet therapy with aspirin, the patient remained anuric. Blood pressure was rapidly controlled with intravenous uradipil and nicardipine. Renal infarction was accompanied by a massive elevation in LDH levels to 7018 UI/L at day 3, whereas SGPT levels and SGOT levels moderately increased up to 213 U/l and 314 U/l, respectively, and CK level remained normal. A transient decrease in haptoglobin was observed but schizocytes were repeatedly negative on blood films (Table 1). Over the following 6 days, platelet count, coagulation parameters and liver enzymes progressively returned to normal values. As anemia progressively worsened, with hemoglobin of 7.4 g/dl at day 13, transfusion of one blood unit was performed. Superficial cutaneous necrosis developed at the bite site and rapidly recovered without skin loss. The patient remained on maintenance hemodialysis for 18 months, until he received a kidney transplant from a cadaveric donor. Post operative course was unremarkable. After 42 months, he was hospitalized for a phlegmon of the right thumb following a Cobra bite, but without hematological or renal complications. Outcome was favorable after antibiotics and surgery. After 48 months of post-transplant follow-up, his condition was excellent, with a serum creatinine level of 1.4 mg/dL [126 mmol/L]. 3. Discussion Diffuse BRCN is a severe renal disorder which frequency has decreased over the years in developed countries, but still represents 2–3% of AKI cases in India (Prakash et al., 2007). It is characterized by massive ischemic necrosis of the renal cortex, caused by occlusion of the glomerular and
interlobular arteries (Chugh et al., 1994). Diagnosis is usually confirmed by CT scan, which demonstrates characteristic lack of enhancement of the renal cortex sparing thin rim of subcapsular cortex, contrasting with enhancement of the medulla, and absent renal excretion. BRCN may result from various pathophysiological mechanisms, including vasospasm, embolism, DIC, and endothelial injury. Obstetric complications (abruptio placentae, toxemia, and septic abortion) account for 40–60% of cases (Chugh et al., 1994; Prakash et al., 2007). BRCN has been rarely described in autoimmune disorders (antiphospholipid syndrome, systemic lupus erythematosous, polyarteritis nodosa), hemolytic uremic syndrome, sepsis, malaria, aortic dissection, acute pancreatitis, allograft rejection, traumas, and after toxic or drug exposure (Chugh et al., 1994; Vigneau et al., 2006; Leroy et al., 2008). A wide spectrum of renal complications has been described following envenoming by exotic snakes, mostly of the Viperinæ, Crotalinae and Elapidæ families and subfamilies (Sitprija, 2006; Sitprija and Sitprija, 2012). The severity is variable, depending on the snake species, severity of the bite, patient’s condition and time elapsed between bite and administration of specific antivenom. Renal manifestations range from mild proteinuria and hematuria, commonly reported after bites by vipers, to severe AKI which frequency varies with species and geographical location from 5% to 29% after myotoxic or hemotoxic snake envenoming, respectively (Sitprija, 2006). The mechanisms involved in AKI are complex and not completely elucidated. They involve both direct toxicity of the venom, and indirect action through the release of cytokines and inflammatory mediators, and coagulation disorders triggered by different enzymes and proteins contained in the venom. Snake venom may induce increased capillary permeability by haemorrhagins, disruption of primary hemostasis
F. Pourreau et al. / Toxicon 84 (2014) 36–40
(disintegrins, type-C lectins, phospholipase A2, serine proteinases, thrombin-like enzymes), interference with coagulation factors (activators of factor V, factor X, protein C and prothrombin, inhibitors of factors IX and X, phospholipases A2) and activation of fibrinolysis (Larréché et al., 2008; Sitprija and Sitprija, 2012). Acute tubular necrosis, directly caused by tubular toxicity, hemodynamic changes, or secondary to hemolysis, rhabdomyolysis accounts for 70–80% of AKI cases (Sitprija, 2006). Severe coagulopathy, that may manifest with glomerular fibrin deposition, hemolytic and uremic syndrome (HUS) and diffuse BRCN is another major cause of AKI (Sitprija, 2006; Sitprija and Sitprija, 2012). Other renal lesions, including diffuse interstitial nephritis, papillary necrosis or glomerular involvement with isolated mesangiolysis, mesangial proliferative glomerulonephritis and crescentic glomerulonephritis are less common (Sitprija, 2006). BRCN has been described mostly after bites of Russell’s viper (Daboia russelii), snakes of the Bothrops genus (Bothrops jararaca), hump-nosed viper (Hypnale hypnale) and saw-scaled viper (Echis carinatus) (Sitprija, 2006). To our knowledge, only two cases of severe AKI following envenoming by P. superciliaris have been previously reported. Because no specific antivenom was available, both patients received symptomatic management, as in the herein reported case. However, renal outcome was strikingly different. The first patient was a 27-year-old man who, 72 h after being bitten on the finger, developed schistocytosis, thrombocytopenia, hyperbilirubinemia, high serum transaminases and AKI. Partial prothrombin time, fibrinogen and fibrinogen degradation products remained within normal range. A diagnosis of thrombotic microangiopathy with HUS was assessed. Patient’s condition improved after 7 plasmapheresis sessions, and hematologic, hepatic and renal parameters progressively normalized over the following three months (Keyler, 2008). The second case was a 57-year-old man who was bitten on the left hand. Within 24 h, he presented vomiting, diarrhea, chest and lumbar pains, hypertension, and oliguria. Laboratory tests revealed leucocytosis, thrombocytopenia, coagulation disorders, hemolysis, rhabdomyolysis, increased transaminase levels and AKI. Initial therapy consisted of frozen plasma infusions that rapidly corrected coagulation parameters, associated with heparin that was rapidly stopped because of thrombocytopenia and risk of bleeding. Continuous venovenous hemodiafiltration followed by intermittent haemodialysis was maintained for 17 days because of persisting renal failure and pulmonary congestion. One month after envenomation, the patient had fully recovered, except for mildly elevated serum creatinine level (168 mmol/L) and anemia (Valenta et al., 2008). Laing et al. showed that whole P. superciliaris venom has no pro-coagulant activity, but stimulates platelet activation. The venom was shown to contain a 50-kDa metalloproteinase with hemorrhagic activity, and, more importantly, a 34-kDA proteinase designed as proatherocytin. Proatherocytin triggered platelet activation in the absence of plasma proteins, through binding on proteaseactivated-receptor-1 (PAR-1), an effect that was blocked by serine proteinase inhibitors. These results suggested
39
that proatherocytin is a selective PAR-1 agonist (Laing et al., 2005). In vivo experiments on isolated perfused rat kidney preparations have demonstrated that PAR-1 activation induced renal vasoconstriction and a marked reduction in glomerular filtration rate (Gui et al., 2003). Although these mechanisms were probably involved in our patient, in whom severe hypertension and AKI developed within few hours after the bite, severe coagulopathy was prominent. Whether diffuse BRCN resulted from platelet activation alone or rather from diffuse endothelial damage by venom proteases remains questionable. The present case demonstrates the potentially devastating effects of envenoming by P. superciliaris. Furthermore, it shows that management of patients bitten by exotic snakes remains a therapeutic challenge. Treatment is a medical emergency that should be performed in intensive care units, due to the risk of severe cardiovascular, respiratory and neurologic failure. Management of AKI relies on fluid replacement, diuretics, correction of metabolic acidosis and prompt initiation of hemodialysis in patients with persistent oliguria. Immunotherapy with anti-venom represents the only specific and effective measure that should be administered early in patients with symptoms of systemic envenoming and as long as coagulation disorders persist (Warrell, 2009). However, when specific antivenom is not available, renal prognosis is likely to be poor despite supportive care, as in the present case. Given the increasing number of exotic pets imported in Western countries, clinicians should be alerted on the potential severe renal consequences of venomous snake bites. Urgent expert advice should be sought from reference centers to provide optimal care. In envenomed patients, education and coaching is crucial to prevent further dramatic accidents. Ethical statement This study was performed in accordance with the Declaration of Helsinki. The patient gave informed consent for publication of the medical information contained in the manuscript. Financial disclosure The authors declare that they have no relevant financial interests. Funding/support None. Acknowledgments We are grateful to Mr. D. HEUCLIN for snake pictures and to Mr. Jeffrey ARSHAM for revising the English usage. Conflict of interest None.
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F. Pourreau et al. / Toxicon 84 (2014) 36–40
Transparency document Transparency document related to this article can be found online at http://dx.doi.org/10.1016/j.toxicon.2014.03. 008. References Chugh, K.S., Jha, V., Sakhuja, V., Joshi, K., 1994. Acute renal cortical necrosis: a study of 113 patients. Ren. Fail. 16, 37–47. Gui, Y., Loutzenhiser, R., Hollenberg, M.D., 2003. Bidirectional regulation of renal hemodynamics by activation of PAR1 and PAR2 in isolated perfused rat kidney. Am. J. Physiol. Ren. Physiol. 285, F95–F104. Keyler, D.E., 2008. Envenomation by the lowland viper (Proatheris superciliaris): severe case profile documentation. Toxicon 52, 836– 841. Laing, G.D., Compton, S.J., Ramachandran, R., Fuller, G.L., Wilkinson, M.C., Wagstaff, S.C., Watson, S.P., Kamiguti, A.S., Theakston, R.D., Senis, Y.A., 2005. Characterization of a novel protein from Proatheris superciliaris venom: proatherocytin, a 34-kDa platelet receptor PAR1 agonist. Toxicon 46, 490–499.
Larréché, S., Mion, G., Goyffon, M., 2008. Haemostasis disorders caused by snake venoms. Ann. Fr. Anesth. Reanim. 27, 302–309. Leroy, F., Bridoux, F., Abou Ayache, R., Belmouaz, S., Desport, E., Thierry, A., Bauwens, M., Touchard, G., 2008. Quinine-induced renal bilateral cortical necrosis. Nephrol. Ther. 4, 181–186. Prakash, J., Vohra, R., Wani, I.A., Murthy, A.S., Srivastva, P.K., Tripathi, K., Pandey, L.K., Usha, Raja, R., 2007. Decreasing incidence of renal cortical necrosis in patients with acute renal failure in developing countries: a single-centre experience of 22 years from Eastern India. Nephrol. Dial. Transplant. 22, 1213–1217. Sitprija, V., 2006. Snakebite nephropathy. Nephrol. (Carlton) 11, 442–448. Sitprija, V., Sitprija, S., 2012. Renal effects and injury induced by animal toxins. Toxicon 60, 943–953. Valenta, J., Stach, Z., Fricova, D., Zak, J., Balik, M., 2008. Envenoming by the viperid snake Proatheris superciliaris: a case report. Toxicon 52, 392– 394. Vigneau, C., Daugas, E., Maury, E., Sokol, H., Offenstadt, G., Rossert, J., Guidet, B., 2006. Renal cortical necrosis related to paraneoplastic antiphospholipid syndrome. Am. J. Kidney Dis. 47, 1072–1074. Warrell, D.A., 2008. Proatheris superciliaris: the deadly venom of a rare and elusive snake revealed. Toxicon 52, 833–835. Warrell, D.A., 2009. Commissioned article: management of exotic snakebites. Q. J. Med. 102, 593–601.
Contents lists available at ScienceDirect
Toxicon journal homepage: www.elsevier.com/locate/toxicon
Clinical report
Bilateral renal cortical necrosis with end-stage renal failure following envenoming by Proatheris superciliaris: A case report François Pourreau a, Michel Pinsard b, Max Goyffon c, Florent Plasse a, Estelle Desport a, Antoine Thierry a, Guy Touchard a, Frank Bridoux a, * a b c
Department of Nephrology and Renal Transplantation, University Hospital and University of Poitiers, France Department of Intensive Care Unit, University Hospital and University of Poitiers, France Museum National d’Histoire Naturelle, Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 January 2014 Received in revised form 10 March 2014 Accepted 25 March 2014 Available online 5 April 2014
Acute bilateral renal cortical necrosis (BRCN) has been reported following envenoming by exotic venomous snakes. Proatheris superciliaris is a rare viper with restricted distribution in east Africa. Very little information is available on envenoming by this species. We herein describe the case of a 60-year-old professional wildlife photographer who was bitten on his thumb while photographing an adult specimen of P. superciliaris that he held at home in France. On admission, physical examination revealed severe hypertension and bruising with edema at the bite site. Within the following 24 h, he developed vomiting, diarrhea, acute lumbar pain and anuria. Laboratory tests showed acute kidney injury (serum creatinine 4.6 mg/dL), with thrombocytopenia, anemia and severe coagulopathy. Contrastenhanced computed tomography scan revealed hypodense areas in the cortex of both kidneys consistent with diffuse BRCN. As no appropriate antivenom existed, only symptomatic care was given to the patient. Coagulation tests returned to normal within 48 h. The patient was placed on chronic hemodialysis, until he underwent successful kidney transplantation 18 months later. In developed countries, severe complications provoked by snake bites tend to be more frequent with the number of trendy exotic pets. Acute kidney injury, including BRCN, is a classic complication of viper bites. The present case of endstage renal failure related to diffuse BRCN illustrates the potentially devastating effects of envenoming by P. superciliaris. Clinicians in developed countries should be informed about renal disorders and other potentially fatal complications of venomous snake bites and seek urgent expert advice for optimizing clinical management. Education and coaching of envenomed patients and exotic snake owners is mandatory to prevent dramatic accidents. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: Snakebite Bilateral cortical renal necrosis Acute kidney injury Proatheris superciliaris
1. Introduction
* Corresponding author. Department of Nephrology and Renal Transplantation, CHU Poitiers, 2 rue de la Milétrie, BP 577, 86021 Poitiers Cedex, France. Tel.: þ33 5 49 44 41 59; fax: þ33 5 49 44 42 36. E-mail address: [email protected] (F. Bridoux). http://dx.doi.org/10.1016/j.toxicon.2014.03.008 0041-0101/Ó 2014 Elsevier Ltd. All rights reserved.
Over the past decade, the fashion of breeding exotic reptiles or spiders has led to the emergence of diseases poorly known in Western countries. A wide range of snake species can be responsible for severe complications, which management is challenging as the medical community is
F. Pourreau et al. / Toxicon 84 (2014) 36–40
not prepared to confront these disorders (Warrell, 2009; Sitprija, 2006). Proatheris superciliaris, also referred to as the swamp viper or domino viper, is native to flood plains and swamps in south-western Tanzania and coastal plain of Mozambique. It is a small snake, 40–50 cm in length, which feeds preferentially on toads and frogs. Due to the rarity of this species and because of its remarkable appearance, it is an increasingly popular snake among amateurs in western countries. Bites have been extremely rarely reported and scarce information on envenoming by P. superciliaris is available (Warrell, 2008). We herein report a case of endstage renal disease secondary to acute bilateral renal cortical necrosis (BRCN) that occurred in France, following bite by P. Superciliaris. 2. Case report A 60-year-old professional wildlife photographer was hospitalized four hours after having been bitten in the left thumb by an adult specimen of P. superciliaris, that he held at home in France among various exotic reptiles (Fig. 1A). His past medical history was marked by tropical diseases (malaria, dengue fever, leishmaniasis and amoebiasis) and 39 previous bites by different species of snakes, most of which had occurred during past expeditions to foreign countries. Of these, two had been associated with lifethreatening complications, including cardiac arrest after envenoming by a rattlesnake and severe anaphylactic reaction after an injection of equine antivenom for a viper bite. On admission, body temperature was 36.8 C, with
37
blood pressure of 190/80 mmHg and pulse rate of 71 bpm. No episode of collapse or hypotension was recorded in the interval between bite and admission. Physical examination was unremarkable, except for bruising at the bite site and edema of the left upper limb with lymphadenopathy. Laboratory tests showed normal full blood count and coagulation profile. Liver enzymes, serum lactate, creatine kinase (CK) and troponin T levels were normal. Serum creatinine was 0.67 mg/dL [59 mmol/L]. Expert advice was required from the National Museum of Natural History (Dr M. Goyffon). Given the past history of allergic reaction, and because a specific antidote did not exist, only prophylactic treatment with amoxicillin and clavulanic acid was introduced. Over the following 24 h, he developed fever, nausea, vomiting, violent bilateral lumbar pain and anuria with persistent severe hypertension. Laboratory investigations showed raised serum transaminases and lactate deshydrogenase level, acute kidney injury (AKI) (serum creatinine 4.6 mg/dL [408 mmol/L]), and coagulopathy with hypofibrinogenemia, decreased prothrombin time, low levels of factor II and factor V, thrombocytopenia, positive D-dimers and fibrin degradation products (Table 1). Blood cultures were negative. Cerebral computed tomography (CT) scan carried out because of headaches and severe hypertension, did not show intra-cranial bleeding. Fundus examination was normal. By Doppler echography, kidneys appeared normal, but with poor and highly resistive arterial flow. Contrast-enhanced CT scan showed hypodense areas in the cortex of both kidneys, consistent with BRCN.
Fig. 1. A. Proatheris supercilaris, also referred to as the “swamp” viper or domino snake. Captive specimen that inflicted the wound (courtesy from D. Heuclin). B. Tc-99m MAG3 scintigraphy. Both kidneys showed very low TC-99m MAG3 uptake, without detectable excretion of the tracer after 30 min. C, D. Contrastenhanced abdominal CT scan. Bilateral lack of enhancement of the renal cortex after contrast infusion on arterial phase (C), contrasting with spared medulla on portal venous phase (D).
38
F. Pourreau et al. / Toxicon 84 (2014) 36–40
Table 1 Main clinical and biological parameters over the first 10 days. Day Clinical parameters SBP/DBP (mmHg) Body temperature ( C) Diuresis (ml/day) Biological parameters sCr (mg/dl) Urea (mg/dl) Creatine kinase (UI/l) Hb (g/dl) WBC (103/mL) Platelets (103/mL) Schistocytes PT APTT D-dimers (mg/l) Fibrinogen (g/dl) Soluble fibrin complexes LDH (U/L) SGOT (U/L) SGPT (U/L) Haptoglobin (g/L) hs-CRP (mg/l)
0
1
2
3
4
5
6
7
8
9
187/71 36.3
169/62 35.8 0
114/64 36.4 0
126/67 37.9 50
140/71 37.3 0
152/71 37.1 0
147/57 37.7 0
145/72 37.6 0
150/65 37.8 0
143/65 37.6 0
0.7 13.1
1.5 16.8 62 15.2 17.8 142 Neg 63 0.9 100,000 1.6 þ 3358 138 61 0.1
4.6* 44.8* 74 12.5 39.1 101 Neg 48 4.28 144,700 1.7 þ
5.5 39.2
5 44.8
5 39.2
5.4 50.4
5.9 50.4
5.5 50.4
6.2 53.2
11.1 36.3 110 Neg 63 2.33 10,000 7.3 þ 7018 314 213 0.89 468
10.2 28.2 123 Neg 84 1.75
9.4 21 148
9.3 17.3 160
9 16.6 185
9 19 257
9.2 18.6 303
94 1.42 8534 6.9 – 3808 101 169
96 1.07
97 1.16
1.3
1.2
6
6.8
57 143
54 113 1.85
63 119
47 102
15 9.8 223 81 0.84
20 24 8
0.15 256
8 5199 131 190 1.35
198
Abbreviations: SBP ¼ systolic blood pressure; DBP ¼ diastolic blood pressure; sCr ¼ serum creatinine; Hb ¼ hemoglobin; WBC ¼ white blood cell count; PT ¼ prothrombin time; APTT ¼ activated partial thromboplastin time; hs-CRP ¼ high sensitivity C-reactive protein; neg ¼ negative; * maintenance hemodialysis was started on day 2.
Technetium-99m mercaptoacetyltriglycine (Tc-99m MAG3) scintigraphy confirmed the absence of renal cortical vascularization (Fig. 1B–D). Despite heparin and antiplatelet therapy with aspirin, the patient remained anuric. Blood pressure was rapidly controlled with intravenous uradipil and nicardipine. Renal infarction was accompanied by a massive elevation in LDH levels to 7018 UI/L at day 3, whereas SGPT levels and SGOT levels moderately increased up to 213 U/l and 314 U/l, respectively, and CK level remained normal. A transient decrease in haptoglobin was observed but schizocytes were repeatedly negative on blood films (Table 1). Over the following 6 days, platelet count, coagulation parameters and liver enzymes progressively returned to normal values. As anemia progressively worsened, with hemoglobin of 7.4 g/dl at day 13, transfusion of one blood unit was performed. Superficial cutaneous necrosis developed at the bite site and rapidly recovered without skin loss. The patient remained on maintenance hemodialysis for 18 months, until he received a kidney transplant from a cadaveric donor. Post operative course was unremarkable. After 42 months, he was hospitalized for a phlegmon of the right thumb following a Cobra bite, but without hematological or renal complications. Outcome was favorable after antibiotics and surgery. After 48 months of post-transplant follow-up, his condition was excellent, with a serum creatinine level of 1.4 mg/dL [126 mmol/L]. 3. Discussion Diffuse BRCN is a severe renal disorder which frequency has decreased over the years in developed countries, but still represents 2–3% of AKI cases in India (Prakash et al., 2007). It is characterized by massive ischemic necrosis of the renal cortex, caused by occlusion of the glomerular and
interlobular arteries (Chugh et al., 1994). Diagnosis is usually confirmed by CT scan, which demonstrates characteristic lack of enhancement of the renal cortex sparing thin rim of subcapsular cortex, contrasting with enhancement of the medulla, and absent renal excretion. BRCN may result from various pathophysiological mechanisms, including vasospasm, embolism, DIC, and endothelial injury. Obstetric complications (abruptio placentae, toxemia, and septic abortion) account for 40–60% of cases (Chugh et al., 1994; Prakash et al., 2007). BRCN has been rarely described in autoimmune disorders (antiphospholipid syndrome, systemic lupus erythematosous, polyarteritis nodosa), hemolytic uremic syndrome, sepsis, malaria, aortic dissection, acute pancreatitis, allograft rejection, traumas, and after toxic or drug exposure (Chugh et al., 1994; Vigneau et al., 2006; Leroy et al., 2008). A wide spectrum of renal complications has been described following envenoming by exotic snakes, mostly of the Viperinæ, Crotalinae and Elapidæ families and subfamilies (Sitprija, 2006; Sitprija and Sitprija, 2012). The severity is variable, depending on the snake species, severity of the bite, patient’s condition and time elapsed between bite and administration of specific antivenom. Renal manifestations range from mild proteinuria and hematuria, commonly reported after bites by vipers, to severe AKI which frequency varies with species and geographical location from 5% to 29% after myotoxic or hemotoxic snake envenoming, respectively (Sitprija, 2006). The mechanisms involved in AKI are complex and not completely elucidated. They involve both direct toxicity of the venom, and indirect action through the release of cytokines and inflammatory mediators, and coagulation disorders triggered by different enzymes and proteins contained in the venom. Snake venom may induce increased capillary permeability by haemorrhagins, disruption of primary hemostasis
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(disintegrins, type-C lectins, phospholipase A2, serine proteinases, thrombin-like enzymes), interference with coagulation factors (activators of factor V, factor X, protein C and prothrombin, inhibitors of factors IX and X, phospholipases A2) and activation of fibrinolysis (Larréché et al., 2008; Sitprija and Sitprija, 2012). Acute tubular necrosis, directly caused by tubular toxicity, hemodynamic changes, or secondary to hemolysis, rhabdomyolysis accounts for 70–80% of AKI cases (Sitprija, 2006). Severe coagulopathy, that may manifest with glomerular fibrin deposition, hemolytic and uremic syndrome (HUS) and diffuse BRCN is another major cause of AKI (Sitprija, 2006; Sitprija and Sitprija, 2012). Other renal lesions, including diffuse interstitial nephritis, papillary necrosis or glomerular involvement with isolated mesangiolysis, mesangial proliferative glomerulonephritis and crescentic glomerulonephritis are less common (Sitprija, 2006). BRCN has been described mostly after bites of Russell’s viper (Daboia russelii), snakes of the Bothrops genus (Bothrops jararaca), hump-nosed viper (Hypnale hypnale) and saw-scaled viper (Echis carinatus) (Sitprija, 2006). To our knowledge, only two cases of severe AKI following envenoming by P. superciliaris have been previously reported. Because no specific antivenom was available, both patients received symptomatic management, as in the herein reported case. However, renal outcome was strikingly different. The first patient was a 27-year-old man who, 72 h after being bitten on the finger, developed schistocytosis, thrombocytopenia, hyperbilirubinemia, high serum transaminases and AKI. Partial prothrombin time, fibrinogen and fibrinogen degradation products remained within normal range. A diagnosis of thrombotic microangiopathy with HUS was assessed. Patient’s condition improved after 7 plasmapheresis sessions, and hematologic, hepatic and renal parameters progressively normalized over the following three months (Keyler, 2008). The second case was a 57-year-old man who was bitten on the left hand. Within 24 h, he presented vomiting, diarrhea, chest and lumbar pains, hypertension, and oliguria. Laboratory tests revealed leucocytosis, thrombocytopenia, coagulation disorders, hemolysis, rhabdomyolysis, increased transaminase levels and AKI. Initial therapy consisted of frozen plasma infusions that rapidly corrected coagulation parameters, associated with heparin that was rapidly stopped because of thrombocytopenia and risk of bleeding. Continuous venovenous hemodiafiltration followed by intermittent haemodialysis was maintained for 17 days because of persisting renal failure and pulmonary congestion. One month after envenomation, the patient had fully recovered, except for mildly elevated serum creatinine level (168 mmol/L) and anemia (Valenta et al., 2008). Laing et al. showed that whole P. superciliaris venom has no pro-coagulant activity, but stimulates platelet activation. The venom was shown to contain a 50-kDa metalloproteinase with hemorrhagic activity, and, more importantly, a 34-kDA proteinase designed as proatherocytin. Proatherocytin triggered platelet activation in the absence of plasma proteins, through binding on proteaseactivated-receptor-1 (PAR-1), an effect that was blocked by serine proteinase inhibitors. These results suggested
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that proatherocytin is a selective PAR-1 agonist (Laing et al., 2005). In vivo experiments on isolated perfused rat kidney preparations have demonstrated that PAR-1 activation induced renal vasoconstriction and a marked reduction in glomerular filtration rate (Gui et al., 2003). Although these mechanisms were probably involved in our patient, in whom severe hypertension and AKI developed within few hours after the bite, severe coagulopathy was prominent. Whether diffuse BRCN resulted from platelet activation alone or rather from diffuse endothelial damage by venom proteases remains questionable. The present case demonstrates the potentially devastating effects of envenoming by P. superciliaris. Furthermore, it shows that management of patients bitten by exotic snakes remains a therapeutic challenge. Treatment is a medical emergency that should be performed in intensive care units, due to the risk of severe cardiovascular, respiratory and neurologic failure. Management of AKI relies on fluid replacement, diuretics, correction of metabolic acidosis and prompt initiation of hemodialysis in patients with persistent oliguria. Immunotherapy with anti-venom represents the only specific and effective measure that should be administered early in patients with symptoms of systemic envenoming and as long as coagulation disorders persist (Warrell, 2009). However, when specific antivenom is not available, renal prognosis is likely to be poor despite supportive care, as in the present case. Given the increasing number of exotic pets imported in Western countries, clinicians should be alerted on the potential severe renal consequences of venomous snake bites. Urgent expert advice should be sought from reference centers to provide optimal care. In envenomed patients, education and coaching is crucial to prevent further dramatic accidents. Ethical statement This study was performed in accordance with the Declaration of Helsinki. The patient gave informed consent for publication of the medical information contained in the manuscript. Financial disclosure The authors declare that they have no relevant financial interests. Funding/support None. Acknowledgments We are grateful to Mr. D. HEUCLIN for snake pictures and to Mr. Jeffrey ARSHAM for revising the English usage. Conflict of interest None.
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Transparency document Transparency document related to this article can be found online at http://dx.doi.org/10.1016/j.toxicon.2014.03. 008. References Chugh, K.S., Jha, V., Sakhuja, V., Joshi, K., 1994. Acute renal cortical necrosis: a study of 113 patients. Ren. Fail. 16, 37–47. Gui, Y., Loutzenhiser, R., Hollenberg, M.D., 2003. Bidirectional regulation of renal hemodynamics by activation of PAR1 and PAR2 in isolated perfused rat kidney. Am. J. Physiol. Ren. Physiol. 285, F95–F104. Keyler, D.E., 2008. Envenomation by the lowland viper (Proatheris superciliaris): severe case profile documentation. Toxicon 52, 836– 841. Laing, G.D., Compton, S.J., Ramachandran, R., Fuller, G.L., Wilkinson, M.C., Wagstaff, S.C., Watson, S.P., Kamiguti, A.S., Theakston, R.D., Senis, Y.A., 2005. Characterization of a novel protein from Proatheris superciliaris venom: proatherocytin, a 34-kDa platelet receptor PAR1 agonist. Toxicon 46, 490–499.
Larréché, S., Mion, G., Goyffon, M., 2008. Haemostasis disorders caused by snake venoms. Ann. Fr. Anesth. Reanim. 27, 302–309. Leroy, F., Bridoux, F., Abou Ayache, R., Belmouaz, S., Desport, E., Thierry, A., Bauwens, M., Touchard, G., 2008. Quinine-induced renal bilateral cortical necrosis. Nephrol. Ther. 4, 181–186. Prakash, J., Vohra, R., Wani, I.A., Murthy, A.S., Srivastva, P.K., Tripathi, K., Pandey, L.K., Usha, Raja, R., 2007. Decreasing incidence of renal cortical necrosis in patients with acute renal failure in developing countries: a single-centre experience of 22 years from Eastern India. Nephrol. Dial. Transplant. 22, 1213–1217. Sitprija, V., 2006. Snakebite nephropathy. Nephrol. (Carlton) 11, 442–448. Sitprija, V., Sitprija, S., 2012. Renal effects and injury induced by animal toxins. Toxicon 60, 943–953. Valenta, J., Stach, Z., Fricova, D., Zak, J., Balik, M., 2008. Envenoming by the viperid snake Proatheris superciliaris: a case report. Toxicon 52, 392– 394. Vigneau, C., Daugas, E., Maury, E., Sokol, H., Offenstadt, G., Rossert, J., Guidet, B., 2006. Renal cortical necrosis related to paraneoplastic antiphospholipid syndrome. Am. J. Kidney Dis. 47, 1072–1074. Warrell, D.A., 2008. Proatheris superciliaris: the deadly venom of a rare and elusive snake revealed. Toxicon 52, 833–835. Warrell, D.A., 2009. Commissioned article: management of exotic snakebites. Q. J. Med. 102, 593–601.
