| Abstract|| |
Acute kidney injury (AKI) is frequently seen in Hemiscorpius lepturus scorpion stung children. We have previously reported several victims with hemolytic uremic syndrome (HUS) and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 deficiency. Hence, we conducted this study to identify predictive factors and clinical features of AKI in H. lepturus scorpion stung patients. We included all 215 H. lepturus scorpion stung children with no previous renal diseases in two groups (with and without AKI) and compared them based on their clinical and laboratory findings. AKI was found in 27.4% of patients, they were significantly younger and with lower body weight (P = 0.006, P = 0.011, respectively). There was a significant difference between groups with and without AKI in findings such as fever (P = 0.003), hypertension (P <0.001), hemolytic anemia (P <0.001), thrombocytopenia (P <0.001), massive proteinuria (P <0.001), hemoglobinuria (P <0.001), pyuria (P <0.001), and hematuria (P = 0.004). HUS was in 5.5% and disseminated intravascular coagulation in 14.6% which had a significant association with AKI (P <0.001).There were several independent predictors for AKI in a multivariate regression model including thrombocytopenia (P = 0.002), pyuria (P = 0.01), proteinuria (P =0.01), and fever (P = 0.02). Hemodialysis was performed in four patients but kidney function improved in all patients and there was no findings of renal impairment after three months follow-up. We found several predictors for AKI in children following H. lepturus scorpion sting including younger age, delay in receiving medical care, pigmenturia, microangiopathic hemolytic anemia, proteinuria, and pyuria.
|How to cite this article:|
Valavi E, Amuri P, Ahmadzadeh A, Cheraghian B, Ahankoob E. Acute kidney injury in Hemiscorpius lepturus scorpion stung children: Risk factors and clinical features. Saudi J Kidney Dis Transpl 2016;27:936-41
|How to cite this URL:|
Valavi E, Amuri P, Ahmadzadeh A, Cheraghian B, Ahankoob E. Acute kidney injury in Hemiscorpius lepturus scorpion stung children: Risk factors and clinical features. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2019 Nov 18];27:936-41. Available from: http://www.sjkdt.org/text.asp?2016/27/5/936/190841
| Introduction|| |
Several low molecular weight proteins are present in the venom of scorpions including neurotoxins, nucleotides, aminoacids, oligopeptides, cardiotoxins, nephrotoxin, hemolytic toxins, phosphodiesterase, phospholipase A, hyaluronidase, acetylcholinesterase, glycosaminoglycans, histamine, serotonin, 5-hydroxyptamine and proteins that inhibit protease, angiotensinase and succinate dehydrogenase, ribonuclease, and 5-nucleotidase. These toxins are capable to produce a potent synergic effects in victim. ,
Hemiscorpius lepturus scorpion envenomation is one of the health problems in some areas including Khuzestan (the South-West Hot Province of Iran) and other Iranian South Provinces, Iraq, South West of Pakistan, and Yemen. The systemic complications such as fever, anorexia, icterus, rhabdomyolysis, hemolysis, restlessness, confusion, seizure, cerebral infarction, renal failure, pulmonary and cardiovascular complications and local erythema, ecchymosis, and necrosis are frequently seen in the victims. ,,,,
The kidney is more vulnerable in H. lepturus scorpion stung patients and have the highest concentration of venom (mainly because of the rapid redistribution of the venom/toxin from the blood to the tissues coupled with slow removal from the kidney cells) compared to the liver, lungs, heart, and the brain.  Moreover, an adrenergic excess-related vasoconstriction or parasympathetic stimulation-related hypotension, systemic inflammatory response syndrome, and other effects such as pulmonary edema and myocarditis cause reduction in renal blood flow and increase the risk of acute tubular necrosis (ATN). ,, Acute kidney injury (AKI) was frequently seen in our H. lepturus scorpion stung children. We also found some evidences of hemolytic uremic syndrome (HUS) and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) deficiency. ,, Therefore, in this study, we decided to find predictive factors and clinical features of AKI in H. lepturus scorpion stung patients.
| Patients and Methods|| |
Patients and data collection
This case-control study was conducted through October 2008 to September 2012 on H. lepturus scorpion stung children admitted in Abuzar Children's Hospital in Ahvaz (the only Referral Center for Scorpion Stung Children in Southwest of Iran) and the Ethical Committee of Ahvaz Jundishapur University of Medical Sciences approved the study protocol.
All enrolled children were stung by the H. lepturus, and we excluded the cases that could not bring the scorpion and patients with a history or sonographic findings of prior renal diseases.
Patients were divided into two groups: with AKI and without AKI, and these two groups were compared based on their clinical and laboratory findings. AKI was defined as doubling of serum creatinine level  or decreased glomerular filtration rate to one half (based on the Schwartz's formula). Other demographic data including age, gender, clinical manifestations, and laboratory findings were also collected. All cases were followed up for three months after discharge from the hospital.
Use of antivenom and other treatments
All patients received 3-5 vials of polyvalent Razi anti-scorpion intravenously produced against H. lepturus and other native scorpions in Iran. In patients with pigmenturia (hemoglobinuria or myoglobinuria), we prescribed alkaline diuresis (15-20 mEq/L sodium bicarbonate in 1.5 daily maintenance fluid) together with furosemide (2 mg/kg/day), and also packed red blood cell (RBC) was transfused in severe anemia. In cases with disseminated intravascular coagulation (DIC), impaired partial thromboplastin (PT), and partial thromboplastin time (PTT) with thrombocytopenia and increased D-dimer) and HUS (microangiopathic hemolytic anemia, uremia, thrombocytopenia, and increased lactate dehydrogenase without impairment of PT or PTT) fresh frozen plasma (FFP) (20-30 mL/kg/day in two doses) in combination with furosemide (1 mg/ kg) or plasma exchange were administered. , This protocol was continued until symptoms improved and evidences of hemolysis were disappeared.
| Statistical Analysis|| |
All the variables were compared using Student's t-test and Chi-square test (for quantitative and qualitative variables, respectively). Moreover, logistic regression analysis was performed to determine independent risk factors of AKI. Quantitative variables are provided as mean and median, qualitative variables were reported as percentages and P <0.05 was considered statistically significant.
| Results|| |
In these four years, 689 scorpion stung children were admitted in our center. Among them, 215 cases (31.2%) were stung by H. lepturus scorpion, the type of scorpion was not defined in 217 cases (31.4%), and the rest were stung by other scorpions (Mesobuthus eupeus in 107 cases and Androctonus crassicauda and Scorpio maurus in 150 cases). The median age in H. lepturus scorpion stung cases was 5.5 years (ranging from 1 month to 14 years) and 56.3% were male. The most stung sites were lower limbs (34.7%) and most of them (46.6%) were stung in summer. Change of urine color due to hemoglobinuria and myoglobinuria (pigmenturia) was the most frequent referring reason. Local erythema found in 95.8%, fever (T >38°C) in 14%, hypertension (>95 th percentile for age) in 8.6%, and sialorrhea in 1.8% [Table 1].
|Table 1: Different factors and their association with acute kidney injury.|
Click here to view
Acute kidney injury in Hemiscorpius lepturus scorpion stung cases
AKI was found in 59 (27.4%) patients. In AKI group, the children were significantly younger and with lower body weight (P = 0.006, P = 0.011, respectively). AKI was significantly associated with more than 3 h delay between the sting and hospital admission, and it was a considerable risk factor for AKI [P = 0.03; odds ratio = 2.29 (95% confidence interval: 1.16-4.52)]. Head and neck were stung in 14.6%, upper limbs in 29.1%, trunk in 21.6%, and lower limbs in 34.7%. However, there was no association between scorpion sting locality and the AKI. Fever, hypertension, anemia (Hb
<10 g/dL), leukocytosis [white blood cell (WBC) >15,000/μL], thrombocytopenia (PLT <150,000/μL), impaired PT and PTT, significant proteinuria (≥2+), hemoglobinuria (≥3+), pyuria (≥10 WBC/HPF), and hematuria (≥10 RBC/HPF) were more frequent in AKI group and had significantly correlated with AKI [Table 1]. Further analysis with logistic regression shows the independent effect of thrombocytopenia (P = 0.002), pyuria (P = 0.01), proteinuria (P = 0.01), and fever (P = 0.02) [Table 2]. DIC was found in 14.6% of our patients which had a significant correlation with AKI (P <0.001). We also found HUS in 5.5% (20.3% of AKI patients).
|Table 2: Independent risk factors for acute kidney injury by multivariate regression analysis.|
Click here to view
Short period of hemodialysis was performed in four patients. However, kidney function improved in all cases during the admission and all victims had no findings of renal impairment after three months follow-up. Local injury in stung site also improved but a large cutaneous scar was found in some cases. In this period, only a five -year-old boy died in first 24 h of admission due to acute respiratory distress syndrome and/or pulmonary hemorrhage. He was referred with hemolytic anemia, hemoglobinuria, and normal serum creatinine but gradually developed fever, hypertension, tachycardia, and respiratory distress.
AKIs were also seen in four (0.037%) M. eupeus stung cases and 16 (0.1%) of black scorpions (A. crassicauda and S. maurus). In all of these patients, AKI improved easily without any major complications.
| Discussion|| |
AKI was frequently seen in our H. lepturus scorpion stung patients. In addition to pigmenturia, several factors including younger age, hypertension, fever, hemolytic anemia, thrombocytopenia, proteinuria, pyuria, leukocytosis, and increased PT and PTT were significantly associated with AKI.
H. lepturus venom can evoke severe inflammatory response syndrome. In severely envenomed patients several pro-inflammatory cytokines including tumor necrosis factor-alpha, interleukin-1 (IL-1), IL-6, metalloproteinase, hyaluronidase, gelatinolytic, and casein lytic toxins cause injury to the skin, muscle cells, RBCs, cardiovascular, and central nervous system. 
Significant anemia was reported by numerous studies in victims of H. lepturus scorpion. ,, We also found a significant association between hemolytic anemia and AKI in the patients (P <0.001). Thrombocytopenia was found in 22.8% of all victims which was significantly more frequent in AKI group (52.8%). Bone marrow aspiration in our previous cases revealed hypercellular marrow with increased megakaryocytes.  Platelet consumption in the process of DIC and HUS can be the cause of thrombocytopenia in these patients.  ADAMTS-13 deficiency was found in HUS patients and the majority of significant hemoglobinuria in our previous study.  ADAMTS-13 cleaves the platelet-adhesive plasma protein von Willebrand factor (VWF). Acquired ADAMTS-13 deficiency is one of the most important causes of atypical HUS and results the formation of ultra large-molecularweight VWF. This allows unrestricted growth of microvascular thrombi, which results in the clinical manifestations of microangiopathic hemolytic anemia. 
Hemoglobinuria in these patients can also be related to microangiopathic hemolysis (in cases with HUS).  The mechanism of AKI following pigmenturia is complex, but it can be related to precipitation of pigments (hemoglobin and myoglobin) in the tubular lumen, vasoconstriction, and also the heme proteininduced oxidant stress.  Most of our AKI cases suffered massive hemoglobinuria and we also found microangiopathic hemolytic anemia and HUS in some cases.
Significant proteinuria which can indicate nephron damage was found in 72.4% of patients and had a significant association with AKI (P <0.001). , Proteinuria was also reported in the AKI patients following snake envenomation. , Moreover, pyuria was significantly associated with AKI. It was found in about 65% of AKI cases which indicates the infiltration of inflammatory cells through the kidney and interstitial nephritis during nephrotoxicity. The acute interstitial nephritis can exacerbate renal dysfunction and has mentioned in other studies. ,
Because hemoglobinuria and myoglobinuria were known as potential risk factors for AKI, alkaline diuresis was a conventional therapeutic program for pigmenturia following H. lepturus scorpion sting. On the other hand, we found some independent risk factors for AKI such as thrombocytopenia, proteinuria, and pyuria which suggest the potential effect of other pathogenesis for AKI including acute interstitial nephritis, HUS, and DIC. Transfusion of FFP that is rich of ADAMTS-13 was obviously useful in the severe cases of HUS and DIC in our previous study but this treatment needs more clinical trial studies in the future. 
| Conclusions|| |
We conclude that H. lepturus scorpion sting can develop AKI in victims with several mechanisms including pigment nephropathy, ATN, HUS, acute interstitial nephritis, and probably direct cytotoxic and nephrotoxic effects of the venom. It seems that early onset and more effective detoxification and adequate treatment of pigmenturia, ADAMTS-13 deficiency, and DIC can decrease the mortality and morbidities including AKI.
| Acknowledgments|| |
We thank the nurses, supervisors, and field staff of nephrology ward for their devotion to the patients and hard work.
Conflict of interest: None declared.
Role of Funding Source: Vice-chancellor of the research center of Ahvaz Jundishapur University of Medical Sciences (No: U89161).
| References|| |
Possani LD, Becerril B, Delepierre M, Tytgat J. Scorpion toxins specific for Na+-channels. Eur J Biochem 1999;264:287-300.
Gwee MC, Nirthanan S, Khoo HE, Gopalakrishnakone P, Kini RM, Cheah LS. Autonomic effects of some scorpion venoms and toxins. Clin Exp Pharmacol Physiol 2002; 29:795-801.
Pipelzadeh MH, Jalali A, Taraz M, Pourabbas R, Zaremirakabadi A. An epidemiological and a clinical study on scorpionism by the Iranian scorpion Hemiscorpius lepturus. Toxicon 2007;50:984-92.
Bonilha L, Cendes F, Ghizoni E, Vieira RJ, Li LM. Epilepsy due to a destructive brain lesion caused by a scorpion sting. Arch Neurol 2004;61:1294-6.
Al-Asmari AK, Al-Seif AA, Hassen MA, Abdulmaksood NA. Role of prazosin on cardiovascular manifestations and pulmonary edema following severe scorpion stings in Saudi Arabia. Saudi Med J 2008;29:299-302.
Bahloul M, Chabchoub I, Chaari A, et al. Scorpion envenomation among children: Clinical manifestations and outcome (analysis of 685 cases). Am J Trop Med Hyg 2010;83: 1084-92.
Bawaskar HS, Bawaskar PH. Scorpion sting: Update. J Assoc Physicians India 2012;60:4655.
de Sousa Alves R, do Nascimento NR, Barbosa PS, et al. Renal effects and vascular reactivity induced by Tityus serrulatus venom. Toxicon 2005;46:271-6.
Viswanathan S, Prabhu C. Scorpion sting nephropathy. NDT Plus 2011;4:376-82.
Krkic-Dautovic S, Begovic B. Acute renal insufficiency and toxic hepatitis following scorpions sting. Med Arh 2007;61:123-4.
Farghly WM, Ali FA. A clinical and neurophysiological study of scorpion envenomation in Assiut, Upper Egypt. Acta Paediatr 1999;88: 290-4.
Valavi E, Ansari MJ. Hemolytic uremic syndrome following Hemiscorpius lepturus (scorpion) sting. Indian J Nephrol 2008;18: 166-8.
Valavi E, Ahmadzadeh A, Amoori P, Daneshgar A. High frequency of acquired ADAMTS13 deficiency after hemolysis in Hemiscorpius lepturus (scorpion) stung children. Indian J Pediatr 2014;81:665-9.
Valavi E, Ansari MJ, Hoseini S. ADAMTS-13 deficiency following Hemiscorpius lepturus scorpion sting. Saudi J Kidney Dis Transpl 2011;22:792-5.
Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: Report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31.
Seyedian R, Pipelzadeh MH, Jalali A, et al. Enzymatic analysis of Hemiscorpius lepturus scorpion venom using zymography and venomspecific antivenin. Toxicon 2010;56:521-5.
Waikhom R, Sircar D, Patil K, Bennikal M, Gupta SD, Pandey R. Long-term renal outcome of snake bite and acute kidney injury: A single-center experience. Ren Fail 2012;34: 271-4.
Watanabe T. Rhabdomyolysis and acute renal failure in children. Pediatr Nephrol 2001;16: 1072-5.
Sitprija V. Snakebite nephropathy. Nephrology (Carlton) 2006;11:442-8.
Gmar-Bouraoui S, Aloui S, Ben Dhia N, et al. Scorpion sting and acute interstitial nephropathy: Apropos of 1 case. Med Trop (Mars) 2000;60:305-6.
Department of Pediatric Nephrology, Chronic Renal Failure Research Center, Abuzar Children's Hospital, Ahvaz
[Table 1], [Table 2]