Snakebite-Induced Acute Kidney Injury: Data from Southeast Anatolia

Abstract

Renal failure is an important complication of snakebite and a major cause of mortality. We aimed to study the clinical profile of snake envenomation in Southeast Anatolia, Turkey, in an adult population. We retrospectively analyzed the records of 200 snakebite victims from 1998 to 2006 at the Dicle University School of Medicine, Diyarbakir, Turkey. Sixteen patients (8%) developed AKI (acute kidney injury). Of those, 25% required dialysis and 18% died. There was no difference between groups in age, arrival time to hospital, and hospital stay time. Both groups received similar hydration and therapy at admission. Disseminated intravascular coagulation (DIC) was observed in 25% of the AKI group and was significantly higher than the non-AKI group (7.1%; p = 0.014). There was no significant difference regarding hemoglobin, platelet levels, and prothrombin time at admission. The prevalence of thrombocytopenia (<150,000 K/UL ) was 60% in the AKI group and 40% in the non-AKI group (p > 0.05). WBC count was significantly higher in the AKI group than in those without AKI (p = 0.001); serum albumin was significantly lower in the AKI group than in those without AKI (p = 0.013). AKI is an important complication of snakebite that may lead to mortality. Despite some troublesome aspects due to its retrospective design, this is a large series from Southeast Anatolia of Turkey in an adult population. Subjects with high WBC, low albumin, and DIC should be closely followed up for the development of AKI.

Keywords:

• snakebite
• acute kidney injury
• viperidae
• disseminated intravascular coagulation

INTRODUCTION

There is a broad clinical spectrum of renal involvement in snakebite. Besides the local and systemic symptoms, clinical renal manifestations vary from mild proteinuria, hematuria, and pigmenturia to acute renal failure. Renal failure is an important complication of snakebite and a major cause of mortality. Renal involvement depends on the type of snake, the degree of envenomation and duration of exposure to the venom. Snakebite evenomation is one of the etiological factors for acute renal failure (ARF) in developing countries. The incidence of kidney dysfunction due to snakebite evenomation is 1.4–28%. The commonest species associated with renal lesions are Russell's viper, Echis carinatus, puff adder, and sea snake.[1],[2]

The viper is the most common poisonous snake in this region of Turkey. In viper bite, renal failure may accompany intravascular hemolysis or intravascular coagulation. Hemoglobinuria and hematuria are observed. Hemolytic uremic syndrome has been reported following hemotoxic snake envenomation.[3]

The early administration of antivenom is a vital therapeutic measure. The timely administration of antivenom completely reverses all clinical manifestations of systemic envenomation.[4] The maintenance of fluid and electrolyte balance, antibiotics, and tetanus toxoid are other therapeutic measures.

We retrospectively analyzed the records of snakebite victims from 1998 to December 2006 at the Dicle University School of Medicine, Diyarbakir, Turkey.

SUBJECTS AND METHODS

This retrospective study was carried out at the Dicle University School of Medicine, Diyarbakir, Turkey. Our hospital is a referral hospital in Southeast Anatolia, Turkey. Patients with a diagnosis of snakebite were included. The records of snakebite victims from 1998 to 2006 were obtained from the records of the hospital.

Even though RIFLE criteria are a new and more standardized system, the current study is retrospective in design, and we were not able to apply all of the RIFLE criteria to define acute kidney injury (AKI). Therefore, AKI was defined as serum creatinine exceeding 150 mmol/L in males and 120 mmol/L in females corresponding to a GFR of 50–60 mL/minute in the first 72 hours after envenomation with subsequent recovery of GFR. Patients who did not improve their GFR were carefully screened, and clinical and/or laboratory evidence of chronic kidney disease were excluded from the analysis. Chronic kidney disease was defined as baseline serum creatinine (previous to the accident) greater than 150 mmol/L in males and 120 mmol/L in females, renal ultrasound with decreased kidney length, loss of the corticomedullary distinction, and/or history of active or past renal disease. At admission, all patients were hydrated with an alkalinizing solution up to 3 to 6L/day, according to clinical picture. Hydration with an alkalinizing solution was used to prevent renal injury by rhabdomyolysis. Tetanus toxoid was applied to all cases.

Clinical Parameters

Age, gender, history of chronic diseases (e.g., heart failure, hypertension, or diabetes mellitus), use of concomitant drugs, hospitalization time, dialysis treatment, and mortality were all recorded.

Laboratory Evaluation

Complete blood count, differential cell count, fibrinogen, fibrin degradation products (FDP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum electrolytes (sodium, potassium), serum urea and creatinine levels, creatinine phosphokinase (CK), and lactate dehydrogenase (LDH) were measured by standard methods. Hemoglobin (Hb) level, white blood cell (WBC), and platelet counts were measured by hemocounter (Cell-Dyne 3700, Abbott, Illinois, USA) and Cell-Dyne 4000 (Abbott). Prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen were made by coagulometry (ACL Advance, Lexington, Kentucky, USA). All other parameters were studied using an autoanalyzer (Abbott Aeroset, Osaka, Japan, 1999).

Statistical Analysis

Results were expressed as mean ± standard deviations. The comparison between groups was performed by using the Student's t-test for parametric values and chi-square for frequencies. We used Fisher's exact test values for frequencies lower than 5. A p value <0.05 was considered statistically significant.

RESULTS

Analyzed Sample

The records of the 200 snakebite victims from 1998 to December 2006 were obtained from the records of the hospital. Time from snakebite to specific antivenom administration was 3.2 ± 1.9 hours in a subject with AKI and 2.8 ± 2.1 hours in a subject without AKI (p > 0.05). Mean age of patients was 40.3 ± 18.8 years with AKI and 34.5 ± 16 years without AKI group.

Comparison of the ARF and Non-ARF Groups

Of the 200 patients studied, 16 (8%) had AKI in the first 72 hours after the snakebite. Of these, four patients required dialysis (25%), and three (18 %) died. Mean time to arrival at our hospital after the bite was 3.2 ± 1.9 hours in patients with AKI and 2.7 ± 2.1 hours those without AKI (p > 0.05). The mean duration of the hospital stay was 6.6 ±3.6 days in patients with AKI and 7.8 ± 4.0 days in those without AKI.

Patients Data

There was no difference between groups regarding age, arrival time to hospital, and hospital stay (see Table 1). Both groups received similar hydration and therapy at admission. All detectable bites were seen on exposed parts of the body: 99 (26%) on the foot, 77 (20%) toe, 74 (19%) fingers, 64 (17%) hands, 41 (11%) legs, 21 (6%) arms, and two faces. Death was due to sepsis (n = 1), multiorgan failure (n = 1), and anaphylactic reaction (n = 1).

Table 1 Characteristics of patients with snakebite

	AKI(+)	AKI(-)	p
Age (years)	40.3 ± 18.8	34.5 ± 16	NS
Sex (F/M)	8/8	97/87	NS
Urea (g/dL)	113 ± 78	38 ± 14	p < 0.001
Creatine (mg/dL)	2.85 ± 2	0.7 ± 0.2	p < 0.001
Albumin (g/dL)	2.9 ± 05	3.7 ± 0.8	p = 0.013
LDH (U/L)	375 ± 224	304 ± 144	NS
AST (U/L)	71 ± 57	37 ± 34	p = 0.002
ALT (U/L)	45 ± 38	31 ± 31.7	NS
CK (U/L)	545 ± 652	369 ± 635	NS
LDH (U/L)	375 ± 224	304 ± 144	NS
DIC (%)	%25	%7.1	p = 0.014
WBC (K/UL)	19.3 ± 3.7	14.5 ± 5.4	p = 0.001
Hb (g/dL)	13.2 ± 3.4	13.2 ± 2.5	NS
Plt (K/UL)	138 ± 137.9	175 ± 96	NS
PTZ (sn)	17.1 ± 2.9	15 ± 3.3	NS
CRP (mg/dL)	26.8 ± 22.5	18.4 ± 20	NS
Arrival time to hospital (hours)	3.2 ± 1.9	2.8 ± 2.1	NS
Duration of hospitalisation (day)	6.7 ± 3.6	7.82 ± 4	NS
AV dose	2.3 ± 0.7	2.3 ± 1.7	NS

Laboratory Evaluation of Rhabdomyolysis

Serum CK levels were high in both groups. But the difference was insignificant. The number of subjects with a CK increased five-fold of upper limits was higher in the AKI group than the non-AKI group, though the difference was insignificant.

Hematology and Coagulation Time

There was no significant difference regarding hemoglobin, platelet levels, and prothrombin time at admission. The prevalence of thrombocytopenia (<150000 K/UL) was 60% in AKI group and 40% in non-AKI group (p > 0.05). WBC were significantly higher in the AKI group when compared to the non-AKI group (p = 0.001). None of the patients had hemorrhage.

DISCUSSION

Snakebite evenomation is not an uncommon etiological factor for acute renal failure (ARF) in developing countries. Nearly all venomous snakes in Turkey and Southeast Anatolia are members of the Viperidae family and show poisonous local and hematoxic effects. Venomous snakes seen in Turkey are subgroups of V.ammodytes, V. barani, V. ursunii, V. raddei, V. kaznokovi, V. pontica, V. wagneri, V. labetina, V. xanthina, Walterinnesea aegyptia, Malpolon monspessulanus, and Telescopus fallaks. Most snakebites are caused by non-venomous snakes.[5]

Prevalence of ARF

The prevalence of AKI our study was 8% (n = 16) and mortality rate of AKI was 18% (n = 3). Dialysis was required in 25% (n = 4) patients. The remaining 13 patients recovered their renal functions completely, and no patient remained dialysis-dependant. The significant recovery of the GFR in almost all patients of the ARF group confirmed the acute nature of the renal insult. The incidence of acute renal failure caused by these snakes varies from 5% to 29%, depending on the species of snake and the severity of envenoming.[6–8] The highly venomous snakes most commonly encountered are Russell's viper (subfamily viperinae), snakes of the bothtrops species (subfamily crotalinea), and rattlesnakes. The incidence of ARF following Russell's viper bite has been estimated to be 13–32%,[1] and the prevalence of ARF following bothtrops snakebite ranges from 2–10%.[6–8].

In a retrospective study of 360 patients envenomed with echis carinatus (saw-scaled viper), 62 (17%) patients developed acute renal failure (ARF), 44 patients (71%) needed dialysis, and 16 patients (25%) died.[9] Another prospective observational study of 100 patients envenomed with crotalus durissus was reported, showing a 29% prevalence of ARF. Of those, 24% required dialysis and 10% died.[10] The prevalence of ARF was reported to 28.6% after viperedia family snake bites in India, yet antivenom administration rate was only 8% in these patients.[1] The low prevalence in our study may be due to early and high antivenom administration rate.

Risk Factors for Development of ARF

The finding that the delay to administer an adequate dose of the antivenom increases more than 10 times the risk of developing ARF.[10] Previous studies have already suggested that there is a correlation between renal injury and time interval between the snakebite and the administration of antivenom.[11–13] Although no significant difference was present between the AKI and non-AKI groups, a possible factor related to the development of renal injury might be the administration of less antivenom in the AKI group. In the literature, it has been shown that early administration of antivenom reverses clinical manifestations of snakebite.[4] Although the time interval from snakebite to antivenom administration was higher in the subject with AKI than the subject without AKI, the difference was not statistically significant (p > 0.05). However, although we believe that the timing for the application of antivenom may be important in prevention of renal failure, we were not able to calculate antivenom per body surface in our patients due to the retrospective nature of the study. Arrival time to hospital (3.2 ± 1.9 hours in AKI, vs. 2.8 ± 2.1 hours) was similar with that reported in literature (i.e., 1–3 hours).[14],[15]

Disseminated intravascular coagulation (DIC) is a consistent feature in patients bitten by several species of snakes.[4],[9] Viper venom produces the activation of factor V with fibrinolysis, leading to DIC. This can result in hemorrhage, hypovolemia, and thrombin in the microvasculature and glomerular capillaries and a microangiopathic hemolytic anemia with subsequent ARF.[16] DIC plays a major pathogenetic role in the renal lesions of snakebite-induced cortical necrosis.[4],[16] DIC was observed in the 25% of AKI group and was significantly higher than the non-AKI group (7.1%) (p = 0.014).

Rhabdomyolysis is a well-known cause of renal injury.[17],[18] The clinical diagnosis of rhabdomyolysis is established when CK increases five or more times above normal levels, with a suggestive clinical picture and without heart and/or cerebral injury. Serum CK levels were increased in both groups, but the difference was insignificant. The percentage of subjects with a CK increased five-fold of upper limits was higher in AKI group than non-AKI group, though again the difference was insignificant. A previous study reported high rhabdomyolysis prevalence in ARF group.[10] The insignificance in our study regarding the prevalence of rhabdomyolysis may be due to a low number of subjects with AKI or extracellular volume expansion administration to our all subjects. Because the most effective measure for the prevention of ARF induced by rhabdomyolysis is extracellular volume expansion with saline solution combined with sodium bicarbonate and mannitol.[18],[19]

It was observed that children have a prevalence of ARF almost three times higher than adults. Comparatively, children have a lower blood volume and smaller body surface, which might be related to a more severe clinical picture due to an increase concentration of the venom.[20] There was no significant difference between AKI and non-AKI groups regarding age in our study.

ARF Characteristics

The onset of renal failure is a few hours to several hours after the bite, suggesting that the direct nephrotoxicity of the venom shown experimentally might also be clinically present.[21] In our study, AKI often occurred within the first 24 to 48 hours. Six of the AKI patients were oligoanuric (37.5%), the others patients nonoligouric (62.5%). Dialysis treatment was indicated in 25% of our cases with AKI. The need for dialysis is similar with that reported by Pinho et al.[10] (24%) but lower than previous studies that reported a greater demand for dialysis, ranging from 68–77% of the patients.[12] This discrepancy is probably related to the low specifity of ARF diagnostic criteria used in these studies, only identifying the more severe cases of renal injury. Renal function was recovered in individuals who survived ARF.

Mortality in snakebite acute renal failure range from 1% to 26.5%, depending on the studies series.[1],[10],[12],[21],[22] The mortality rate was 25% in our patients and compatible with the literature.

The presence of DIC is significantly higher in the AKI group than the non-AKI group (p = 0.014). Viper bite can cause mild renal failure.[23] A low demand for dialysis in our study supports this finding. WBC count was significantly higher in the AKI group than those without AKI (p = 0.001), and serum albumin was significantly lower in the AKI group than those without AKI (p = 0.013). Because albumin is a relatively slow-reacting negative acute-phase reactant that may be associated with high mortality in acute renal failure,[24] serum high WBC and low albumin may reflect the severity of inflammation in our cases.

CONCLUSION

AKI is an important complication of snakebite and a may lead mortality. Although it has some troublesome aspects due to its retrospective design, this is a large series from Southeast Anatolia of Turkey in an adult population. Subjects with high WBC or low albumin or those complicated with DIC should be closely followed up for development of AKI.