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Saudi J Kidney Dis Transpl 2012;23(6):1262-1267 2012 Saudi Center for Organ Transplantation

Saudi Journal of Kidney Diseases and Transplantation

Brief Communication
Acute Interstitial Nephritis in Patients with Viperine Snake Bite: Single Center Experience of a Rare Presentation
Vishal Golay1, Arpita Roychowdhary1, Rajendra Pandey1, Ametashver Singh1, Amit Pasari1, Anila Abraham2

Department of Nephrology, Institute of Postgraduate Medical Education and Research, Kolkata, 2 Consultant in Nephropathology, The Madras Medical Mission, Chennai, India

ABSTRACT. Acute renal failure following vasculotoxic viperine snake bites is very common in South Asia. Acute tubular necrosis and acute cortical necrosis are the common findings, with acute interstitial nephritis (AIN) being a rare presentation. We conducted renal biopsies in all patients who were admitted in our institute with viperine snake bite-related acute kidney injury (AKI) and who did not improve after three weeks of supportive care. Patients who had findings of AIN on renal histology were included for this study. Of a total of 42 patients, there were five patients (11.9%) with AIN. Our series of five patients is the largest series of this rare presentation in the literature. All of these five patients had features of severe envenomation, severe AKI network stage of AKI and very high antivenom requirements. They had a very prolonged stay in the hospital, and four of the five patients developed chronic kidney disease on follow-up. The overall outcome in this group was worse as compared with those who did not have AIN. AIN following viperine snake bites is not a very rare presentation. The reason for the development of this pathology is unclear, but direct venom-related effects are possible. This presentation portends a poor overall long-term prognosis as demonstrated in our case series. Introduction Venomous snakes are found throughout the world, and the incidence of snake bite and related mortality are encountered all over the globe. An incidence of renal involvement with Correspondence to: Dr. Vishal Golay Department of Nephrology, Institute of Postgraduate Medical Education and Research, Kolkata, India E-mail: snakebite envenomation of 1.428% has been reported in various series. The most common species associated with renal lesions are Russells viper, Echis carinatus, puff adder and sea snake. In India, the incidence of acute kidney injury (AKI) is 1332% following Echis carinatus or Russells viper bite.1 Renal failure averages two to three weeks in duration. Prolonged renal failure with oligo-anuria is observed in patients with cortical necrosis or acute tubular necrosis (ATN) associated with either interstitial nephritis or extracapillary glomerulonephritis. Acute glomerulonephritis in


Acute interstitial nephritis with viperine snake bite


Figure 1. Renal biopsies (A, B, C, D of case 3, 4, 1 and 2, respectively) showing marked interstitial inflammatory infiltrates consisting of lymphocytes and occasional eosinophils (black arrow, A). The interstitium is edematous (A) and the glomeruli are normal (C and D). There is also evidence of tubular damage in the form of loss of the brush border and denudation with cellular debris in the tubular lumen (white arrow, D). Hematoxylin and eosin 400 (A, B), 100 (C, D).

viper bite can cause mild renal failure.2 We present a series of five patients who underwent renal biopsies and had a histological finding of acute interstitial nephritis (AIN). Materials and Methods We included cases from a cohort of 42 patients admitted in the Nephrology Department of the Institute of Postgraduate Medical Education and Research, Kolkata, from January to December 2011 with AKI following snake bite envenomation. AKI was diagnosed as per the AKI network criteria.3 The severity of the snake bite was assessed by a scoring system that included local effects, systemic features and coagulation abnormalities, taking the most severe of the three as the severity grade.4 All these patients received standard care for snake bite envenomation, including anti-snake venom (ASV) and renal replacement therapies.5 Severity of the renal failure on admission was assessed according to the Stuivenberg Hospital Acute Renal Failure (SHARF) II and Sequential

Organ Failure Assessment (SOFA) scoring systems at the time of admission and 48 h later.6,7 Patients who remained oliguric or whose serum creatinine did not satisfactorily decrease (defined for this study as a failure of serum creatinine to decrease to less than 50% of the peak value attained) at the end of three weeks underwent a renal biopsy after an informed consent. The renal biopsy sample was examined with light and immunofluorescence microscopy. Results We identified five patients of 42 (11.9%) of the originally screened patients with renal biopsy findings of AIN (Figure 1). The clinical, laboratory and treatment details of all the patients were recorded and are represented in Tables 1 and 2. None of the patients had complained of bilateral flank pains and an ultrasound of KUB showed normal-sized kidneys with increased echo-texture. All our five patients were adult agricultural workers who were bit while working in the



Golay V, Roychowdhary A, Pandey R, Singh A, Pasari A, Abraham A Case 3 (Male) 38 Russells viper Left foot Severe Stage 3 21 (dialysis dependent) 30 days 42 300 Case 4 (Male) 24 Russells viper Right foot Severe Stage 3 15 20 days 46 240 Case 5 (Male) 32 Russells viper Right foot Severe Stage 3 20 24 days 45 350

Table 1. Clinical characteristics of the five cases. Case 1 Case 2 (Male) (Female) Age (years) 21 33 Russells Russells Snake species viper viper Right little Site of bite Left toe Severity of snake bite Severe Severe envenomation AKI stage on admission Stage 3 Stage 2 Number of hemodialysis sessions Time to good urine output (>1000 mL/day) Number of days of admission Total dose of ASV given (mL) 15 25 days 41 250 11 16 days 28 370

fields. Russells viper was the snake species that was identified by the patients and bystanders in all the five cases. All the five patients had severe grade of snake bite envenomation, and four of the patients (except case 2) had Stage 3 AKI on admission. The patients had a relatively severe degree of hypercatabolic renal failure; hypercatabolism was defined as a rise in serum creatinine of 1.5 mg/dL/24 h or a rise in serum urea of 30 mg/dL/24 h.8 All the five patients had very high SHARF II and SOFA scores at 0 and 48 h. There was also a worsening of the SOFA score, i.e. SOFA 48 0, which is a predictor of poor overall outcomes. All the five patients received very high doses of ASV that required repetition due to the severity of the disease. ASV was administered initially in the prescribed test dose, followed by the complete dosage, if there was no hypersensitivity reaction; none of the patients demonstrated any hypersensitivity reaction to ASV. The eosinophil count in the CBC, which was done once every three days during hospitalization, remained within normal limits. The baseline and the clinical progression had significant bearing on the overall outcome. Case 2 had a complete recovery of renal function at the last follow-up (11 months). She had a relatively less-severe grade of envenomation

and had an earlier onset of good urine output and improvement of renal function and, thus, a shorter duration of hospital admission. Even though she had high AKI severity scores with significant coagulopathy, she was hemodynamically more stable than the other cases who all had hypotension on admission. All the cases except case 2 received a course of prednisolone at a dose of 1 mg/kg/day with tapering over one month, but the overall outcome did not improve in any of the cases, with two of them ending as chronic kidney disease (CKD) Stage 4 (cases 1 and 5), one as CKD Stage 3 (case 4) and one of them became dialysis dependent (case 3). Renal biopsies showed extensive interstitial inflammation in all the five cases, with predominantly lymphocytic infiltration in all of them except case 4, where eosinophils were predominant along with lymphocytes. All the cases (except case 1) had eosinophils as a component of the inflammatory infiltrate. Cases 25 had some evidence of secondary tubular injury along with the AIN; case 2 had evidence of tubular necrosis as well. The glomeruli and the blood vessels were normal and there was no evidence of immune deposits on immunofluorescence microscopy. Of the remaining 37 patients, 10 (27%) patients


Acute interstitial nephritis with viperine snake bite Table 2. Laboratory, histology and other associated characteristics. Case 1 Case 2 Case 3 (Male) (Female) (Male) Hypercatabolic Yes Yes Yes Peak creatinine 9.4 (day 15) 6.8 (day 3) 9.1 (day 4) (mg/dL) Creatinine at 3.9 1.8 8 discharge (mg/dL) Platelet count 9000/L 10,000/L 11,000/L (nadir) (Day 4) (Day 3) (Day 4) Coagulopathy Yes Yes Yes SHARF II score(0 59.1/48.8 47/41.5 73.5/38.6 and 48) SOFA score (0, 48 9/12/3 8/10/2 8/10/2 and 480) Tubular injury on No Yes Yes histology Lymphocytes, Lymphocytes, plasma cells, Cell types in the Lymphocytes neutrophils, neutrophils, interstitial infiltrate eosinophils eosinophils eGFR at last visit 24.6 95.8 8.5 (mL/min) Clinical outcome at CKD Stage 4 Recovered CKD Stage 5-D last follow-up (10 months) (11 months) (6 months) Case 4 (Male) Yes 6.4 (day 9) 2.9 8000/L (Day 4) Yes 64.6/49.2 9/10/1 Yes Eosinophils, neutrophils, lymphocytes 42 CKD Stage 3 (7 months)

1265 Case 5 (Male) Yes 11.8 (day 8) 4.2 15,000/L (Day 5) Yes 72/42.1 8/11/3 Yes Lymphocytes, eosinophils

CKD Stage 4 (4 months)

died within three weeks, 19 (52%) recovered within two to three weeks of the snake bite and did not undergo renal biopsy and all of them had a good long-term outcome with complete recovery of their renal function and eight (21%) patients had a renal biopsy finding of ATN. These eight patients also had evidence of severe envenomation, but had better AKI scores and had an earlier recovery of renal function. Two of the eight (25%) patients with ATN developed CKD (3 and 4 in each) on follow-up. Discussion Renal involvement following snake bite envenomation has been reported with many snake species, but the most severe of these, i.e. acute renal failure, is seen predominantly with the bite of the vipers. In India, this is usually seen with Russells viper and the Saw-scaled viper bites that are the most widespread viper species in India.9 The frequency of snake bite as a cause of acute renal failure has been variably reported as 1.2% in Thailand, 3% in

India and as high as 40% in Myanmar.10,11 Snake venoms can cause cellular injury through enzymes, polypeptide toxins, cytokines and mediators. Snakes that cause renal failure are either myotoxic or hemotoxic snakes causing rhabdomyolysis, intravascular hemolysis, disseminated intravascular coagulation (DIC) or hemorrhage.12 Renal failure occurs a few hours to several hours after the bite, with a rapid rise of blood urea nitrogen and serum creatinine. Non-oliguric renal failure is not uncommon, and averages two to three weeks in duration. The renal histology mainly consists of ATN and AIN, while glomerular changes are rare. In one of the early reports of snake bite from India, Chugh et al described renal histology in 44 patients of snake-bite related ARF. Thirtytwo of these 44 patients (73%) had predominant changes of ATN. Forty-six patients (66%) recovered and four patients (6%) had persistent mild to moderate renal insufficiency.11 Pal et al from Kolkata reported histology of the kidneys from 20 lethal cases of snake biterelated ARF. Histopathological changes re-



Golay V, Roychowdhary A, Pandey R, Singh A, Pasari A, Abraham A

vealed ATN and cortical necrosis as the predominant finding along with glomerular changes in a few cases.12 Degeneration, necrosis and regeneration of tubular epithelial cells have been observed in renal failure following the bite by either hematotoxic or myotoxic snakes,11,14-16 in addition to interstitial edema and cellular infiltration, which consist of lymphocytes, plasma cells and mononuclear phagocytic cells. However, diffuse AIN out of proportion to tubular degeneration has been rarely observed in Russells viper bite. Although AIN accounts for 515% of all cases of ARF,17 only four single case reports of AIN following snake bite have been reported earlier. Sant and Purandare reported an autopsy study of a patient with hemorrhagic interstitial nephritis.18 Sitprija et al and Indraprasit et al from Thailand reported one case each of AIN following Russell viper bite.19,20 The fourth case was reported by Gundappa et al. from India following a viperine bite.21 Our series of five cases is thus the largest collection of cases reported so far in the literature to the best of our knowledge. All the three cases reported previously were patients who were oliguric with prolonged course of renal failure, which prompted the clinicians to consider diagnoses other than ATN. The histopathology of the two cases reported from Thailand and the one from India were similar in the presence of severe interstitial inflammation, which comprised of lymphomononuclear cells. However, the latter was distinct in the presence of eosinophils in the interstitial infiltrate. The five cases in our series marked a similar clinical course of prolonged duration of renal failure with prolonged oliguric phase and presence of eosinophils in the interstitial infiltrate in four cases. The incidence of AIN was 11.9% among all cases of renal failure in our institute, which gives an interesting observation that AIN following snake bite is not such a rare entity as described previously. Although many factors can contribute to the development of AIN, snake venom has been postulated to directly result in the development of the interstitial inflammation via various

cytokines, mediators and adhesion molecules.12 The presence of eosinophils in the interstitium in four of the five cases in our series may suggest some contribution by drugs that were given in the management of these cases (proton pump inhibitors and penicillin antibiotics, which were prescribed in all cases). Nevertheless, the role of direct nephrotoxicity of snake venom is still not clear, but hypersensitivity to venomous or antivenom protein has been occasionally found to cause acute renal failure.11 An interesting observation in our series was that all the cases received a very high dose of ASV due to the severe envenomation. The contribution of the anti-venom to the development of the AIN needs to be determined as there is no significant data to implicate this relationship. The histological finding of AIN correlated with poor prognosis in our study as four of the five patients developed CKD. References
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