Acute renal failure following poisonous snake bite.

BV Mittal 
 Department of Pathology, Seth G.S.Med. College, Bombay.

Correspondence Address:
B V Mittal
Department of Pathology, Seth G.S.Med. College, Bombay.

Full Text



Snake bite poisoning is known to man since antiquity. References to snake bite are found even in the oldest medical writings. It constitutes a significant cause of mortality in tropical countries. The annual mortality is around 30,000, most of them from South East Asia and West Africa. Approximately 10,000 deaths occur in India[1],[2].

Acute renal failure is mainly observed following bites by the viperidae group, sea snakes and the colubridae group, but the substantial proportion of these cases result from viper bites[3],[4],[5],[6],[7],[8],[9],[10]. In India, particularly in the Ratnagiri district of Maharashtra, Punjab, Kashmir, sandy deserts of Rajasthan and West coast upto Karwar. Echis carinatus or saw scaled vipers are found in incredible numbers, followed next in frequency by the Rusjok's viper[11]. Cobra. Krait and other snakes of the Elipiclaa group are neurotoxic.

The incidence of acute renal failure (ARF) following poisonous snakes varies from 13 to 22% following Echis carinatus or Russell's viper bite[4],[12]. In our institution, 16.2% of the cases admitted to the medical intensive care unit (198793) following snake bite developed renal failure. The lesions responsible for ARF foliowing snake bite and the pathogenesis has been extensively reviewed by Prof. Chugh in the Nephrology forum[13] In most cases, the renal failure is attributed to tubular necrosis and cortical necrosis[3],[10], though necrotising arteritisil and nephrotic syndrome's have also been reported.

Proliferative glomerutonephritis due to toxic action of the venom was reported by Seedat et al[16]. Sant and Purandare[17],[18],[19] from this Institute have reported toxic proliferative glomerulitis in patients as well as experimental animals following viperine snake envenomation. However most of the other reporls do not mention the glomerular changes following snake bite. In view of this controversy, we reviewed the cases from 1971 to 1986 and these findings (27 cases) were earlier reported in 1986[20]. We have seen an additional 14 cases in the last nine years and a combined review of 41 cases from 19711993 will be presented. These cases were analysed with special reference to (a) the lesions responsible for ARF, (b) glomerular changes and (c) pathogenesis of the lesions.

Forty-one cases were included in the study. There were 24 males and 17 females. Their average age was 35.2 years, the youngest patient was 4 years old and the oldest 80 years old. The snake was identified as Russell's viper in 14, echis cannatus or saw scaled viper in 20 and sea snake in one case respectively.

Identification of the snake was based on the actual examination of the snake brought by the patient or witness, supported by the clinical features of envenomation. Exact identification of the snake was not possible in six cases, however, those patients had renal manifestations and bleeding diathesis followed the bite, which was a pointer to the viperidae group.

Oligoanuria (100%) and bleeding diathesis were the commonest clinical manifestations (73.17%). Oliguria was observed within 24 hours to 96 hours after envenomation. The serum creatinine ranged from 1.5 to 20 mg%. There was however, no correlation between the highest creatinine values and survival. One case revealed eosinophilia but none had any allergic rash.

Coagulation profile was abnormal in 31 cases (73.17%) and was suggestive of DIC. No case had fibrinolysis (primary). The type of snake associated with DIC was observed to be Russel's viper in 12. Echis carinatus in 13, sea snake in one and in five cases the exact type of snake was not known. Patients were treated with peritoneal and haemodialysis. Despite aggressive management, 20 cases had a fatal outcome and autopsy was available, Death had occurred within six days in 17. One case each had died in 10 days, 15 days and one month following the bite. In 21 cases, renal biopsies were carried out to ascertain the cause of renal failure.

The time interval between the bite and biopsy varied from three weeks to eight weeks. The tissues were fixed in 10% buttered formalin and 3 micron sections were stained by H & E, PAS, PASM and Putt's fibrin stain. Glomerular and tubular changes were scored as described by Striker et al[21]. Direct immunofluorescence was carried out on 7 biopsies.

Histopathological changes are depicted In [Table:1]. Tubular necrosis (53.6%) and cortical necrosis (24.3%) were the main causes of ARF. Cortical necrosis was seen in 10 cases. In six of these, it had resulted in death. Based on the extent of nocrosis and medium sized vessel involvement by thrombosis, these were classified as diffuse in 3, focal confluent (no thrombosis in medium sized vessel) in 2 and patchy cortical necrosis in one case. In tour cases, the diagnosis of cortical necrosis was rendered on the biopsy findings, one of these biopsied showed thrombosis in medium sized vessel. Fresh capillary thrombosis was seen in seven of the 10 cases with cortical necrosis, one case showed occasional endothelialised thrombi too.

Extensive tubular necrosis (4+) was seen in all cases of cortical necrosis. However, excluding these cases, tubular necrosis alone was responsible for renal failure in 22 cases (53.6%). In three of these cases, there was superadded pyelonephritis. 2+ tubular necrosis was seen in six cases, while in 10 cases, it was +. In six biopsied cases recovering tubular damage with tubules lined by flat regenerative epithelium was observed. In one of these cases, it was seen alongwith moderate tubular necrosis. Tubular degeneration in the form of cloudy or vacuolar change in the absence of frank tubular necrosis was seen in five biopsies. Haemorrhagic interstitial nephritis with haemorrhage in subcapsular and subpolvic was seen in one case while in the other case, interstitial haemorrhage was seen at the junction of cortex and medulla.

Glomerular changes are depicted in [Table:1].

Ballooning dilatation of the glomerular capillary loops was the most striking finding in 60.9% of cases. It was best appreciated at the tips of the capillary loops. It was graded from 0 to 4+, equivocal +, 50% loops involved ++, 75% loops +++ and all capillary loops.

Involved ++++, 25 of the 41 cases (60.9%) revealed ballooning changes, six had + dilatation, in 13 cases it was ++, five cases +++ and severe 4+ dilatation was seen in one case. Masanglolysis was seen along with ballooning in 11 cases. Endothelial cell swelling was seen in 13 cases (31.7%) and splitting of GBM in 16 cases (39.08%). Age related wrinkling and patchy thickening of GBM was seen in three cases.

In order to remove the subjectivity of the assessment of glomerular cellularity, glomerular cell count was carried out. We found the average number of cell count per glomerular in 16 normal control cases to be 83 + 33 cells per glomerulus while in the snake bite case, the call count was 85 + 35 cells per glomerulus. However, in five cases (2 autopsies and 3 biopsies) focal mesangial proliferation with an occasional glomerulus showing 120150 nuclei per glomerulus was observed. If the criteria of Striker[21] were to be used, this could be categorised as equivocal cellularity.

Direct immunofluorescence was carded out on the 7 biopsies carded out from 198693. Weak (+) positivity for IgG (2 cases) and IgM (1 case) in the mesangial area, and C3 was also seen (+) in two cases. However, none of these cases revealed mesangial or endothelial proliferation. One other case revealed presence of fibrin in the mesangial area. On the other hand, DIF was negative in the cases with mesangial proliferation.

Incidence of tubular necrosis in cases of ARF following snake bite varies from 7080%[3],[4],[5],[6],[7],[8],[9],[10]. It was seen in 53.6% of cases. In surviving patients late biopsies from 3 to 8 weeks following the bite also revealed evidence of regeneration. Chugh et a1[4] have described infective complication more commonly in cases of bilateral renal cortical necrosis than in tubular necrosis, while in our series, two biopsies showed evidence of pyelonephritis complicating tubular necrosis and one autopsied case revealed abscesses. Haemorrhagic interstitial nephritis has been described by Sant & Purandare[17] in one case, it was observed in two of our cases.

Viperine snake venom contains proteases, amino acid esterases and nonenzymatic protein haemorrhagins as their constituents[22]. With small doses of the venom, the procoagulant action predominates[23] and intravascular coagulation and cortical necrosis results. Consumptive coagulopathy and bleeding diathesis results with higher doses[23]. Primary excessive fibrinolysis is rarely observed[24]. In 73.17% of our cases, DIC was observed and in 24.3% cortical necrosis was seen.

The presence of glomerular lesions in envenomated patients has aroused curiosity and controversy over the past few years. In 1960, Steinbeck[15] described a patient who developed nephrotic syndrome however, histopathology was not described. Sant & Purandare[17],[18],[19] and Tembe and Sant[19] described toxic proliferative glomerulitis with proliferation and swelling of endothelial cells, in six and three cases respectively. In their experimental studies too (rabbits and Bonnet monkeys) injection of echis Carinatus venom produced endothelial swelling (25%) and proliferation (30%). The earliest changes were seen by them within 12 hours. However, sections studied by them appear to be 6 microns in thickness. The actual thickness of sections studied has not been mentioned in the text. The ideal section thickness for studying kidney sections for glomerular changes is 2 to 3 microns. We have studied 3 microns thick sections. Increased thickness would give an erroneous impression of proliferation due to layering of nuclei. In our study, we found the average cell count in snake bite cases to be no different from the control, however, in five cases, focal equivocal increase in cellularity was observed. The significance of this is difficult to assess. Three of these cases wore biopsies from living patients and follow up available in two cases (6 mo, 3 yrs) did not reveal any deterioration in renal function. Secondly, direct immunofluorescence study carried out in one of these biopsies was negative. Three other biopsies with normal cell count revealed faint positivity with lgM, lgG or C3. Chugh et al[4] have reported hypocomplementemia following injection of lethal and sublethal doses of Russell's and saw scaled viper venom in Rhesus monkeys. However, in none of these, nor in their patients with ARF following snake envenomation, any significant glomerular changes were seen.

Mesangiolysis, ballooning of glomerular capillaries, endothelial swelling and splitting of GBM is seen in a significant number of our cases. In order to evaluate the significance of these findings, we analysed kidneys from 44 patients who had died of nonrenal conditions. 28 cases of methanol poisoning, 8 cases of septicaemia, 4 of burns were seen. Also included were two postoperative deaths (congenital heart disease) and one case each of myotarditis and aortitis. The glomerular changes are depicted in [Table:II].

45.4% of these showed endothelial swelling, 40.9% mild mesangial proliferation, 77.2% ballooning and4.5% revealed mesangiolysis. 11 cases of obstetric deaths with haemorrhage following labour or LSCS and four cases of haemolytic uraemic syndrome with cortical necrosis wore also studied. In the viable glomeruli, 53.3% cases revealed endothelial swelling and ballooning of capillaries in 66.6%. Mesangiolysis has been described in experimental studies with Habu snake venom[23]. This is thought to be due to the toxic action of the venom on the glomerular mesangium. However, it has been reported with a wide variety of conditions including chemicals[26], thrombotic microangiopathy, malignant hyperlension, radiation injury, rejected grafts and diabetes[27] etc.

Thus in our series glomerular changes have been observed in a significant number of cases of viperine envenomation, however, its significance is difficult to ascertain. Further studies and follow  up of cases would be required to confirm these findings.

::   Acknowledgment

References