Snakebite nephropathy (Review Article)

Blackwell Publishing AsiaMelbourne, AustraliaNEPNephrology1320-5358© 2006 The Author; Journal compilation © 2006 Asian Pacific Society of Nephrology2006115442448Review ArticleSnakebite nephrologyV Sitprija

NEPHROLOGY 2006; 11, 442–448 doi:10.1111/j.1440-1797.2006.00599.x

Review Article

Snakebite nephropathy

VISITH SITPRIJA

Queen Saovabha Memorial Institute and King Chulalongkorn Memorial Hospital, Bangkok, Thailand

SUMMARY: There is a broad clinical spectrum of renal involvement in snakebite. Besides the local and sys-
temic symptoms, clinical renal manifestations vary from mild proteinuria, haematuria, pigmenturia to acute renal
failure. Bites by haemotoxic snakes and myotoxic snakes are the common causes of renal involvement especially
acute renal failure. Therefore, renal failure is often associated with haemorrhagic diathesis, intravascular haemol-
ysis and rhabdomyolysis. Renal pathological changes include mesangiolysis, glomerulonephritis, vasculitis, tubu-
lar necrosis, interstitial nephritis and cortical necrosis. Tubular necrosis is an important pathological counterpart
of acute renal failure. Haemodynamic alterations induced by cytokines and vasoactive mediators leading to renal
ischaemia are important in the pathogenesis of acute renal failure. Haemolysis, intravascular coagulation and
rhabdomyolysis are important contributing factors. Direct nephrotoxicity can be induced by the venom through
metalloproteases and phosphilipase A2. Immunologic mechanism plays a minor role in the pathogenesis of the
renal lesion.

KEY WORDS: glomerulonephritis, haemodynamics, metalloproteases, phospholipase A2, renal failure,
snakebite.

Clinical toxicology from natural toxins is an important A highly vascularized organ, the kidney is prone to venom
health problem in the tropics. With biological diversities toxicity. Renal involvement in snakebite varies widely.7–10
and a favourable environment, tropical areas are rich in ani- Acute renal failure is frequently described and is life threat-
mals, plants, microbes and their toxins. Snake bites, animal ening. Haematuria and proteinuria are common. There is a
bites and stings are common occurrences, and snake bites broad spectrum of renal pathological changes.11–14 All renal
are the highest among animal toxin poisoning. The total structures are involved. A review of snakebite nephropathy
number of snake bites has been estimated to be 5.4 million is necessary due to the proliferation of clinical and scientific
per year, with 125 345 deaths, 100 000 of which were in data on the topic.
Asia and 20 000 in Africa.1 These data are perhaps under-
estimated due to the difficultly in accessing accurate data. CLINICAL RENAL MANIFESTATIONS

Snake venoms can cause cellular injury through Proteinuria, haematuria and acute renal failure are among
enzymes, polypeptide toxins, cytokines and mediators.2 the common clinical renal manifestations in snakebite.
Important venom enzymes consist of proteases, hydrolases,
hyaluroxidase, oxidases, phospholipases and esterases. Proteinuria
Among these enzymes, phospholipases A2 and proteases
(especially metalloproteases), contribute significantly to Proteinuria may be observed following snakebite. Pro-
tissue injury. Cytokines and vasoactive mediators are teinuria has been noted in rats following intrarenal injec-
responsible for inflammatory changes and haemodynamic tion of cobra venom.15 The incidence of proteinuria in
alterations that can ultimately lead to cellular injury.3–6 snakebite is variable depending on the kind of snakes
involved and there is also geographical variation. In a series
The clinical symptoms in snakebite vary from local pain, of 400 tropical snakebite patients proteinuria was observed
swelling and necrosis at the site of the bite to systemic in 4%.16 The magnitude of proteinuria is less than 500 mg/
involvement, including hypotension, haemorrhage, con- 24 h, and this is usually a transient finding which com-
junctival oedema, chemosis, central nervous system symp- pletely resolves when the patient recovers. However, signif-
toms, myalgia, paralysis, abdominal pain and renal failure.2 icant proteinuria over 1 g/24 h has been observed in 50% of
Russell’s viper bite patients in Myanmar, suggesting that
Correspondence: Dr Visith Sitprija, Queen Saovabha Memorial geographical variation can have an effect on the venom
Institute, 1871 Rama 4 Road, Bangkok 10330, Thailand. Email: composition of the snake of the same species.17 Despite
[email protected]; [email protected] heavy proteinuria the effect is temporary and completely

Accepted for publication 13 May 2006.
© 2006 The Author
Journal compilation © 2006 Asian Pacific Society of Nephrology

Snakebite nephrology 443

resolves during the recovery phase. Nephrotic syndrome in adults.23 Table 1 lists the snakes with myotoxicity and hae-
snakebite has been reported,18 but the cause and effect rela- motoxicity that can cause acute renal failure. The incidence
tionship was not substantiated. of acute renal failure caused by these snakes varies from 5%
to 29% depending on the species of snake and the severity
Haematuria of envenoming.7,23,24 The onset of renal failure is a few hours
to several hours after the bite. Renal angle tenderness may
Haematuria is often seen in the patient bitten by haemo- be observed. In a series of 123 patients bitten by Russell’s
toxic snakes, either viperid or crotalid snakes due to haem- viper, renal angle tenderness was noted in 39% and
orrhagic diatheses, and this can be either microscopic or hypotension noted in 35%.24 Renal failure may not be asso-
gross haematuria depending upon the severity of envenom- ciated with hypotension, however, transient hypertension
ation. The incidence can be as high as 35%.16 Although not has been observed. In viper bite renal failure may accom-
common, nephritic syndrome has been described in viper pany intravascular haemolysis or intravascular coagulation.
bite with pathological changes of diffuse proliferative and Haemoglobinuria and haematuria are observed. Haemolytic
crescentic glomerulonephritis.19,20 There is some diminution uraemic syndrome has been reported following haemotoxic
of renal function. The clinical outcome is usually favour- snake envenomation.25 In myotoxic snakebite renal failure
able; however, with associated tubular necrosis, renal failure is associated with muscular pain, weakness, myoglobinuria
can be severe. and high serum creatine phosphokinase due to rhabdomy-
olysis. In both instances hyperkalaemia may be of an alarm-
Pigmenturia ing degree. Renal failure is catabolic with rapid rises in
blood urea nitrogen and serum creatinine. Hyperuricaemia
Intravascular haemolysis is common in viperid and crotalid may be present. Nonoliguric renal failure is not uncommon.
snake bites. Haemoglobinuria is therefore frequently Renal failure averages 2–3 weeks in duration. Prolonged
observed in these haemotoxic snake bites. Haemolysis is renal failure with oligo-anuria is observed in the patient
preceded by erythrocyte swelling with the rise in haemat- with cortical necrosis or acute tubular necrosis associated
ocrit.21,22 Chelation of calcium by citrate decreases erythro- with either interstitial nephritis or extracapillary glomeru-
cyte swelling and raises the threshold for intravascular lonephritis. Acute glomerulonephritis in viper bite can
haemolysis.22 Rhabdomyolysis induced by phospholipase A2 cause mild renal failure.20 The patient usually completely
in myotoxic snake envenoming results in myoglobinuria. recovers except for those with cortical necrosis. Mortality in
Both haemoglobinuria and myoglobinuria are important in snakebite acute renal failure range from 1% to 20%.7,23,24
the pathogenesis of acute renal failure in snakebite. Bad prognosis is observed in the elderly and those with cor-
tical necrosis or severe haemorrhagic complications.10
Acute renal failure
MANAGEMENT
Snakes that cause renal failure are either myotoxic or hae-
motoxic snakes causing rhabdomyolysis, intravascular Specific antivenom treatment is important and this is usu-
haemolysis, disseminated intravascular coagulation (DIC) ally given before renal failure sets in. Monovalent antiven-
or haemorrhage. In tropical Asia acute renal failure (ARF) oms are preferred. Phasmapheresis and blood exchange have
in snakebite constitutes 1.2% of total acute renal failure in been used in snake envenomation where antivenom was
Thailand, 3% in India, and as high as 70% in Myanmar. unavailable.25,26 However, this is not practical since it has to
Children are more prone to develop renal failure than be performed very early before the venom fixes to the tissue.
Either peritoneal dialysis or haemodialysis is life saving.

Table 1 Snakes with nephrotoxicity Myotoxic snakes

Haemotoxic snakes Sea snakes (Family Hydrophidae)
Mulga snake (Pseudechis australis)
Russell’s viper (Daboia russelli siamensis) Rough-scaled snake (Tropidechis carinatus)
Saw-scaled viper (Echis carinatus) Taipan (Oxyuranus scutellatus)
Lance-headed viper (Genus Bothrops) Tiger snake (Notechis scutatus)
Puff Adder (Bitis arietans) Small-eyed snake (Cryptophis nigrescens)
Pit viper (Family Crotalidae)
Rattlesnake (Genus Crotalus)
Tiger snake (Notechis scutatus)
Brown snake (Genus Pseudonaja)
Taipan (Oxyuranus scutellatus)
Moccasin (Agkistrodon piscivorus)
Boomslang (Dispholidus typus)

© 2006 The Author
Journal compilation © 2006 Asian Pacific Society of Nephrology

444 V Sitprija

Dialysis should be performed early and frequently. Early and In humans, mild mesangial proliferative glomerulone-
frequent dialyses are important for the patient survival. phritis has been observed following the bite of Russell’s
Haemodialysis improves muscular symptoms in sea- viper, cobra, green pit viper and Habu snake.9 There is wid-
snakebite, and suggests that dialysis corrects hyperkalaemia ening of mesangial areas due to proliferation of mesangial
and removes some postsynaptic neurotoxin with small cells or an increase in the amount of mesangial matrix or
molecular weight.27 Renal failure should be prevented. both. Irregular thickening of the wall of peripheral capillary
Prompt treatment with specific antivenom is required. loops may be observed. In addition, mononuclear leucocytes
Maintenance of good urine flow is important. Alkalization and a small number of polymorphonuclear cells are occa-
of urine by sodium bicarbonate helps in the prevention of sionally present within glomerular capillary lumens. This is
acute renal failure in the patients with myoglobinuria or a non-specific finding and may be seen in other snake bites
haemoglobinuria provided that this is done early when dark also. Deposition of IgM and C3 in the glomeruli may be
urine is observed or the snake is known to be myotoxic or intense, negligible or absent depending upon the time renal
haemotoxic. In animal studies alkalization of urine prior to biopsy is performed. IgM and C3 deposition may be absent
envenomation prevents pathological changes and impair- when renal biopsy is performed early after the bite. In most
ment of renal function.28,29 In established acute renal failure, cases in which renal biopsy was performed late in the course
administration of sodium bicarbonate and mannitol can be of the disease, the deposition appears fine and granular and
dangerous and should be avoided due to fluid overload and is commonly located in the mesangial areas and sometimes
hyperosmololity. Dopamine and furosemide attenuated along the capillary loops.9 This is different from IgM mesan-
impaired renal function in animal model of Russell’s viper gial proliferative glomerulonephritis in which deposition of
envenomation at the early stage.30 In tropical infectious dis- IgM and C3 is more intense along the capillary loops. IgM
ease models, dopamine and furosemide given at the prerenal deposits are more prominent in Russell’s viper bite than in
failure stage induced diuresis and prevented renal failure. cobra bite and green pit viper bite. Deposition of C3 is more
There are no clinical data in the snakebite model. Of inter- intense in cobra cases. Fibrin deposition in the peripheral
est, hyperparathyroidectomy in a canine prior to Russell’s capillary loops and the Bowman’s space is observed in some
viper venom administration attenuated the decrease in green pit viper and Russell’s viper cases. Mesangiolysis is
glomerular filtration and renal blood flow.31 demonstrable in the patient bitten by Russell’s viper or
green pit viper.38
RENAL PATHOLOGY
In some instances the severe form of glomerulonephritis
All renal structures can be involved in snake may occur. Extracapillary proliferative glomerulonephritis
envenomation. with fibrin deposition and crescent formation without
immunoglobulins and C3 has been shown in puff adder
Glomerular changes bite19 and Russell’s viper bite.39 Diffuse proliferative glom-
erulonephritis can be observed in occasional green pit viper
Glomerular involvement in snakebite is often overlooked. bite victims.20
In animal experiments focal mesangial proliferative glomer-
ulonephritis can be induced by injection of Habu snake (Tri- Tubulointerstitial changes
meresurus flavoviridis) venom.32 Mesangiolysis is the early
appearance of the glomerular lesions.33,34 There is dissolu- Degeneration, necrosis, and regeneration of tubular epithe-
tion of the mesangial matrix. Hypercellularity of mesangial lial cells have been observed in renal failure following the
cells appears later as a healing reaction. The mesangial pro- bite by either haematotoxic or myotoxic snakes.7–9,40 These
liferative lesion is inhibited in the platelet-depleted animal. changes occur in any part of the renal tubule. Interstitial
Habu snake venom induced proliferation of mesangial cells oedema and cellular infiltration are observed. The infiltrates
with a significant elevation of monocyte chemoattractant consist of lymphocytes, plasma cells, and mononuclear
protein (MCP-1) mRNA. Positive storming of MCP-1 is phagocytic cells. Interstitial lesions are more prominent in
shown in the marginal area of glomeruli with mesangiolysis. the area where there is tubulorhexis. In haemotoxic snake-
Extracellular matrix glycoprotein tenascin C expression, bite fine granules of haemoglobin can be observed in the
especially domain D and platelet-derived growth factor, are proximal tubular cells, and haemoglobin casts are seen in
significant in the healing process of glomerulonephritis.35,36 the lumen of necrotic tubules. In myotoxic snakebite the
Vascular endothelial growth factor regulates angiogenesis tubules contain myoglobin casts. Mild tubular degeneration
and plays an important role in capillary repair and resolu- is present in green pit viper bite and has been observed occa-
tion of glomerulonephritis. Over the course of the disease sionally in cobra bite. Tubular necrosis is the common cause
mesangial cells migrate into the lesion, proliferate and form of acute renal failure in snakebite.
a confluent cellular mass. Fibronectin derived from platelets
and macrophages provides a matrix with mesangial cell Acute diffuse interstitial nephritis has been observed in
migration into glomerular lesions. The venom of Bothrops Russell’s viper bite.11,12,41,42 There is diffuse and intense
moojeni can also cause mesangiolysis, glomerular micro- interstitial infiltration with mononuclear cells out of
aneurysm and proteinuria in rats.37 proportion to tubular degeneration. Immunofluorescence
study shows no deposition of immunoglobulins and
complement.

© 2006 The Author
Journal compilation © 2006 Asian Pacific Society of Nephrology

Snakebite nephrology 445

Vascular changes pressin and acute phase response.48 Histamine, kinins,
eicosanoids, platelet activating factor, catecholamines and
Segmental necrotizing arteritis of the interlobular arteries endothelin are among the involved mediators. Zinc metal-
has been described in Russell’s viper bite.9,43 The lesion loprotease can cleave glutathione-S-transferase-tumour
could have been missed if the renal biopsy was superficial. necrosis factor-alpha fusion protein (GST-TNF-α) substrate
Segmental thrombophlebitis of the arcuate vein and its trib- to generate biologically active TNF-α.49 In a recent study of
utaries has been reported in both Russell’s viper bite and vasoactive mediator release following Russell’s viper
green pit viper bite.9,43 Deposition of C3 without immuno- envenomation the plasma concentrations of norepinephine,
globulins in the wall of necrotizing arteries is demonstrable. epinephrine, dopamine, thromboxane B2, endothelins and 6
Deposition of C3 in the wall of afferent and efferent arteri- keto PGFα were elevated.5 Besides these vasoactive media-
oles without any vascular change has been shown in both tors cytokines are important in cellular interaction in a
viper bite and cobra bite patients. variety of immunological and inflammatory processes.
Envenomation of mice by the venom of Bothrops asper
Renal infarction and cortical necrosis and Bothrops jararaca induced striking elevations of serum
TNF-α, IL-1, IL-6, IL-10 IFN-γ and NO.50,51 The effects of
In animal experiments, renal infarction has been demon- cytokines and vasoactive mediators are reflected by haemo-
strated following crotalid snake venom administration.44 In dynamic changes and immune response. Snake venom poi-
human, haemorrhagic infarct has been observed in the soning shares the same inflammatory process as infection or
patients bitten by rattlesnake and Russell’s viper. Fibrin sepsis with the roles of cytokines, mediators, complement
platelet thrombi appear in interlobular arteries within or activation, reactive oxygen species and immunologic reac-
near the infarcted areas. Necrotic tubules containing hae- tion. Haemodynamic changes therefore play an important
moglobin casts are demonstrable. role in snake envenomation. Figure 1 summarizes the patho-
genesis of nephropathy in snakebite.
Cortical necrosis has been observed following the bite of
Russell’s viper, Echis carinatus, Bothrops jararaca, and Agki- SNAKE VENOM
strodon hypnale.14,45–47 The lesion is associated with dissemi-
nated intravascular coagulation. There is necrosis of all IMMUNE CYTOKINES DIRECT INJURY
elements of the kidney with thrombi in the renal vascular RESPONSE MEDIATORS
bed. In cases with recovery there is residual impairment of ADHESION MOLECULES
renal function, and calcification of the renal cortex may be INTERSTITIAL
seen by radiography.45,47 NEPHRITIS HEMOLYSIS
MYONECROSIS
The relationship between renal pathological changes
and clinical renal manifestation is shown in Table 2. INTRAVASCULAR
COAGULATION
PATHOGENESIS
RBF HEMORRHAGE
The pathogenesis of renal lesions in snakebite is complex VASCULITIS
involving both the direct action of venom on the kidney
and the inflammatory effects due to the release of various MESANGIOLYSIS
endogenous cytokines and mediators. Phospholipase A2, an
important toxic component of the venom, stimulates TUBULAR NECROSIS
hypothalamus-pituitary and immune axes to increase ader- CORTICAL NECROSIS
enocorticotrophic hormone, corticosteroid, arginine vaso- GLOMERULONEPHRITIS

Fig. 1 Pathogenisis of nephropathy in snakebite. RBF, renal
blood flow.

Table 2 Clinicopathological correlation Clinical renal manifestation

Pathology Normal renal function, normal urine finding, or haematuria
Normal renal function, normal urine finding or haematuria, or mild
Mesangiolysis
Mesangial proliferative glomerulonephritis proteinuria, occasional heavy proteinuria with complete resolution
Mild renal failure, haematuria, proteinuria
Diffuse proliferative glomerulonephritis Severe renal failure and haematuria with prolonged
Extracapillary proliferative glomerulonephritis clinical course
(usually associated with tubular necrosis) Severe renal failure with prolonged clinical course
Vasculitis (usually associated with tubular necrosis) Acute renal failure
Tubular necrosis Severe renal failure with prolonged clinical course
Acute diffuse interstitial nephritis(usually associated
Severe acute renal failure with residual damage or without recovery
with tubular necrosis)
Cortical necrosis

© 2006 The Author
Journal compilation © 2006 Asian Pacific Society of Nephrology

446 V Sitprija

Haemodynamic alterations unchanged, presumably due to the effect of natriuretic pep-
tides in the venom.55,56
Haemodynamic changes in snakebite vary among snakes
involved. In a study of Russell’s viper envenomation in Although haemodynamic changes are basic in the devel-
canines, initially the cardiac output was decreased, systemic opment of ARF, the duration of decreased GFR and RBF
vascular resistance (SVR) and renal vascular resistance and the associated complications are important. There is
(RVR) was increased; the renal blood flow (RBF) and the good correlation between the renal function and the
glomerular filtration rate (GFR) were decreased.52 Haemo- haematologic profile in viper bite.57 Additional insults
dynamic changes are consistent with the effects of vasocon- including haemoglobinuria, myoglobinuria, haemorrhage,
strictive mediators. The decreased cardiac output is believed complement activation and reactive oxygen species play
to be attributed to the effect of thromboxane A2 resulting in contributing roles in prolonging the duration of decreased
pulmonary artery constriction and decreased blood return to GFR and RBF. Experimentally, cobra envenomation causes
the heart. Later at 6.00 h after envenomation the cardiac the decrease in GFR and RBF of short duration without
output was increased; SVR was decreased; RVR was mark- developing ARF, while Russell’s viper and sea snake
edly increased; RBF and GFR further decreased (Fig. 2). envenomation, which cause longer duration of renal
Haemodynamic alteration at this stage is similar to that of ischaemia associated with DIC, haemoglobinuria and
sepsis with prominent effects of NO and PGI2 on systemic myoglobinuria result in the development of acute renal
circulation and the effect of vasoconstrictive mediators on failure.29,52
the kidney. In a sea snake study envenomation by Lapemis
hardwicke in canines revealed there was no change in car- Direct nephrotoxicity
diac output (CO) and SVR, but RVR was increased.29 RBF
and GFR were decreased, and renal failure developed. There Renal failure has been observed in patients a few hours after
was no change in renal haemodynamics when sodium bicar- snakebite without hypotension, haemorrhage, intravascular
bonate was given before envenomation.29 Renal failure was haemolysis and rhabdomyolysis. The clinical evidence sug-
prevented. It was suggested that decreased RBF and GFR gests direct nephrotoxicity of the venom. Mesangiolysis,33,34
were due to renal tubular obstruction by myoglobin. Sodium glomerulonephritis19,20,39 and vasculitis9,38 without immuno-
bicarbonate prevents tubular obstruction thus maintaining logic clues indicate direct glomerular and vascular injury
RBF and GFR. Intravenous injection of cobra venom (Naja by the venom. Venomous snakes have enzymes that can
kaouthia) in canines decreased GFR and RBF of short dura- directly cause cellular injury. Metalloprotease can cause pro-
tion without causing renal failure. teolysis of the extracellular matrix and disrupts cell-matrix
and cellular adhesion. The enzymes are present in the ven-
In isolated renal perfusion there are great variations in oms of snakes in the Viperinae and Crotalinae subfamilies,58
venom effects not only among different snakes but also and bind with various degrees of specificity to integrin alpha
among snakes of the same genus but different subspecies. 4 beta 1, alpha 4 beta 7, alpha 5 beta 1, alpha 6 beta 1, alpha
However, in most snake envenomations, the glomerular fil- 9 beta 1, alpha V beta 3 and alpha V beta 5, expressed on
tration rate and renal blood flow are decreased where renal cells.59–61 Integrity of cellular junctions is disrupted as a
vascular resistance is increased.53–55 In a study of Bothrop result of disruption of the actin cytoskeleton resulting in a
moojeni venom, decreased RVR and increased RBF were loss of cell polarity. Integrins which are critical for cellular
observed following envenomation.55 GFR remained adhesion, redistribute away from the basal cell surface, con-
tributing to the loss of adhesion to the basement membrane.
110 Metalloproteases can induce apoptosis of vascular endothe-
lial cells.62 Phospholipase A2 enzymes are present in several
90 poisonous snakes including crotalids, viperids, elapids and
hydrophids. The enzymes are toxic and induce a wide spec-
70 trum of pharmacological effects. Phospholipase A2 can
cause membrane injury and tubular necrosis. The enzymes
Change (%) 50 interact with the biological membranes via a distinct molec-
ular region. This active region is likely to be formed by a
30 combination of basic hydrophobic amino acid residues near
the C-terminal of the protein. The high affinity interaction
10 of PLA2 with its target protein is probably due to the inter-
action of charges, hydrophobicity and van der Waal’s con-
0 tact surfaces between the toxin and the binding site as the
surface of the cell membrane.63,64 These events lead to mem-
–10 brane destabilization and loss of permeability and cellular
necrosis. In animal experiments, Bothrops moojeni crude
–30 venom decreases transepithelial electrical resistance across
the cultured Madin-Darby canine kidney (MDCK) cell
–50 24 h 48 h monolayers, causes disarray of the cytoskeleton and impairs
2h cell to matrix adhesion.37 Bothrops venom decreased neutral

Post-envenomation © 2006 The Author
Journal compilation © 2006 Asian Pacific Society of Nephrology
Fig. 2 Haemodynamic changes in Russell’s viper envenoma-
tion. ᭿, cardiac output; , glomerular filtration rate; , renal
blood flow; , renal vascular resistance; ᮀ, systemic vascular
resistance.

Snakebite nephrology 447

red uptake of vero cells.65 Notexin from tiger snake venom vein endothelial cells. J. Med. Assoc. Thai. 2001; 84 (Suppl 1):
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Journal compilation © 2006 Asian Pacific Society of Nephrology