|Year : 2021 | Volume
| Issue : 1 | Page : 146-156
|Chronic Kidney Disease after Snake Envenomation Induced Acute Kidney Injury
Kishore Ariga1, Tarun Kumar Dutta1, Satish Haridasan2, Priyamvada Sivan Pillai Puthenpurackal2, KT Harichandrakumar3, Sreejith Parameswaran2
1 Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
2 Department of Nephrology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
3 Department of Medical Biometrics and Informatics, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
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|Date of Web Publication||16-Jun-2021|
| Abstract|| |
Snake bite is an important cause for acute kidney injury (AKI) in the tropics and the victims are often otherwise healthy young adults without conventional risk factors for chronic kidney disease (CKD). Available literature on long-term outcomes of AKI –snake envenomation is limited, with only two small retrospective studies with follow-up periods of two years or less. In a hospital-based prospective and retrospective follow-up study, all consecutive adult patients who developed AKI and discharged alive were recruited in the prospective group and for retrospective analysis, we retrieved medical records of patients hospitalized with snake bite from the digitized medical records. Clinical and biochemical characteristics during hospitalization and on follow-up were collected. We recruited 193 patients with snake bite and AKI in a prospective (140) and a retrospective (53) group. Of the 193 AKI patients, 162 (84%) had estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at the time of discharge from hospital and at follow-up (n = 171) 29 (16.9%) had eGFR<60 mL/min/1.73 m2. Of the 116 patients with follow-up beyond one year, 30 (26%) had CKD. Overall 26 to 28% of patients went on to develop CKD depending on the duration of follow-up. Only very few (1.16%) patients progressed to ESRD. This is the largest follow-up study so far on snake bite-related AKI and provides further evidence that snake bite-associated AKI causes CKD on long-term follow-up. Older age, diabetes, severe AKI, and inadequate anti-snake venom administration were risk factors for the development of CKD on follow-up.
|How to cite this article:|
Ariga K, Dutta TK, Haridasan S, Pillai Puthenpurackal PS, Harichandrakumar K T, Parameswaran S. Chronic Kidney Disease after Snake Envenomation Induced Acute Kidney Injury. Saudi J Kidney Dis Transpl 2021;32:146-56
|How to cite this URL:|
Ariga K, Dutta TK, Haridasan S, Pillai Puthenpurackal PS, Harichandrakumar K T, Parameswaran S. Chronic Kidney Disease after Snake Envenomation Induced Acute Kidney Injury. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2021 Sep 17];32:146-56. Available from: https://www.sjkdt.org/text.asp?2021/32/1/146/318516
| Introduction|| |
Snake envenomation (SE) is an occupational hazard for people engaged in farming and is an important cause of acute kidney injury (AKI) in many regions in tropics and subtropics. AKI is a devastating complication, with mortality rates of up to 21%–50% in snake bite victims., In 15%–84%, AKI is severe enough to necessitate institution of renal replacement therapy (RRT) and despite surviving the episode, about 40% of patients are discharged with incomplete recovery of renal function.,,,,, AKI and chronic kidney disease (CKD) are now well recognized as interconnected syndromes, with increasingly convincing evidence that AKI episodes lead to CKD later in life. Severity of AKI, number of episodes of AKI, duration of AKI, and comorbidities are known to influence the risk of CKD.,, A meta-analysis by Sawhney et al reported that the long-term prognosis after AKI in influenced by the cause and the clinical setting. AKI from SE (AKI–SE) typically is community acquired and the victims are often otherwise healthy and physically active adults. In view of the unique settings, in which AKI–SE develop; it is conceivable that the long-term outcomes of AKI–SE may be different from AKI in other settings. Available literature on long-term outcomes of AKI–SE is limited, with one study from Sri Lanka reporting outcomes at one year for 54 patients and another study from India reported outcomes in 60 patients for an average of 45 months. Both were retrospective studies with small sample size and limited follow-up duration. We studied the long-term renal outcome in patients with snake-bite-related AKI in a larger sample size over a longer period and identified clinical and laboratory factors predictive of renal outcomes.
| Methods|| |
The institute ethics committee approved the study. All the patients provided written informed consent before inclusion. No industry support was provided.
Setting and study participants
This study was a hospital-based prospective and retrospective follow-up study done in a tertiary care academic medical center in the public sector, from July 2012 to March 2014. All consecutive patients who developed AKI [Kidney Disease: Improving Global Outcomes (KDIGO) definition], survived the episode and were discharged alive from the hospital were recruited to constitute the prospective group. For retrospective analysis, we retrieved medical records of patients hospitalized with snake bite from the digitized medical records of our hospital for the period 2005–2012.Out of 850 case records [2005 (40), 2006 (Nil), 2007 (Nil), 2008 (80), 2009 (220), 2010 (260), 2011 (150), 2012 (90)], we excluded children, animal bites other than those identified as snake bite, snake bite with neurotoxic envenomation without AKI, patients who expired and patients whose medical records were incomplete with regard to details of envenomation and renal function tests. The rest of the patients were contacted by means of phone calls and written communications and requested to report to the hospital for tests.
In the prospective group, information regarding details of snake bite, treatment with anti-snake venom (ASV), comorbidities, RRT, duration of hospital stay, serum creatinine at discharge, blood pressure at discharge, details of systemic manifestations at admission regarding disseminated intravascular coagulation (DIC), hemolysis, cellulitis, bleeding manifestations, capillary leak, hypotension, and sepsis were noted. In the retrospective group, same information was collected by review of records. In India, polyvalent ASV is effective against all the four-common species; Russell's viper, common cobra, common Krait, and saw-scaled viper and no monovalent ASVs are available. Each vial of polyvalent ASV available in India contains antivenom against Naja 0.60 mg, Bungarus caeruleus 0.45 mg, Daboia ruselli 0.60 mg, and Echis carinata 0.45 mg. Dose of anti-snake venom – Each vial is 10 mL of reconstituted ASV. Total required dose will be between 10 vials to 30 vials usually. After 6 h of initial dose, a further coagulation test is performed, and a further dose administered in the event of continued coagulation defect.
Participants were selected if they fulfilled the criteria of (a) age >18 years, and (b) AKI as defined by KDIGO Clinical Practice Guideline, and those with previously diagnosed CKD patients or having contracted kidneys on ultrasound during the acute episode were excluded. All patients in the retrospective cohort were reclassified to KDIGO Staging by an independent observer.
A detailed history was taken in the prospective cohort and during the stay in hospital, information regarding ASV administration, amount of ASV, admission creatinine value, oliguria, anuria, dialysis requirement, indication for dialysis, number of dialysis session, days of hospital stay, and discharge creatinine were noted. Urine routine microscopy was done for all the patients. Ultrasound kidneys and urinary bladder were done to see the kidney morphology and to rule out CKD. Patients in the prospective group were asked to report for follow up visits at 1, 3, 6, and 12 months and then once in a year. Symptoms, blood pressure, serum creatinine, estimated glomerular filtration rate (eGFR) [4 variable Modification of Diet in Renal Disease (MDRD) equation] andurine albumin were recorded at every follow-up visit.
In the retrospective group, baseline information was collected from medical records. History was noted from case records about the age, occupation, comorbidities such as diabetes mellitus, hypertension, renal stone disease or cardiac disorder, site, time of the snake bite, dialysis details, and days of hospital stay. Information regarding outside hospital admission, ASV administration, the amount of ASV given and time gap between ASV and snake bite in outside hospital was noted from the records brought by the patients. Symptoms, blood pressure, serum creatinine, eGFR (four variable MDRD equation), and urine albumin were recorded when the subjects reported for the follow-up visit. The duration since the AKI episode was noted, along with any significant medical events in the intervening period.
High participation rate was ensured to achieve a representative cross-section of the population. Follow-up of 65.7% was within the range of recommended follow-up threshold for cohort studies. Information bias was avoided by adhering to data noted down in the records.
| Statistical Methods|| |
Sample size was estimated with an expected prevalence of kidney dysfunction in patients with snake-bite AKI in one-year period as 10%. The minimum sample size required for the study was estimated to be 138 with 5% precision and 95% confidence interval.
Sample size of both prospective and retrospective groups together was 193. In the prospective group, follow-up data beyond three months after discharge from hospital was available for 84% (n = 118) of patients, with more than one-year follow-up data available for 45% (n = 63). The minimum and maximum follow-up duration was 91 days and 712 days, and 746 days and 2985 days, respectively, in the prospective and retrospective cohorts. Outcome analysis was done for 171 patients with 118 patients from prospective and 53 from retrospective group. Data were entered in Microsoft Excel and analyzed using IBM SPSS Statistics version 20.0 (IBM Corp., Armonk, NY, USA) and GraphPad InStat softwares. The data on all clinical and laboratory parameters which are continuous are expressed as mean with standard deviation or median with interquartile range based on the normality of the data. All categorical variables related to clinical and laboratory parameters are expressed as frequencies and percentages and compared using Chi-square test or Fisher’ s exact test. The baseline continuous variables between groups were compared using Student’s t-test or Mann–Whitney U-test whichever is appropriate. All statistical analysis was carried out at 5% level of significance and P <0.05 considered as significant.
| Results|| |
A total of 193 patients with snake bite and AKI were identified and included in the prospective (140) and the retrospective (53) study groups. Follow-up data were available for 171 patients [Figure 1]. The median follow-up duration was 432 days (273–1053). Minimum follow-up duration was three months and maximum were eightyears. The baseline characteristics of these patients are presented in [Table 1].
In most of the incidents, snake was not identified and the median bite-to-needle time of 180 minutes. Among all patients who were treated with ASV (n = 160), 58% (n = 94) received ASV at the referring hospital itself) before reaching our center. The severity of envenomation can be assumed by the symptoms, signs and laboratory parameters enumerated in [Table 1]. Significant number of cases had extensive cellulitis (84%), thrombocytopenia (83.4%), DIC (34%), and intravascular hemolysis (51.3%). Thrombocytopenia (RR-1.7; 1.04–2.82), DIC (RR-1.6; 1.24–2.12), hemolysis (RR -2.1; 1.56–2.8), capillary leak (RR-1.7; 1.37–2.12) and systemic bleeding were present in higher proportion in dialysis group with statistically significant risk association.
Of the 193 AKI patients, 162 (84%) had eGFR <60 mL/min/1.73 m2 at the time of discharge from hospital and at follow-up (n = 171), 29 (16.9%) had eGFR<60 mL/min/1.73 m2. Of the 116 patients with follow-up beyond one year, 30 (26%) had CKD. Overall, only very few (1.16%) patients progressed to ESRD on follow-up [Table 2].
[Table 3] shows the comparison between those who had progressed to CKD to those who had completely recovered renal function. The stage-wise distribution of patients who developed CKD on follow up is depicted in [Figure 2]. In univariate analysis age, female gender, diabetes, hypertension, dialysis-dependent AKI, days of hospital stay, serum creatinine (eGFR) at admission and discharge, and total dose of ASV received had statistically significant between-group differences. In cases with more than one-year follow-up, those without CKD had parameters of age, diabetes, dialysis-dependent AKI, total ASV dose, and serum creatinine at discharge significantly different from the CKD cohort. Diabetes, hypertension, and low ASV dose (<100 mL) had significant relative risks of 4.4, 3.1, and 2.1, respectively, about long-term outcome of CKD. Out of 17 patients who were newly found to be hypertensive in hospital, seven patients continued to be hypertensive while the remaining became normotensive.
|Figure 2: Stage-wise distribution of patients who developed CKD on follow-up.|
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|Table 3: Comparison between CKD and non-CKD after minimal follow-up and follow-up more than one year.|
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Six patients underwent renal biopsy during the hospital stay, two biopsies revealed ATN, and four patients had marked acute interstitial nephritis and were treated with 1 mg/kg of steroids for six to eight weeks. One of the patients treated with steroids completely recovered, two recovered partially with eGFR <60 mL/min/1.73 m2 (at >240 days follow-up) and one developed ESRD.
| Discussion|| |
SE is an important cause of AKI in India, as evident from the large number of patients recruited in the study over a period of 21 months. This form of AKI is typically “community acquired” with relatively young, otherwise healthy adult subjects without comorbidities, being the victims, which is also apparent from the characteristics of our patients. Data from various parts of India have underscored certain risk factors for developing AKI after a poisonous snake bite, including age <12 years, time from snakebite to receiving antivenom >2h–12h, cellulitis, regional lymphadenopathy, vomiting, muscle pain, abdominal pain, hypotension, hyperbilirubinemia, intravascular hemolysis, coagulopathy, and dark or brown urine color. Patients seeking treatment from practitioners of indigenous medicine with ensuing delay in administering ASV, severe envenomation (cellulitis, vomiting, and coagulopathy) and AKI was the usual pattern in most of the studies.,,,,,, In this study, severity of systemic envenomation indicated by thrombocytopenia, DIC, capillary leak and hemolysis correlated with the severity of AKI and requirement of dialysis; with 54.9% receiving a median of three sessions of dialysis. Mean hospital stay was 11.9 ± 9.7 days similar to other cohorts of snake bite AKI (12.4 ± 7.7 days) and a median of 31 (16–39) ASV vials was administered which was more than the national standards (25 vials) in several instances., Nationwide, there is an average incidence of 15.0%–55.0% of dialysis in snake-bite AKI, while some report even 100% incidence.,,,,, Snake-bite AKI is consequential on account of the dire outcomes of longer duration of hospitalization, greater requirement for RRT, and high mortality rate. We found that, overall, 26%–28% of our subjects went on to develop CKD depending on the duration of follow-up.
The apparent correlation of severity of AKI with subsequent risk of progression to CKD is brought out in our study. A higher serum creatinine at presentation and at discharge, oligo-anuria, stage III AKI, severe AKI necessitating RRT, and duration of hospital stay were all predictive of progression to CKD. This observation is consistent with previous studies which have demonstrated severity of AKI as a robust predictor of progression to AKI. Advanced age, dialysis-requiring AKI, and duration of RRT have been associated with 28-fold risk of developing CKD Stage 4/5., In a retrospective analysis of snake-bite AKI followed up for one year, 20/54 (37%) patients had developed CKD on follow-up. In our analysis also, older age group were more predisposed to develop CKD. Among the patients who required dialysis during hospitalization, 36.8% developed CKD during follow up, like the rates reported by previous studies., Out of the patients who did not require dialysis 17% had developed CKD. Having diabetes mellitus (RR 4.4) and requiring dialysis during hospitalization (RR 1.9) were significant risk factors for developing CKD later.
Studies by Herath et al and Waikhom et al reported that 37% and 40% of patients respectively had progressed to CKD on long-term follow-up., The study by Herath et al had follow-up duration of one year, whereas Waikhom et al followed up patients for mean duration of 45.34 months and persistent renal abnormalities with functional derangement, hypertension, or proteinuria were seen in 41% at the end of follow-up. Both these studies followed up only those patients who underwent dialysis and hence those with more severe renal failure. The difference in follow-up duration might also explain the lower incidence of CKD in our population because some patients may develop CKD after many years of AKI [Table 4].
|Table 4: Comparing present study with previous two long term follow-up studies.|
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In the retrospective group, 11 (20.7%) out of 53 patients developed CKD on follow-up. Follow-up duration was 1.2 to 8 years. In the retrospective group, out of 41 patients who had follow-up duration of more than three years, 10 (24.4%) patients developed CKD. Out of 13 patients with follow-up duration of more than four years, four patients developed CKD. However, this might as well be due to selection bias; it is possible that patients who were symptomatic or were told to have kidney disease responded to our invitation while others who were healthy did not respond and hence were not included in the study.
It appears that treatment with ASV may also influence progression to CKD. Patients who received ASV less than 100 mL had 2.4 times the risk of developing CKD with reference to more than 100 mL ASV. This observation is relevant in the context of previous reports suggesting beneficial role of prompt administration of ASV in preventing AKI.,,,,
Given the fact that 84% of our patients were attended to elsewhere before being referred to our center, it is curious to note that only 58% of patients (out of 162 patients for whom information on ASV administration was available) had received ASV before reaching JIPMER. The reasons behind this apparent delay in instituting specific treatment needs further study and is possibly a window of opportunity in this patient population for prevention of AKI and its consequences. An observational prospective case–control study may help to compare earlier institution of ASV, incidence of AKI, severity of AKI, and long-term outcomes including mortality.
The most frequent renal histological abnormality found in snake venom-associated AKI is acute tubular necrosis (70%–80%) and a small minority develop acute cortical necrosis (ACN) or acute interstitial nephritis (AIN). Injury due to ATN and AIN may recover by few weeks, but ACN often requires long-term RRT., In various reports, acute interstitial nephritis cases were characterized by severe envenomation, very high ASV requirement, and prolonged renal dysfunction., Out of the four biopsy-proven acute interstitial nephritis in our study, three progressed to CKD in spite of steroid therapy.
Our patients were young, and it is possible that prevalence of CKD in this cohort may progressively increase, with passage of time. While evaluating a patient with CKD of no apparent etiology, it may be prudent to inquire about history of AKI–SE in the remote past, in areas where SE is endemic.
Our observational study has several strengths but also some notable limitations. Given the observational nature, this cannot be a complete comparison of the effect of factors on the long-term renal outcomes. All patients could not be followed up, thereby compromising our ability to properly ascertain outcomes. The profile of patients seeking health care at our institution is such that regular and long-term follow-up, especially following acute illnesses (vs. chronic diseases like DM, CAD, CKD, etc.) is poor, particularly if symptoms subside completely. Overall, we were able to collect follow-up information at or beyond one year for 116 patients (63 from the prospective group and 53 from the retrospective group). Follow-up data at or beyond three monthswas available for 171 patients. This prevented us from analyzing the renal function at specific time points of follow-up from the index event. Information was not available for a significant number of patients regarding bite needle time and coagulation profile and snake could not be identified in most of the cases. Besides, the follow-up duration was not uniform in all the patients and we did not collect data on mortality in this cohort. Nevertheless, this study reaffirms the link between AKI and CKD with increased risk in diabetics, severe AKI, and elderly.
| Conclusion|| |
This study provides further evidence that SE associated AKI causes CKD on long-term follow-up, even in a young and otherwise healthy population. Factors like advancing age, diabetes, severe AKI with dialysis requirement, and inadequate ASV administration are all risk factors for the development of CKD on long-term follow-up. After SE-related AKI 1.16% of patients progressed to ESRD on follow-up. Snake bite AKI may be contributing to the burden of CKD in regions where SE is common.
Conflict of interest: None declared.
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Department of Nephrology, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]
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