Abstract
Introduction
Acute Renal Failure (RF) is a rare but well recognized complication of Dengue Infection (DI). There has been paucity of published data regarding renal involvement in DI.
Aim
The aim of the present study was to elucidate different clinical presentations, disease outcomes of DI. To study the frequency, severity and predictors of RF in DI.
Materials and Methods
Patients diagnosed either as Dengue Fever (DF) or Dengue Haemorrhagic Fever/Dengue Shock Syndrome (DHF/DSS) respectively were enrolled for this study. The diagnostic criteria for DI were febrile illness associated with one of the following: 1) detection of dengue-specific IgM capture antibody or Non-Structural Protein1 (NS1) antigen; or 2) a four-fold or greater increase of dengue-specific IgG capture antibody by ELISA and haemoagglutination inhibition assay. Patients were diagnosed as having Acute RF, if serum creatinine was >1.2 mg/dl or who showed improvement by 50% in serum creatinine from the initial value. It is an observational study of medical charts, data of age, gender, and medical history of any underlying diseases in association with the severity of DI of each patient recorded. All of the laboratory results were collected. Parameters that influenced the clinical presentations and outcomes for development of classical DF or DHF/DSS in patients with or without RF were analysed and compared. Descriptive and inferential statistical analysis was carried. The Statistical software namely SAS 9.2, SPSS 15.0, Stata 10.1, Med Calc 9.0.1, Systat 12.0 and R environment ver.2.11.1 were used.
Results
Most common symptoms were fever followed by headache and pain in abdomen. Among the patients with RF, all patients had recovery. The patients with DHF/DSS were more susceptible to develop renal failure compared to DF group. There were statistically significant higher frequencies of renal failure, haemoconcentration, thrombocytopenia, low serum cholesterol. Patients in the RF group also had significantly higher percentages of shock, haemoconcentration, thrombocytopenia, raised AST and low serum cholesterol compared to non-RF group. There were no mortality and none of them had to receive renal replacement therapy during hospitalization.
Conclusion
Patients with DHF/DSS were more susceptible to develop renal failure compared to DF group. Patients in the RF group had higher percentages of shock, haemoconcentration, thrombocytopenia, raised AST and low serum cholesterol.
Keywords: Cholesterol, Fever, Headache, Renal replacement therapy, Thrombocytopenia
Introduction
Dengue infection (DI) is a tropical illness caused by Dengue virus [1]. The incidence of DI is increasing at estimate of 50 to 100 million cases per annum worldwide [2]. The presentation of DI can be a classical Dengue Fever (DF) or Dengue Haemorrhagic Fever (DHF) or Dengue Shock Syndrome (DSS) [2]. Acute RF is a rare but well-recognized complication of DI, with an incidence which varies from 0.3% to 3.3% in different populations [3]. The presence of comorbid illness like diabetes mellitus, hypertension can have impact on prognosis of DI [2]. To our knowledge, there has been paucity of published data regarding renal involvement in DI. The aim of this study was to elucidate about different clinical presentations, disease outcomes of dengue viral infection and to study the frequency, severity and predictors of RF in DI.
Materials and Methods
Participants and Definitions: From January 2013 to January 2015, 101 patients diagnosed either as DF or DHF/DSS at Vydehi Hospital were enrolled for this study from the total of 139 DI patients after satisfying inclusion/exclusion criteria. The diagnostic criteria for DI were febrile illness associated with one of the following laboratory confirmation tests: 1) detection of dengue specific IgM capture antibody or NS1 antigen; or (2) a four-fold or greater increase of dengue-specific IgG capture antibody by ELISA and haemoagglutination inhibition assay in paired serum samples.
Cases with only a single positive dengue IgG result or without detailed history were excluded. Patients with no serum creatinine data at admission or with incomplete demographic data were excluded.
According to the criteria from the World Health Organization (WHO), patients who have DF and haemorrhagic manifestations, low platelet count, and objective evidence of leaky capillaries (≥20% elevation in haematocrit, lower serum albumin, and pleural or other effusions) were classified as having DHF (WHO classification, DHF grades I/II). Those with evidence of circulatory failure (pulse pressure ≤20 mmHg, hypotension, or frank shock) were classified as having DSS (WHO classification, DHF grades III/IV) [2]. Patients were diagnosed as having Acute RF, if serum creatinine was >1.2 mg/dl or who showed improvement by 50% on follow up from initial serum creatinine [4,5].
Study Design: It is an observational study of medical charts, demographic data of age, gender, and medical history of any underlying diseases in association with the severity of dengue infection of each patient recorded. All of the laboratory results at first hospital visit were collected for statistical analyses. The recording of underlying chronic diseases like hypertension, diabetes mellitus was done. Proteinuria was defined as urinary protein appearing ≥1+ (30mg/dl) by dipstick test [6], and microscopic haematuria was defined as >5RBC/HPF [7]. Parameters that possibly influenced the clinical presentations and outcomes for development of classical DF or DHF/DSS in patients with or without RF were analysed and compared.
Study hypothesis was based on: a) varying clinical presentations, disease outcomes of DI; b) higher incidence of bleeding tendency, shock, proteinuria, haemoconcentration, thrombocytopenia, low serum cholesterol in RF group in DI; and c) higher incidence of bleeding tendency, shock, proteinuria, RF, haemoconcentration, thrombocytopenia, low serum cholesterol in more severe forms of DI like DHF/DSS.
Statistical Analysis
Descriptive statistical analysis was done for parameters like raised transaminases, raised LDH level and inferential statistical analysis was done for parameters like incidence of bleeding tendency, shock, proteinuria and RF, haemoconcentration, thrombocytopenia, low serum cholesterol, where statistically significant p-value was found. Results on continuous measurements were presented on Mean±SD (Min-Max) and results on categorical measurements were presented in Number (%). Significance was assessed at 5% level of significance. The following assumptions on data are made, Assumptions: 1) Dependent variables should be normally distributed; 2) Samples drawn from the population should be random, and cases of the samples should be independent [8–10]. Analysis of Variance (ANOVA) was used to find the significance of study parameters between three or more groups of patients, Student t-test (two tailed, independent) was used to find the significance of study parameters on continuous scale between two groups (Inter group analysis) on metric parameters. Chi-square/Fisher-Exact test was used to find the significance of study parameters on categorical scale between two or more groups.
Significant figures
+ Suggestive significance (p-value: 0.05<p<0.10)
* Moderately significant (p-value: 0.01<p£ 0.05)
** Strongly significant (p-value: p£0.01)
Statistical Software: The Statistical software namely SAS 9.2, SPSS 15.0, Stata 10.1, Med Calc 9.0.1, Systat 12.0 and R environment ver. 2.11.1 were used for the analysis of the data and Microsoft word and Excel were used to generate graphs, tables etc.
Results
Among 101 patients with confirmed DI, 74 (73.3%) were men and 27(26.7%) were women with a mean age of 31.62±12.62 years. A total of 70 (70.2%) patients had classical DF, and 31(29.2%) patients had DHF/DSS. RF group with 16 (15.8%) patients was defined as serum creatinine of >1.2mg%. Most common symptoms were fever (100%) followed by headache (82%) and pain in abdomen (75%). Statistically significant (p<0.001) bleeding tendency, shock, proteinuria and RF [Table/Fig-1] were present more in DHF/DSS than in DF. Analysis by Fisher-exact test revealed that the DF group had no significant presence of hypertension, diabetes compared with the DHF/DSS group (strongly significant was if p≤0.01). The time from the onset of fever to the detection of fever in DF, DHS and DSS groups did not show a significant difference (4.41±1.62 days versus 3.73±1.56 days versus 4.58±2.54 days) with p=0.275 on analysis of variance (ANOVA) test, checked at 5% level of significance (strongly significant was if p≤0.01). Among the 16 patients with RF, all patients had recovery from renal failure. The differences in clinical presentations of DF and DHF/DSS are shown in [Table/Fig-2]. The patients with DHF/DSS were more susceptible to develop renal failure compared to DF group (62% versus 38%). There were statistically significant higher frequencies of renal failure, haemoconcentration, thrombocytopenia, low serum cholesterol in DHF/DSS group. Raised transaminases, raised LDH level were noted in the DHF/DSS group compared with DF, however, there was no significant difference in frequency of other mentioned symptoms/signs and parameters like serum bilirubin, serum electrolytes, prothrombin time, APTT between DF and DHF/DSS in the patients with RF. Patients in the RF group also had significantly higher percentages of shock, haemoconcentration, thrombocytopenia, raised AST and low serum cholesterol [Tables/Fig-3,4]. There were no mortality and none of them had to receive renal replacement therapy during hospitalization.
[Table/Fig-1]:
Comparison of frequency of variables like bleeding/renal failure/shock/haematuria/proteinuria in different groups of patients studied.
| DF (n=70) |
DHF (n=19) |
DSS (n=12) |
Total (n=101) |
p-value | |
|---|---|---|---|---|---|
| Bleeding | 0(0%) | 19(100%) | 6(50%) | 25(24.8%) | <0.001** |
| Renal failure (RF) | 1(1.4%) | 4(21.1%) | 11(91.7%) | 16(15.8%) | <0.001** |
| Shock | 2(2.9%) | 2(10.5%) | 12(100%) | 16(15.8%) | <0.001** |
| Haematuria | 2(2.9%) | 1(5.3%) | 2(16.7%) | 5(5%) | 0.104 |
| Proteinuria | 4(5.7%) | 4(21.1%) | 4(33.3%) | 12(11.9%) | 0.008** |
Chi-Square test/Fisher-exact test
[Table/Fig-2]:
Comparison of mean of clinical variables in relation to different groups of patients studied.
| Variables | DF | DHF | DSS | Total | p-value |
|---|---|---|---|---|---|
| Urea (mg%) | 29.44±9.41 | 35.92±18.34 | 53.53±8.96 | 33.52±13.83 | <0.001** |
| Creatinine mg% (Day1) | 0.88±0.23 | 1.04±0.39 | 1.52±0.30 | 0.99±0.34 | <0.001** |
| Creatinine mg% (Day 14) | 0.66±0.19 | 0.65±0.22 | 0.88±0.19 | 0.69±0.20 | 0.001** |
| Haematocrit (%) | 44.16±6.43 | 46.93±3.62 | 47.71±7.89 | 45.10±6.31 | 0.073+ |
| Haemoglobin (g/dl) | 13.91±2.18 | 15.13±1.34 | 14.97±2.75 | 14.26±2.17 | 0.045* |
| Platelets (cells/cmm) | 83754.29±71560.12 | 47815.79±39127 | 24258.33±20133.67 | 69924.75±65806.89 | 0.003** |
| Creatine kinase (U/L) | 122.14±219.87 | 140.79±145.73 | 100.83±132.75 | 123.12±198.08 | 0.861 |
| Total Bilirubin (mg/dl) | 1.15±1.08 | 0.97±0.72 | 1.99±2.85 | 1.22±1.37 | 0.101 |
| Direct Bilirubin (mg/dl) | 0.45±0.61 | 0.47±0.51 | 0.75±0.83 | 0.49±0.63 | 0.307 |
| Albumin (g/l) | 3.33±0.77 | 3.55±0.97 | 3.37±0.53 | 3.38±0.78 | 0.559 |
| AST (U/l) | 164.73±240.87 | 349.79±1102.96 | 891.00±2502.45 | 285.83±1001.42 | 0.063+ |
| ALT (U/l) | 94.90±148.80 | 125.37±201.66 | 331.83±803.51 | 128.78±315.23 | 0.054+ |
| ALP (U/l) | 105.81±65.20 | 94.00±39.04 | 83.67±39.47 | 100.96±58.65 | 0.413 |
| Lactate Dehydrogenase (U/L) | 85.49±63.85 | 304.95±854.41 | 164.50±124.14 | 136.16±378.44 | 0.077+ |
| Sodium (mmol/L) | 135.64±16.59 | 136.96±4.08 | 135.05±1.91 | 135.82±13.92 | 0.917 |
| Potassium (mmol/L) | 11.31±45.37 | 4.15±0.43 | 4.22±0.58 | 9.12±37.84 | 0.686 |
| Cholesterol (mg/dl) | 141.59±36.45 | 159.96±28.26 | 120.58±45.49 | 142.55±37.47 | 0.015* |
| Total Leucocyte count (cells/cmm) | 11048.64±19180.19 | 7668.42±10572.5 | 18691.67±29127.82 | 11320.84±19400.78 | 0.301 |
| Prothrombin time | 12.24±2.20 | 12.53±1.27 | 12.95±3.11 | 12.38±2.18 | 0.555 |
| Activated partial thromboplastin time (seconds) | 31.63±8.67 | 31.29±10.74 | 31.11±7.33 | 31.50±8.87 | 0.977 |
ANOVA test
[Table/Fig-3]:
Comparison of vitals in relation to renal failure status of patients studied.
| Renal failure (RF) | All patients (n=101) |
p-value | ||
|---|---|---|---|---|
| Absent (n=85) |
Present (n=16) |
|||
| Pulse (per minute) | 85.31±11.82 | 87.00±11.91 | 85.57±11.79 | 0.600 |
| SBP (mm Hg) | 111.79±11.46 | 93.13±9.69 | 108.83±13.09 | <0.001** |
| DBP (mm Hg) | 73.04±7.41 | 66.63±10.60 | 72.02±8.27 | 0.004** |
| Respiratory Rate (per minute) |
17.33±5.04 | 17.31±3.53 | 17.33±4.82 | 0.990 |
| Temp (°F) | 99.57±1.12 | 100.12±1.35 | 99.66±1.17 | 0.086+ |
Student t-test
[Table/Fig-4]:
Blood investigations in relation to Renal failure status of patients studied.
| Variables | Renal failure (RF) | All patients (n=101) |
p-value | |
|---|---|---|---|---|
| Absent (n=85) |
Present (n=16) |
|||
| Urea (mg%) | 28.98±8.91 | 57.64±9.69 | 33.52±13.83 | <0.001** |
| Creatinine mg% (Day1) | 0.87±0.21 | 1.59±0.29 | 0.99±0.34 | <0.001** |
| Creatinine mg% (Day 14) | 0.64±0.18 | 0.93±0.11 | 0.69±0.20 | <0.001** |
| Haematocrit (%) | 44.64±6.18 | 47.58±6.62 | 45.10±6.31 | 0.088+ |
| Hemoglobin (g/dl) | 14.06±2.10 | 15.34±2.32 | 14.26±2.17 | 0.030* |
| Platelets (cells/cmm) | 77832.94±68221.56 | 27912.50±23870.68 | 69924.75±65806.89 | 0.005** |
| Creatine kinase (U/L) | 127.59±210.53 | 99.38±112.46 | 123.12±198.08 | 0.604 |
| Total Bilirubin (mg/dl) | 1.10±1.02 | 1.82±2.49 | 1.22±1.37 | 0.053+ |
| Direct Bilirubin (mg/dl) | 0.45±0.58 | 0.74±0.79 | 0.49±0.63 | 0.086+ |
| Albumin (g/l) | 3.40±0.82 | 3.28±0.54 | 3.38±0.78 | 0.590 |
| AST (U/l) | 207.73±560.37 | 700.75±2170.00 | 285.83±1001.42 | 0.071+ |
| ALT (U/l) | 101.75±164.5 | 272.38±696.27 | 128.78±315.23 | 0.046 |
| ALP (U/l) | 103.27±61.75 | 88.69±37.28 | 100.96±58.65 | 0.364 |
| Lactate Dehydrogenase (U/L) | 134.86±409.94 | 143.06±116.73 | 136.16±378.44 | 0.937 |
| Sodium (mmol/L) | 135.90±15.13 | 135.37±3.13 | 135.82±13.92 | 0.889 |
| Potassium (mmol/L) | 10.04±41.22 | 4.22±0.51 | 9.12±37.84 | 0.575 |
| Cholesterol (mg/dl) | 145.57±34.00 | 126.50±50.62 | 142.55±37.47 | 0.062+ |
| Total Leucocyte count (cells/cmm) | 9943.59±17565.66 | 18637.50±26711.89 | 11320.84±19400.78 | 0.100 |
| Prothrombin time | 12.22±2.03 | 13.22±2.76 | 12.38±2.18 | 0.090+ |
| Activated partial thromboplastin time (seconds) | 31.82±9.08 | 29.83±7.66 | 31.50±8.87 | 0.414 |
Student t-test
Discussion
Classic DF often presents as a self-limiting febrile illness, whereas DHF and DSS have high mortality [1]. Dengue infection has been associated with a variety of renal disorders [11]. Significant proteinuria of 74% was seen in severe DI. Similar to our study, haematuria has been noted in up to 12.5% in DI [1,11]. Unlike in other reported studies, incidence of Acute Kidney Injury was found to be higher in our study [11,12]. When RF complicates DI, it is almost always due to extensive capillary leak, hypotension, rhabdomyolysis, haemolysis and severe disseminated intravascular coagulation, which lead to hypoxia/ischemia and multiple organ dysfunction as reported in various case report studies [11,12]. In some patients, acute tubular necrosis is associated with interstitial oedema and mononuclear cell infiltration may lead to RF [1]. The exact mechanism of renal involvement in patients with DF who have no bleeding or hypotension is not clear. Whether the virus causes direct damage by invasion of the kidneys is not known [1]. Gender distribution showed male domination in this study to suffer from AKI. The male gender susceptibility could be related to more males working outside the house exposing them to greater risk of mosquito bite or whether social cause like better medical facility to males in this part of world, as mentioned in other studies [12,13]. In our study, the patients with DHF/DSS were more susceptible to develop RF compared to DF group due to hypotension, bleeding and shock like in other study [12]. In our study, there were statistically significant higher frequencies of RF, haemoconcentration, thrombocytopenia, low serum cholesterol in DHF/DSS group than DF as in other study [2]. In our study, patients in the RF group had significantly higher percentages of shock, haemoconcentration, thrombocytopenia, raised AST and low serum cholesterol like in other studies [12,14,15]. Unusual features in DF like hepatic, cardiac and nervous system involvement in DF has poor prognosis. Liver dysfunction manifests by the elevation of transaminases representing reactive hepatitis. Elevated transaminases in DF may be due to use of hepatotoxic drugs and direct attack of virus itself. There is hepatic inflammation leading to transaminitis in DF [14]. The mainstay of management of dengue fever is to give fluids to maintain adequate circulation while being careful not to deliver more than is absolutely necessary–a very delicate balancing act to prevent fluid overload [4,15].
Limitation
This study is one hospital-based design with the disadvantage of limited case number and the advantage of reducing bias on the factor of difference in medical care quality. Patients were only followed up until discharge and there was a lack of long-term follow-up.
Conclusion
Patients with DHF/DSS were more susceptible to develop renal failure compared to DF group. Patients in the RF group had higher percentages of shock, haemoconcentration, thrombocytopenia, raised AST and low serum cholesterol.
Financial or Other Competing Interests
None.
References
- [1].Nair VR, Unnikrishnan D, Satish B, Sahadulla MI. Acute renal failure (RF) in dengue fever in the absence of bleeding manifestations or shock. Infect Dis Clin Pract. 2005;13:142–143. [Google Scholar]
- [2].Kuo MC, Lu PL, Chang JM, Lin MY, Tsa JJ, Chen YH, et al. Impact of renal failure on the outcome of dengue viral infection. Clin J Am Soc Nephro. 2008;3:1350–56. doi: 10.2215/CJN.00020108. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [3].Wijesinghe A, Gnanapragash N, Ranasinghe G, Ragunathan MK. Acute renal failure due to rhabdomyolysis following dengue viral infection: A case report. Journal of Medical Case Reports. 2013;7:195. doi: 10.1186/1752-1947-7-195. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].Vakrani GP, Ramakrishnan S, Rangarajan D. Acute renal failure in diabetes mellitus (prospective study) J Nephrol Ther. 2013;3:137. [Google Scholar]
- [5].Mehta RL, Chertow GM. Acute renal failure definitions and classification: Time for change? J Am Soc Nephrol. 2003;14:2178–87. doi: 10.1097/01.asn.0000079042.13465.1a. [DOI] [PubMed] [Google Scholar]
- [6].Pan HC, Chen YJ, Lin HP, Tsai MJ, Jenq CC, Lee WC, et al. Proteinuria can predict prognosis after liver transplantation. BMC Surgery series – open, inclusive and trusted. 2016;16:63. doi: 10.1186/s12893-016-0176-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [7].Robert W. Schrier. Urinalysis. 8th ed. Phildelphia: Lippincott Williams & wilkins; 2007. pp. 286–296. [Google Scholar]
- [8].Bernard Rosner. Fundamentals of Biostatistics. 5th ed. Duxbury: 2000. pp. 80–240. [Google Scholar]
- [9].Robert H Riffenburg. Statistics in Medicine. 2nd ed. Academic press; 2005. pp. 85–125. [Google Scholar]
- [10].Sunder Rao PSS, Richard J. An Introduction to Biostatistics, A manual for students in health sciences. 4th ed. New Delhi: Prentice hall of India; 2006. pp. 86–160. [Google Scholar]
- [11].Lizarraga KJ, Nayer A. Dengue-associated kidney disease. J Nephropathol. 2014;3(2):57–62. doi: 10.12860/jnp.2014.13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [12].Khalil MAM, Sarwar S, Chaudry MA, Maqbool B, Khalil Z, Tan J, et al. Acute kidney injury in dengue virus infection. Clin Kidney J. 2012;5:390–94. doi: 10.1093/ckj/sfs117. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [13].Lee IK, Liu JW, Yang KD. Clinical characteristics, risk factors, and outcomes in adults experiencing dengue haemorrhagic fever complicated with acute renal failure. Am J Trop Med Hyg. 2009;80:651–55. [PubMed] [Google Scholar]
- [14].Parkash O, Almas A, Wasim Jafri SM, Hamid S, Akhtar J, Alishah H. Severity of acute hepatitis and its outcome in patients with dengue fever in a tertiary care hospital Karachi, Pakistan (South Asia) BMC Gastroenterology. 2010;10:43. doi: 10.1186/1471-230X-10-43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [15].Ralapanawa DMPUK, Kularatne SAM. Current Management of Dengue in Adults: A Review. IMJM. 2015;14:29–44. [Google Scholar]