| Abstract|| |
Dengue-related renal manifestations such as proteinuria, hematuria in the absence of thrombocytopenia, rhabdomyolysis, and acute kidney injury (AKI) are not uncommon. There is relatively sparse data on the renal manifestations of dengue viral infection (DVI). Hence, a retrospective study was conducted to investigate the incidence, characteristics, and clinical outcome of DVI with renal manifestations. A total of 2416 patients were admitted to our hospital with the diagnosis of dengue fever during the study period from 2012 to 2015. Data were collected from the electronic medical records and were analyzed retrospectively. The disease severity was classified according to the World Health Organization criteria. The renal manifestations were divided into AKI and non-AKI groups using AKI Network (AKIN) criteria. Proteinuria was defined as urinary protein >1+ (30 mg/dL) by dipstick test. A total of 218 patients were found to have proteinuria (9.56%). Most of the patients [135 (58.44%) with renal manifestations] were aged between 15 and 30 years. Comorbid conditions including diabetes mellitus, hypertension, and ischemic heart disease were seen in 10 (4.31%), 11 (4.76%), and six (2.59%) patients, respectively. Nephrotic-range proteinuria was seen in five patients (2.16%). AKI was seen in 82 patients (3.4%); 58 (70.73%) had AKIN-I, 19 (23.17%) had AKIN-II, and five patients (6.09%) had AKIN-III. Death occurred in 11 patients (39.28%) with AKI. The incidence of renal manifestations (proteinuria, hematuria, and AKI) is high at 9.59% among patients with dengue, and those with AKI had significant morbidity, mortality, longer hospital stay, and poor renal outcomes. Our findings suggest that AKI in dengue is likely to increase health-care burden that underscores the need for clinician’s alertness to this highly morbid and potentially fatal complication for optimal prevention and management.
|How to cite this article:|
Eswarappa M, Reddy SB, John MM, Suryadevara S, Madhyashatha RP. Renal manifestations of dengue viral infection. Saudi J Kidney Dis Transpl 2019;30:394-400
|How to cite this URL:|
Eswarappa M, Reddy SB, John MM, Suryadevara S, Madhyashatha RP. Renal manifestations of dengue viral infection. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Jul 21];30:394-400. Available from: http://www.sjkdt.org/text.asp?2019/30/2/394/256847
| Introduction|| |
Dengue viral infection (DVI) is a mosquito-borne illness highly prevalent in the tropics and subtropics and is considered a major global health threat by the World Health Organization (WHO). Approximately one-third of the world’s population is at risk for dengue infection. The worldwide infection rate approaches 50–100 million each year.
The dengue virus is an RNA virus from the genus Flaviviridae which is transmitted by the bite of Aedes aegypti mosquito. There are four serotypes of dengue virus; infection with one serotype produces lifelong immunity to that serotype, but the immunity lasts only a few months for other serotypes. The dengue virus has an incubation period of 3–14 days. DVI is manifested by a variety of clinical presentations including asymptomatic infection, undifferentiated fever, dengue fever (DF), dengue hemorrhagic fever (DHF), and life-threatening dengue shock syndrome (DSS). Like other tropical infections, DVI is associated with multiple organ dysfunction involving liver, muscles, heart, brain, and kidneys., DVI has been associated with a variety of renal manifestations such as proteinuria, hematuria, glomerulonephritis, and acute kidney injury (AKI), which have been reported during or shortly after acute dengue infection. The incidence of the above renal manifestations varies between 17% and 62% in patients with DVI. Such complications impose a heavy burden on the country not only in terms of morbidity and mortality but also impacts the economic growth of the country. Currently, there is relatively sparse data from India on the renal manifestations of DVI and their outcome. Hence, this retrospective study was designed to analyze the incidence, characteristics, and clinical outcome of DVI with renal manifestations.
| Methodology|| |
The study was conducted at a tertiary care teaching hospital in Bengaluru, India. We retrospectively reviewed medical records of all dengue patients admitted from January 2012 to December 2015. All dengue patients were identified by registration number using hospital record management system. Patients aged >15 years, admitted with primary and confirmed diagnosis of DVI, irrespective of severity were included in this study. Patients having incomplete demographics and hospital stay <48 h were excluded from the study. [Table 1] shows the inclusion and exclusion criteria for this study.
The diagnosis of dengue was made using WHO definitions. Suspected DVI cases were diagnosed by using at least one of the following criteria:
- Positive reverse transcriptase polymerase chain reaction.
- Presence of dengue immunoglobulin M and G antibodies in acute-phase serum by enzyme-linked immunosorbent assay.
The serum samples were also tested for dengue-specific NS1 antigen.
Serologically confirmed dengue patients were subjected to clinical case definition, and disease severity was classified according to the WHO criteria [Table 2].
DF: clinical diagnosis of DF requires fever and two or more of the following symptoms: headache, retro-orbital pain, myalgia, arthralgia, rash, hemorrhagic manifestations, or leukopenia.
DHF requires the presence of fever, thrombocytopenia (<100,000), any bleeding, and plasma leakage described as either hematocrit change <20%, clinical fluid accumulation (pleural effusion or ascites), or hypoproteinemia.
DSS requires the presence of rapid and weak pulse with narrow pulse pressure <20 mm Hg or hypotension for age in a patient with DHF. The presence of warning signs is indicated by the presence of at least one of the following: abdominal pain or tenderness, persistent vomiting, clinical fluid accumulation, mucosal bleed, lethargy/restlessness, liver enlargement more than 2 cm, or concurrent increase in hematocrit with thrombocytopenia [Table 2]. AKI was defined by AKI Network (AKIN) classification.
It was a retrospective review of medical records, and details on demographic data, underlying comorbidities, and mortality in association with the severity of dengue infection of each patient were recorded. All the laboratory results at first hospital visit (at the time of admission) were collected for statistical analyses. The nadir or peak of the levels of liver enzymes and complete blood counts during hospitalization were also recorded. Proteinuria was defined as urinary protein of one plus by dipstick test, and the same criterion was used for urinary occult blood for microscopic hematuria. Biochemistries of blood and urine were measured by autoanalyzer. Parameters that possibly influenced the clinical presentations and outcomes in patients with or without renal failure were analyzed and compared.
| Results|| |
A total of 2416 patients with DVI were enrolled in the study. The characteristic features of the study patients are shown in [Table 3]. The mean age of patients was 31.26 ± 12.6 years with the youngest being 15 years and eldest patient being 83 years. Most of our patients were in the age group of 15–45 years (15–30 years: 58.4%, 31–45 years: 30.7%, 46–60 years: 7.8%, and >60 years: 3 %). Males were more frequently affected than females in our study population (72.29% vs. 27.71%). Comorbid conditions were less prevalent, and our study population was otherwise healthy; (hypertension - 4.74%, diabetes mellitus - 4.31%, ischemic heart disease - 2.59%, and hypothyroidism - 7.3%).
|Table 3: Demographic, clinical, and laboratory characteristics of dengue viral infection.|
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Proteinuria was seen in all the 218 patients presenting with renal manifestations (9.02% of study population). Most commonly, they had one plus proteinuria on dipstick (184 patients: 84.40%). Five of our patients had nephrotic-range proteinuria (2.29%). Of them, two patients had spontaneous resolution of proteinuria by two weeks and three patients had persistent nephrotic-range proteinuria and microscopic hematuria; they underwent renal biopsy which showed features suggestive of prolife-rative and exudative glomerulonephritis in all three [Table 4].
AKI was seen in 82 patients (3.4%); 58 (70.73%) had AKIN-I, 19 (23.17%) had AKIN-II, and five patients (6.09%) had AKIN-III. Three patients with AKI underwent hemodialysis and one patient underwent continuous renal replacement therapy. Two patients with persistent renal dysfunction after three weeks of illness underwent renal biopsy, which was suggestive of acute tubular necrosis in one patient and acute interstitial nephritis in the other [Table 5].
Other findings of clinical importance noted in the study were leukopenia seen in 101 patients (43.7%) with renal manifestations and 1214 patients (55.56%) without renal manifestations; thrombocytopenia was noted in 197 patients (85.3%) with renal manifestations and 1791 patients (81.96%) without renal manifestations. Among patients with DVI, 132 patients (57.14%) with renal manifestations and 754 patients (34.5%) without renal manifestations required blood and blood product transfusions (random donor platelets, single donor platelet, and fresh frozen plasma transfusions). However, none of these above data found any statistical significance.
The duration of hospital stay in patients with AKI was 4 ± 2 days in AKIN-I, 6 ± 5 days in AKIN-II, and 11 ± 2 days in patients with AKIN-III. Recovery of renal function was seen in all 58 patients with AKIN-I, 12 patients with AKIN-II, and one patient with AKIN-III. The time period of recovery to normal renal function was 3 ± 2 days in patients with AKIN-I, 7 ± 11 days in patients with AKIN-II, and six weeks in only one patient who survived in AKIN-III.
Of all patients with DVI, 28 patients died, of which 11 had AKI (39.28%). Degree of thrombocytopenia was an independent marker of mortality; eight patients out of 11 deaths (72.7%) with AKI had platelet count <50,000/ μL, two patients (18.2%) had platelet count between 50,000 and 100,000/μL, and one patient (9.1%) had platelet count between 100,000 and 150,000/μL [Table 6].
| Discussion|| |
Acute febrile illnesses are common causes of AKI in developing countries. DF along with other tropical infections such as malaria, scrub typhus, enteric fever, leptospirosis, and hantavirus have been reported to cause AKI. AKI as a complication of DVI has not been studied much. There are multiple proposed mechanisms for etiopathogenesis of renal impairment in DVI. Dengue causes capillary leakage and loss of fluid from the intravascular compartment leading to shock which may lead to decreased kidney perfusion and acute tubular necrosis., Other possible etiological factors for AKI in DF include either hemolysis or rhabdomyolysis as reported in various case reports.,,,, On the other hand, unexplained AKI has also been reported in the literature. Interestingly, dengue may cause glomerular injury in addition to the above-mentioned mechanisms as reported in one study. The presence of viral antigen in tubular epithelial cells has also been demonstrated. Two experimental studies also provide evidence supporting possible glomerular injury in DVI.,
In our study, most of the patients (58.4%) were young, aged between 15 and 30 years and 72.29% patients were males, indicating a higher incidence in males compared to females. These results were similar to a study conducted by Khalil et al where younger age and male gender were independent predictors for AKI.
Proteinuria was the most common presentation seen in our study noted in 9.02% of patients. García et al evaluated 174 patients with DF or DHF who had a platelet count <125,000/mm3 and noted the prevalence of proteinuria in 21% of patients. Horvath et al. from Queensland, Australia, recorded hematuria in 31% and proteinuria in 74% of patients in whom urine examination was performed. Vasanwala et al reported two DHF patients with nephrotic-range proteinuria, without increase in serum creatinine, hematuria, or urinary casts. Proteinuria of 8.09 g and 8.97 g/day was noted, with spontaneous remission seen by day-10 in the first patient and spontaneous reduction of proteinuria by more than 50% on day-11 in the second patient. In our study, five patients had nephrotic-range proteinuria. Of these five patients, two had spontaneous resolution of proteinuria by two weeks; three patients with persistent nephrotic-range proteinuria and microscopic hematuria underwent renal biopsy, which was suggestive of proliferative and exudative glomerulonephritis in all three patients. A short course of steroids was given in two patients who had persistent nephrotic-range proteinuria after four weeks and one patient was managed conservatively as he had a spontaneous decline in proteinuria by 50% at four weeks. Both patients treated with steroids had decline in proteinuria, and steroids were tapered and stopped within six weeks of initiation of therapy. Although podocytopathy with DVI has been mentioned in published literature, the presence of infection-related glomerulonephritis-proliferative and exudative glomerulonephritis (IRGN) with DVI is the first according to our knowledge. We did not perform viral antigen study on the biopsy specimen which could prove their causal relationship.
Mallhi et al retrospectively described 667 dengue patients from 2008 to 2013. The patients were stratified into AKI and non-AKI groups by using AKIN criteria. Significant differences (P <0.05) in clinicolaboratory characteristics were observed between patients with and without AKI. The presence of DHF, rhabdomyolysis, multiple organ dysfunction syndrome (MODS), diabetes mellitus, and use of nephrotoxic drugs were associated with AKI. AKI was noted in 82 patients (3.4%) in our study with AKIN stage I seen in 58 patients (70.73 %). The incidence of AKI found in our study is similar to other studies like Lee et al, who described the incidence of AKI in 3.3% of patients. Factors associated with AKI in our study were younger age at presentation, hypotension, diabetes mellitus, and MODS. Kuo et al retrospectively evaluated patients with DVI and divided them into renal failure and nonrenal failure groups. AKI was defined by RIFLE criteria and was seen in 4.2% of patients. A higher mortality rate (41.6%) was seen in the renal failure group than the nonrenal failure group (5.2%). Similar results were seen in our study where the mortality was higher (39.28% of all deaths) in patients with AKI. Other factors influencing mortality were patients with late presentation, inadequate fluid administration, and comorbidities such as diabetes mellitus and hypertension. Severe degree of thrombocytopenia was associated with increased mortality among patients with renal manifestations. Eight patients out of 11 (72.7%) with AKI had platelet count less than 50,000/μL.
| Conclusion|| |
Renal manifestations of DVI are varied, ranging for mild electrolyte imbalance and tubular injury to dialysis requiring AKI. Podocytopathy is not uncommon with DVI, but the occurrence of IRGN is an eye-opener and requires further investigation. In comparison with non-AKI patients, patients with AKI portended significant morbidity, mortality, longer hospital stay, and poor renal outcomes, and these are likely to add to the health-care burden. The presence of male gender, DHF, MODS, and diabetes mellitus increase incidence of AKI among dengue patients. These findings underscore the need for clinicians’ alertness to this highly morbid and potentially fatal complication of dengue infection. Prior knowledge of expected clinical profile and predictors of AKI development would provide information to identify individuals at higher risk and on the other hand provide opportunity to clinicians for appropriate management of such patients in a timely manner.
| References|| |
Guzmán MG, Kourí G. Dengue: An update. Lancet Infect Dis 2002;2:33-42.
Udwadia FE. Multiple organ dysfunction syndrome due to tropical infections. Indian J Crit Care Med 2003;7:233-6. [Full text]
Halstead SB. Dengue. Lancet 2007;370:1644-52.
Lizarraga KJ, Nayer A. Dengue-associated kidney disease. J Nephropathol 2014;3:57-62.
Mehta RL, Kellum JA, Shah SV, et al. Acute kidney injury network: Report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31.
George R, Liam CK, Chua CT, et al. Unusual clinical manifestations of dengue virus infection. Southeast Asian J Trop Med Public Health 1988;19:585-90.
Chacko B, John GT, Jacob CK, Vijayakumar TS. Dengue shock syndrome in a renal transplant recipient. Transplantation 2004;77:634-5.
Karakus A, Banga N, Voorn GP, Meinders AJ. Dengue shock syndrome and rhabdomyolysis. Neth J Med 2007;65:78-81.
Garcia JH, Rocha TD, Viana CF, et al. Dengue shock syndrome in a liver transplant recipient. Transplantation 2006;82:850-1.
Gunasekera HH, Adikaram AV, Herath CA, Samarasinghe HH. Myoglobinuric acute renal failure following dengue viral infection. Ceylon Med J 2000;45:181.
Radakovic-Fijan S, Graninger W, Müller C, Hönigsmann H, Tanew A. Dengue hemorrhagic fever in a British travel guide. J Am Acad Dermatol 2002;46:430-3.
Wiersinga WJ, Scheepstra CG, Kasanardjo JS, de Vries PJ, Zaaijer H, Geerlings SE. Dengue fever-induced hemolytic uremic syndrome. Clin Infect Dis 2006;43:800-1.
Lima EQ, Gorayeb FS, Zanon JR, Nogueira ML, Ramalho HJ, Burdmann EA. Dengue haemorrhagic fever-induced acute kidney injury without hypotension, haemolysis or rhabdomyolysis. Nephrol Dial Transplant 2007; 22:3322-6.
Boonpucknavig V, Bhamarapravati N, Boonpucknavig S, Futrakul P, Tanpaichitr P. Glomerular changes in dengue hemorrhagic fever. Arch Pathol Lab Med 1976;100:206-12.
Jessie K, Fong MY, Devi S, Lam SK, Wong KT. Localization of dengue virus in naturally infected human tissues, by immunohistochemistry and in situ
hybridization. J Infect Dis 2004;189:1411-8.
Boonpucknavig S, Vuttiviroj O, Boonpucknavig V. Infection of young adult mice with dengue virus type 2. Trans R Soc Trop Med Hyg 1981; 75:647-53.
Barreto DF, Takiya CM, Paes MV, et al. Histopathological aspects of dengue-2 virus infected mice tissues and complementary virus isolation. J Submicrosc Cytol Pathol 2004;36: 121-30.
Khalil MA, Sarwar S, Chaudry MA, et al. Acute kidney injury in dengue virus infection. Clin Kidney J 2012;5:390-4.
García S, Morales R, Hunter RF. Dengue fever with thrombocytopenia: Studies towards defining vulnerability of bleeding. Bol Asoc Med P R 1995;87:2-7.
Horvath R, McBride WJ, Hanna JN. Clinical features of hospitalized patients during dengue-3 epidemic in far North Queensland 1997-99. Dengue Bull 1999;23:24-9.
Vasanwala FF, Puvanendran R, Ng JM, Suhail SM. Two cases of self-limiting nephropathies secondary to dengue haemorrhagic fever. Singapore Med J 2009;50:e253-5.
Mallhi TH, Khan AH, Adnan AS, Sarriff A, Khan YH, Jummaat F. Incidence, characteristics and risk factors of acute kidney injury among dengue patients: A retrospective analysis. PLoS One 2015;10:e0138465.
Lee IK, Liu JW, Yang KD. Clinical characteristics and risk factors for concurrent bacteremia in adults with dengue hemorrhagic fever. Am J Trop Med Hyg 2005;72:221-6.
Kuo MC, Lu PL, Chang JM, et al. Impact of renal failure on the outcome of dengue viral infection. Clin J Am Soc Nephrol 2008;3: 1350-6.
Department of Nephrology, Ramaiah Medical College and Hospitals, Bengaluru, Karnataka
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]