Year : 2010 | Volume
: 21 | Issue : 3 | Page : 521--525
Transient IgA nephropathy with acute kidney injury in a patient with dengue fever
Bala Krishna Upadhaya1, Alok Sharma2, Ambar Khaira1, Amit K Dinda2, Sanjay K Agarwal1, Suresh C Tiwari1,
1 Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
Amit K Dinda
Department of Pathology, All India Institute of Medical Sciences, New Delhi
Dengue virus infection can clinically manifest as dengue fever, dengue shock syndrome and dengue hemorrhagic fever. Acute kidney injury as a result of dengue virus infection can occur due to various reasons including hypotension, rhabdomyolysis, sepsis and rarely immune complex mediated glomerular injury. However, glomerulonephritis associated with IgA Nephropathy in dengue virus infection has not been reported previously. We report a case of 15year-old boy who was admitted with dengue fever and dialysis dependant acute kidney injury. Urine examination showed microscopic glomerular hematuria and proteinuria. Kidney biopsy showed mesangial proliferation with mesangial IgA dominant immune complex deposits and acute tubular necrosis. A repeated kidney biopsy 6 weeks after clinical recovery showed reversal of glomerular changes as well as resolution of mesangial IgA deposits.
|How to cite this article:|
Upadhaya BK, Sharma A, Khaira A, Dinda AK, Agarwal SK, Tiwari SC. Transient IgA nephropathy with acute kidney injury in a patient with dengue fever.Saudi J Kidney Dis Transpl 2010;21:521-525
|How to cite this URL:|
Upadhaya BK, Sharma A, Khaira A, Dinda AK, Agarwal SK, Tiwari SC. Transient IgA nephropathy with acute kidney injury in a patient with dengue fever. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2020 Jul 3 ];21:521-525
Available from: http://www.sjkdt.org/text.asp?2010/21/3/521/62702
Dengue virus infection clinically manifests as uncomplicated Dengue Fever (DF), Dengue Hemorrhagic fever (DHF) or Dengue Shock syndrome (DSS). DF is a common arthropodborne viral disease endemic in more than 100 countries of the world and is caused by one of the four serotypes (types 1-4) of Dengue virus, an RNA flavivirus within family flaviviridae. Worldwide, more than 2.5 billion people are at risk, and about 50-100 million cases of Dengue virus infection occur annually. 
Renal involvement and acute kidney injury has been reported in patients with dengue virus infection as a result of shock, hemolysis, rhabdomyolysis, sepsis, and rarely immune complex mediated glomerular injury. ,,,, Although immunoglobulin A (IgA) containing immune complex deposits in glomeruli may be seen in several viral infections, , these have not been reported in association with dengue virus infection.
We present a case of acute kidney injury (RIFLE-F) (P0/C0) that needed hemodialysis support for four weeks. A kidney biopsy evaluation for prolonged renal shutdown showed mesangioproliferative glomerulonephritis with mesangial IgA deposition and features of acute tubular necrosis (ATN). A repeat kidney biopsy after six weeks; once the patient had clinically recovered showed resolution of mesangial proliferation as well as the IgA immune complex deposits.
A previously healthy 15-year-old boy was admitted with complaints of fever with chills of one week duration. He also complained of oliguria for two days. There was no history of rash or bleeding from any muco-cutaneous site. Examination showed blood pressure of 150/90 mm Hg and mild icterus sclerae. The rest of the systemic examination including fundi was unremarkable. Investigations revealed anemia (hemoglobin 9.2 mg/dL), mild neutrophilic leukocytosis (total count-16500/mm 3 ) with and mild thrombocytopenia (platelets-100000/mm 3 ). The total serum bilirubin was 2.1 mg% with direct fraction of 1.2 mg/dL. Liver enzymes aspartate transaminase (AST) and alanine transaminase (ALT) were elevated (AST 120 IU/L and ALT 140 IU/L). Serum total protein and albumin were 6.0 gm/dL and 3.2 gm/dL respectively. Blood urea was 167 mg/dL and serum creatinine was 8.4 mg/dL at presentation. Urine dipstick examination showed 2 + proteinuria, while microscopy revealed glomerular hematuria (8-10 RBC's/hpf with 30% dysmorphic forms). The peripheral smear examination revealed normocytic and mildly hypochromic RBC's and was negative for malarial parasite and fragmented red blood cells. Immunological spot test for malarial antigen was negative. Serological tests for leptospira, Hepatitis B surface antigen (HBsAg), Hepatitis C virus (HCV) and Human immunodeficiency virus (HIV) were negative. Dengue serology showed elevated titres of dengue specific IgM and was negative for IgG. The patient had normal anti neutrophilic antibody (ANA) titres and was negative for c and p anti neutrophilic cytoplasmic antibody (ANCA). Serum C3 (complement) levels were normal (112 mg%)
The patient was hemodialyzed along with intravenous piperacillin + tazobactum and levofloxacin in renal modified doses. After two weeks, the hematological profile and liver function parameters returned to normal values.
However, as the patient's renal functions did not improve, and he remained oliguric (urine output 100-150 mL/day) a repeated kidney biopsy was performed. The light microscopic examination of the renal biopsy revealed eight glomeruli with increased mesangial cellularity and mild mesangial matrix expansion, [Figure 1]. The tubules showed features of acute tubular necrosis, and the interstitium showed widespread edema mild endothelial swelling of the blood vessels. The direct immunofluoroscence examination of the biopsy showed mesangial deposits of IgA (++), IgM (+) and C3 (+), [Figure 2]; no IgG deposits were detected. Based on the above features, a diagnosis of mesangioproliferative glomerulonephritis associated with IgA nephropathy was made. Subsequently, the patient's serum IgA levels were found to be mildly elevated (247 mg%) with preponderence of IgA 1 (219 mg%).
By the end of four weeks, the patient had received 6 sessions of hemodialysis along with two units of blood transfusion. Around this time, his renal functions showed improvement and urine output increased to 2.5-3.0 liters/day by the end of 5 th week. Serum creatinine decreased to 1.3 mg%. A routine urine examination at the time of discharge showed no hematuria.
As the finding of glomerular IgA deposits and mesangioproliferative glomerulonephritis coinciding with dengue virus infection was unusual, we decided to perform a repeat renal biopsy after 6 weeks of clinical remission to further evaluate this association. A urine examination prior to the repeat biopsy did not show any RBC's. Serum IgA levels were normal (180 mg%). The light microscopic examination of the renal biopsy showed resolution of the mesangioproliferative changes. The tubulointerstitial changes had recovered with no residual inflammation or fibrosis [Figure 3]. The direct immunofluoroscence examination showed mesangial deposits of IgM (+) and C3 (+) and was negative for IgA and IgG.
The pathogenic links between viral infections and concomitant renal dysfunction are often difficult to establish. The causal association could be suggested by factors such as the serological identification of specific viral antigenemia and detection of viral antigens and host antibodies in renal structures. While it may not be possible to demonstrate complete cure after eradication of the virus in all the cases, improvement of the renal disease concomitant with clearance of the suspected antigen or recurrence of the glomerulonephritis after reinfection may be additional criteria to prove the cause-effect link. The present case provokes several such issues, which relate to the immunopathologic mechanisms operating in the course of DF and its implications in the development of acute kidney injury.
Various mechanisms are implicated in the pathogenesis of renal injury associated with viral infections. These include the direct cytopathic effects of viral proteins on glomerular and tubular cells, in-situ immune mediated mechanisms involving viral antigens bound to glomerular structures, injury due to circulating immune complexes composed of viral antigens and host anti-viral antibodies and injury due to various inflammatory mediators released in response to glomerular or tubular cytopathic effects. ,
While transient renal abnormalities are seen in several viral infections, acute kidney injury is associated mostly with arboviral hemorrhagic fevers, parvo virus B 19, measles, yellow fever and rarely dengue virus infections. ,,,, Renal involvement in dengue virus infection may occur with any of the clinical syndromes including DF, DHF, and DSS. Acute kidney injury in association with DF is rare and only eight cases have been adequately described in the literature. ,,, Most of these patients presented with hypotension, shock, hemolysis, rhabdomyolysis and required HD support for varying durations. An eventual recovery was seen in most of the cases where follow-up was available. Our patient did not show any features of shock, hemolysis, or rhabdomyolysis, and he required hemodialysis support for three weeks and showed complete clinical recovery in five weeks. The acute renal failure could be in part mediated by the tubular damage mediated by direct cytopathic effects of the virus and cytokine induced injury.
Furthermore, the finding of glomerular hematuria at presentation and the presence of mesangial IgA deposits followed by eventual resolution of IgA deposits and hematuria concomitant with clinical recovery point towards an association between the IgA deposits and viral infection. Studies on the kinetics of dengue virus specific serum immunoglobulin classes in patients with DF have shown that virus specific IgA antibodies are detectable between days 811 after the onset of fever and levels of dengue specific IgA correlate with the severity of disease outcome, thus emphasizing their role in the pathogenesis of the disease.  Indeed, the measurement of dengue specific IgA antibodies in serum is considered an important tool for diagnosis of a primary dengue virus infection.  In the present case, total serum IgA levels were elevated when performed three weeks after the onset of fever and touched normal values after 12 weeks. This coincided with the resolution of the mesangial IgA deposits in the repeat renal biopsy performed at the same time.
We hypothesize that Dengue virus infection was able to elicit an altered IgA immune response to viral antigens and resulted in the formation of nephritogenic circulating immune complexes, which subsequently deposited in the glomerular mesangium, and the ensuing cytokine and chemokines response resulted in the mesangial proliferation. This phenomenon may be transient and could be similar to that observed in other infections where immune complexes are cleared from the glomerulus in about three to four weeks time. , Immune complex mediated glomerulonephritis associated with DHF has been reported earlier, however, the immune complex deposits in these cases consisted predominantly of IgG, IgM and C3 and deposited in the mesangium in a coarse granular pattern.  The renal biopsy findings have been described in only one case of acute renal injury associated with DF, which revealed features of a thrombotic microangiopathy. 
In conclusion we have presented a case of acute kidney injury related to dengue fever without any evidence of third space loss, hypovolemia, hypotension, sepsis, or rhabdomyolysis. We attribute the renal failure to acute tubular necrosis with transient IgA nephropathy due to an immune related phenomenon. This phenomenon may be under-recognized and contribute to the severity of renal injury in the setting of dengue viral infection particularly DF.
|1||Gubler DJ. Epidemic dengue and dengue hemorrhagic fever: A global public health problem in the 21st century. In: Scheld, WM, Armstrong, D, Hughes, JM (Eds). Emerging Infections. ASM Press, Washington DC; 1998:1.|
|2||Boonpucknavig V, Bhamarapravati N, Boonpucknavig S, Futrakul P, Tanpaichitr P. Glomerular changes in dengue hemorrhagic fever. Arch Pathol Lab Med 1976;100:206-12.|
|3||Hommel D, Talarmin A, Reynes JM, Hulin A. Acute renal failure associated with dengue fever in French Guiana. Nephron 1999;83:183.|
|4||Nair VR, Unnikrishnan D, Sathish B, Sahadulla MI. Acute renal failure in dengue fever in absence of bleeding manifestations or shock. Infec Dis Clin Pract 2005;13:142-43.|
|5||Weirsinga WJ, Scheepstra CG, Kasanaedjo JS, de Vries PJ, Zaaijer H, Geerlings SE. Dengue fever induced hemolytic uremic syndrome. Clin Infec Dis 2006;43:800-1.|
|6||Karakus A, Banga N, Voorn GP, Meinders AJ. Dengue shock syndrome and rhabdomyolysis. Neth J Med 2007;65:78-81.|
|7||Cheema SR, Arif F, Charney D, Meisels IS. IgA dominant glomerulonephritis associated with hepatitis A. Clin Nephrol 2004;62:1238-143.|
|8||Lai KN, Lai FM, Tam JS, Vallance-Owen J. Strong association between IgA nephropathy and hepatitis B surface antigenemia in endemic areas. Clin Nephrol 1988;29:229-34.|
|9||Glassock RJ. Immune complex-induced glomerular injury in viral diseases: an overview. Kidney Int 1991;40(supp 35):S5-7.|
|10||Couser WG. Mechanisms of glomerular injury in immune complex disease. Kidney Int 1985; 28:569-83.|
|11||Globus SM, Wilson C. Experimental glomerulonephritis induced by in-situ formation of immune complexes in glomerular capillary wall. Kidney Int 1979;16:148-57.|
|12||Nakazawa T, Tomosugi N , Sakamoto K, et al. Acute glomerulonephritis after human parvovirus B19 infection. Am J Kidney Dis 2000;35:E31.|
|13||Monath TP. Yellow fever: a medically neglected disease: Report on a seminar. Rev Infect Dis 1987;9:165-75.|
|14||Lin CY, Hsu HC. Measles and acute glome rulonephritis. Pediatrics 1983;71:398-401.|
|15||Lima EQ, Gorayeb FS, Zanon JR, Nogueira ML, Ramalho HJ, Burdmann EA. Dengue hemorrhagic fever induced acute kidney injury without hypotension, hemolysis or rhabdomyolysis. Nephrol Dial Transplant 2007;22: 3322-6.|
|16||George R, Liam CK, Chua CT, Lam SK, Pang T, Geethan R, Foo LS. Unusual clinical manifestations of dengue virus infection. Southeast Asian J Trop Med Public Health 1988;19:585-90.|
|17||Koraka P, Suharti C, Setiati TE, et al. Kinetics of Dengue virus specific serum immunoglobulin classes correlate with clinical outcome of infection. J Clin Microbiol 2001;39:4332-8.|
|18||Nawa M, Takasaki T, Ito M, Inoue S, Morita K, Kurane I. Immunoglobulin A antibody responses in dengue patients: A useful marker for serodiagnosis of dengue virus infection. Clin Diag Lab Immunol 2005;12:1235-7.|
|19||Bhamarapravati, N, Boonpucknavig S, Boonpucknavig V, Yaemboonruang C. Glomerular changes in acute falciparum infection. Arch Pathol 1973;96:289-93.|
|20||Sitprija V, Pipatanagul V, Boonpucknavig V, Boonpucknavig S. Glomerulitis in typhoid fever. Ann Intern Med 1974;81:210-3.|