Volume 54, Issue 6 , Pages 1162-1166, December 2009
Young Man With Kidney Failure and Hemorrhagic Interstitial Nephritis
Article Outline
Index Words: Hantavirus, interstitial nephritis, nephropathia epidemica
Hantaviruses, which are single-stranded negative-sense RNA viruses, make up a genus of the family Bunyaviridae. They are prevalent in the Americas, Europe, and Asia, but not in Australia. Beginning with the American Civil War, later in World War I and II, and then in the Korean War in the 1950s and the wars in former Yugoslavia in the 1990s, hantaviruses have had a long history linked to trench warfare and associated contact with rodent reservoirs (reviewed in1). Hantaviruses were identified first as pathogens in the course of their isolation in 1978 by Lee et al,2 and today, at least 30 serotypes that differ in geographic distribution, rodent reservoirs, and clinical features are known (reviewed in3, 4, 5, 6, 7, 8, 9). Although hantaviruses in North and South America cause hantavirus cardiopulmonary syndrome, hantaviruses in Asia and Europe usually cause hemorrhagic fever with renal syndrome (HFRS).
The most prevalent serotypes in Europe are Dobrava (which causes the most severe clinical manifestations) and Puumala (which causes the mildest form of HFRS, nephropathia epidemica). After incubation of approximately 2 to 3 weeks, a multiphasic illness begins. The first phase, with a duration of 3 to 7 days, is characterized by fever and pain in the abdomen and back. In the second phase, lasting from a few hours to 2 days, proteinuria develops and is accompanied by capillary leakage and hemorrhage. In the third or oliguric phase, nausea, vomiting, and acute kidney injury with hypovolemia develop. Patients who die of HFRS most often do so in the second and third phases. In the fourth, or polyuric, phase, which lasts from days to weeks, diuresis resumes. In this phase, the patient is threatened by shifts in fluid and electrolytes. In the fifth phase, which has a duration of 2 to 3 months, complete recovery of kidney function usually occurs (reviewed in3, 4, 5, 10, 11, 12, 13).
HFRS is a mostly benign self-limiting disease. However, fatal cases and such severe complications as Guillain-Barré and empty sella syndrome have been reported.14 Some patients are left with mild, but long-term, decreases in kidney function.15 A recent study showed that although patients had a slight decrease in glomerular filtration rate and mild proteinuria 5 years after developing nephropathia epidemica, these features disappeared after an additional 5 years. Patients still showed a propensity to develop hypertension in later life.16
Case Report
Clinical History
A previously healthy 14-year-old boy experienced an episode of high fever (temperature, 104°F [40°C]), headache, nausea, and lumbar pain for several days. Because of suspected encephalitis, he was admitted to the hospital, but cerebrospinal fluid testing and brain magnetic resonance imaging showed normal results.
Initial laboratory findings were a low platelet count of 108 × 103/μL (108 × 109/L) with a normal hemoglobin level of 16.1 g/dL (161 g/L) and normal white blood cell count of 8 × 103/μL (8 × 109/L). The initial serum creatinine level of 0.75 mg/dL (66.3 μmol/L) and creatinine clearance calculated by using the Schwartz equation of 135 mL/min (2.25 mL/s) were normal. However, on day 5, serum creatinine level increased to 3.9 mg/dL (344.8 μmol/L), lactate dehydrogenase level was increased at 318 U/L, and platelet count decreased to 80 × 103/μL (80 × 109/L). Acute kidney injury was diagnosed, and the patient was referred to the Clinic of Pediatric Nephrology, University Hospital Essen, Germany.
On arrival, the patient was normotensive and afebrile. Except for diffuse lumbar pain, findings on physical examination were normal. Laboratory studies confirmed thrombocytopenia (platelet count, 88 × 103/μL [88 × 109/L]) and acute kidney injury (serum creatinine, 4.2 mg/dL [371.3 μmol/L]; creatinine clearance, 24 mL/min [0.4 mL/s]). The patient had proteinuria with protein of 2 g/d and microscopic hematuria. Kidney ultrasound showed enlarged kidneys with a total kidney volume of 820 mL (reference value, 310 mL). A kidney biopsy was performed on day 5 after the onset of symptoms.
Kidney Biopsy
On examination with a stereo microscope, a portion of the 2 biopsy cores was intensely red. In paraffin sections, the microscopic correlate for this finding was massive interstitial hemorrhage confined to the medulla and corticomedullary junction (Fig 1). In this area, capillaries were either congested or ruptured and endothelial cells were either swollen or absent. The interstitium was edematous and moderately infiltrated by lymphocytes, plasma cells, and macrophages, as well as neutrophils and a very few eosinophils. Intraepithelial infiltrates were not apparent (Fig 2). The cortical tubular epithelial cytoplasm was flattened and had lost its brush borders. In contrast, tubular basement membranes, surrounding interstitium, and glomeruli were virtually normal (Fig 3). No immunoglobulin or complement deposits were found on immunohistochemical staining of the paraffin-embedded material. Additional immunohistochemistry (IHC) for hantavirus antigen, performed at the Department of Pathology at the University of New Mexico, Albuquerque, NM, was negative. Ultrastructural examination did not show immune deposits or viral particles. Foot processes of the podocytes were well preserved, the endothelium in glomeruli and cortical peritubular capillaries was unremarkable, and the specimen did not contain medulla.
Figure 1.
Tubulointerstitial hemorrhage and infiltrate in the medulla (upper core); the cortex (lower core) shows no hemorrhage, only widened tubular lumina indicative of acute tubular damage (hematoxylin and eosin stain; original magnification ×25).
Figure 2.
Medulla with congested and ruptured capillaries, edema, interstitial hemorrhage, and moderate infiltrate of lymphocytes, plasma cells, neutrophils, and few eosinophils. Note the absence of intraepithelial infiltrates (hematoxylin and eosin stain; original magnification ×200).
Figure 3.
Virtually normal glomerulus and preglomerular vessel (left). Cortical tubules with flattened epithelium and attenuated brush border indicating acute tubular damage. Note the absence of hemorrhage and inflammatory infiltrates in this portion of the midcortex (periodic acid–Schiff stain; original magnification ×200).
Diagnosis
A diagnosis of acute medullary hemorrhagic interstitial nephritis with acute tubular damage, suggestive of acute hantavirus nephritis, was made. Acute hantavirus infection was confirmed serologically by means of Western blot of the patient's serum against recombinant antigens of the Puumala serotype; isotype-specific conjugates were used to confirm positive immunoglobulin M and immunoglobulin G signals. Further questioning showed that the patient lives in a rural area and frequently comes into contact with bank voles when cleaning mouse traps at his parents' house. Bank voles are the main reservoir of hantavirus in this region of Germany; therefore, he most likely caught the infection by inhalation of aerosolized hantavirus particles.
Clinical Follow-up
Kidney function recovered fully within 10 days and kidney volume decreased to normal. Two years after the infection, the patient remains well. He is normotensive and does not have renal sequelae, with a creatinine clearance of 170 mL/min (2.8 mL/s, calculated by using the Schwartz equation).
Discussion
Despite our inability to detect hantavirus antigens in the kidney, the present case is a typical example of HFRS. As a clinical teaching point, the combination of thrombocytopenia, fever, loin pain, and acute kidney injury in patients with potential contact with mice or other rodents (camping trips, living in rural areas, and so on) should alert physicians to the possibility of hantavirus nephritis.
In terms of pathology, the present case covers the differential diagnosis of hemorrhagic interstitial nephritis. Several infectious and noninfectious conditions are on the list of differential diagnoses (Box 1). Other infectious nephritides to be considered are kidney involvement in leptospirosis and rickettsiosis, and in other clinical settings and areas, also infections with other RNA viruses from the hemorrhagic fever group, such as Marburg, Ebola, Dengue-fever virus, or flaviridae. Kidney histological findings in patients with leptospirosis and rickettsiosis are poorly defined in the literature, and these diagnoses should be excluded by means of serological or polymerase chain reaction (PCR) testing. According to our limited experience with histological characteristics of hantavirus nephritis and leptospirosis, both are similar in the composition of the inflammatory infiltrate and in having peritubular capillaritis without significant tubulitis. Usually, the amount of hemorrhage is more extensive in hantavirus nephritis and the infiltrate spares the cortex, in contrast to kidney involvement in leptospirosis.
Hantavirus nephritisLeptospirosisRickettsiosisOther hemorrhagic fever RNA viruses
In kidney transplant recipients, the differential diagnosis between acute cellular rejection (with hemorrhage as an indicator of a humoral rejection component) and hantavirus nephritis can be challenging.17 Interstitial hemorrhage is a rare feature of acute humoral rejection and can be ruled out by means of negative C4d stains, negative serological test results for panel-reactive antibodies, and lack of such additional histological findings suggestive of acute humoral rejection as transplant glomerulitis. Also, the observation that the area of hemorrhage is confined to the medulla and corticomedullary junction in hantavirus nephritis should help exclude acute humoral rejection, in which there is both medullary and cortical hemorrhage. The latter feature also distinguishes hantavirus nephritis from hemorrhagic margins of anemic and hemorrhagic infarcts caused by renal vein thrombosis, which also involve both the cortex and medulla. Focal inflammation and hemorrhage also can result from needle tracks from previous biopsies or injury from other procedures; such causes are best ruled out by reviewing the medical history.
The diagnosis of HFRS can also be confirmed by using PCR, even on formalin-fixed paraffin-embedded kidney biopsy specimens.18 IHC of formalin-fixed paraffin-embedded kidney tissue can be performed only in reference pathology departments because appropriate diagnostic antibodies are not available commercially. The majority of the experience with diagnostic detection of hantavirus RNA by using reverse-transcription PCR or hantavirus antigens by using IHC has been obtained by using necropsy-derived samples from patients who died of infection caused by Sin Nombre virus or Andes hantavirus. In the case of Sin Nombre virus infections that led to the patient's rapid death, the sensitivity of either IHC or reverse-transcription PCR is believed to approximate 100%. However, the sensitivity of staining or reverse-transcription PCR studies with milder infections caused by HFRS-associated hantaviruses or any infection for which the biopsy sample is collected outside the earliest times relative to the onset of symptoms may be relatively reduced17, 19 and may explain the negative result in our case.
Hantaviruses enter cells through β3 integrin, which is present on platelets, macrophages, and endothelial cells. The inflammatory infiltrate typically is mild and consists of plasma cells, T lymphocytes (more CD8+ than CD4+), and a few CD22+ B lymphocytes, as well as macrophages, eosinophils, and neutrophils.20, 21 Endothelial damage is believed to occur primarily from immune mechanisms and not viral cytopathic effects and explains the characteristic hemorrhage. Interestingly, despite the massive endothelial damage, capillary thrombi are not a typical feature of hantavirus nephritis. The reason for the proteinuria in patients with HFRS is still unclear. The normal ultrastructural appearance of glomerular endothelium and podocytes and lack of the mesangial immunoglobulin M and C1q staining we usually observe in patients with glomerular proteinuria lead us to speculate that the observed proteinuria is caused by leakage from the injured peritubular capillaries in the medulla.
In summary, hemorrhagic interstitial nephritis confined to the medulla and corticomedullary junction is highly suggestive of hantavirus nephritis, and this diagnosis can be confirmed by means of serological tests22 or direct demonstration of the virus by using IHC or PCR.
Acknowledgements
Support: Dr Hjelle is the recipient of US Public Health Service Grant UO1 AI56618.
Financial Disclosure: This work was supported by Forschungsunterstützungskreis Kindernephrologie e. V., Essen, Germany.
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Originally published online as doi: 10.1053/j.ajkd.2009.04.025 on June 26, 2009.
PII: S0272-6386(09)00756-2
doi:10.1053/j.ajkd.2009.04.025
© 2009 National Kidney Foundation, Inc. Published by Elsevier Inc All rights reserved.
Volume 54, Issue 6 , Pages 1162-1166, December 2009
