Brucella glomerulonephritis.

Reports of renal involvement with brucellosis are rare and anecdotal even though patients can excrete brucellae in the urine. Mild proteinuria may be commonly seen with brucellosis. However, cases of interstitial nephritis, pyelonephritis, immunoglobulin (Ig)A and membranous nephropathy, massive proteinuria, and caseating granulomas have all been reported in the literature. (1-5) Renal involvement has been classified into three main groups. (1-3) Firstly, an acute interstitial nephritis (AIN) with associated proteinuria, hematuria, pyuria, urinary frequency and dysuria, is commonly seen in the acute phase of brucella infection and is caused by direct invasion of the bacterium. (3) The interstitial nephritis does not seem to be due to infection of the renal parenchyma but rather an immune response targeting the interstitium. Secondly, a chronic granulomatous interstitial nephritis that mimics renal tuberculosis or chronic pyelonephritis is characterized by lymphocytic infiltrates and occasional granulomas. Thirdly, an immune-complex mediated glomerulonephritis in which circulating antigen-antibody complexes are deposited on the epithelial side of the basement membrane.

This infection-related glomerulonephritis can be seen in patients with Brucella endocarditis. (3) Low complement levels have been reported with the mesangiocapillary form of glomerulonephritis. Renal biopsies have shown a variety of lesions that include mesangial proliferation, focal segmental proliferation, diffuse proliferation, and crescents. Cases with lesions seen in IgA nephropathy or membranous and membranoproliferative glomerulonephritis have also been reported. (1-5)

Immunofluorescence may show no deposits, IgG, or occasionally IgA. (1-10) In infections with brucella, there is usually improvement after antibiotics, but histologic abnormalities, proteinuria, and hypertension may persist. It is likely that resolution of the proteinuria, abnormal urinary findings, and correction of renal function after treatment of brucellosis suggests an association between the infection and renal findings. (1)

Apart from renal involvement, other serious complications resulting from brucellosis have been reported in large series. (6,7) These include endocarditis (1 to 2% of cases) with aortic valve involvement being the most common followed by the mitral. Mycotic aneurysms of the ventricle, brain, and aorta have also been described. Nervous system involvement is rare (1 to 5% of cases) with cases of meningitis and encephalitis described. Noncaseating granulomas in the liver, spleen, lung, and bone marrow are reported. Musculoskeletal complications may include sacroiliitis, spondylitis, osteomyelitis, and synovitis. Microangiopathic hemolytic anemia, and thrombocytopenia have also been reported. Epididymo-orchitis in males and spontaneous abortions in pregnant women with brucellosis are well known presentations.

Brucellosis (undulant fever, Mediterranean fever, Malta fever) is a zoonotic infection transmitted from animals to humans. Humans are accidental hosts acquiring the disease by direct contact with an infected animal, ingestion of infected food products, or inhalation of aerosols. The organism was first isolated in 1887 by Dr. David Bruce, a British army physician. The highest incidence is observed in the Middle East, Mediterranean region, China, India, Peru, and Mexico. A concerted effort by the United States Department of Agriculture has reduced the incidence of brucella infection seen in cattle in the United States. Cases in the US are generally found in Texas, California, Virginia and Florida.

Presently, four species have human pathogenicity, namely Brucella suis (pigs), Brucella melitensis (sheep), Brucella abortus (cattle), and Brucella canis (dogs). Brucellae are small, Gram negative coccobacilli that lack flagella, endospores, and a capsule. The bacteria invade through the alimentary tract, lungs, conjunctivae, and skin abrasions. The use of fresh unpasteurized milk or milk products such as cheese may be the source in places where the disease is endemic. The organisms localize in the reticuloendothelial system with involvement of lymph nodes, spleen, liver, and bone marrow. The disease is characterized by nonspecific clinical manifestations such as fever, chills, profuse sweats, body aches, lethargy, and fatigue.

A definitive diagnosis of brucellosis is made by recovering brucellae from the blood or other tissues. A presumptive diagnosis in patients with active infections may also be made by demonstrating high or rising titers of specific antibodies (1:160 or higher) to brucella. The serum agglutination test is the most widely used indicator. (8) Recently, an indirect enzyme-linked immunosorbent assay and polymerase chain reaction have also been used. (11-12) The speed and technical simplicity of light cycler polymerase chain reaction in serum samples make it a useful alternative to blood cultures for patients with suspected brucellosis and negative or doubtful serologic test results. (11-12)

Simple infections may be treated with doxycycline (100 mg, orally twice a day for 6 weeks), but the relapse rate is around 40% for monotherapy. (13) Therefore, a combination of doxycycline with rifampin, gentamicin, streptomycin or trimethoprim/sulfamethoxazole have all been used for treatment of acute brucellosis. (10-12)

The nonspecific clinical manifestations make the diagnosis difficult. Failure to entertain the possible diagnosis in a patient with a history suggestive of a possible source of infection (farmer, slaughterhouse worker, traveler to endemic region, veterinarian, laboratory workers) may delay the diagnosis and lead to more severe complications. Prompt diagnosis and treatment results in resolution of the clinical and renal findings in the majority of cases.

References

1. Altiparmak MR, Pamuk GE, Pamuk ON, et al. Brucella glomerulonephritis: review of the literature and report on the first patient with brucellosis and mesangiocapillary glomerulonephritis. Scand J Infect Dis 2002;34:477-480. Review

2. Sharivker D, Vazan A, Varkel J. Brucella endocarditis complicated by acute glomerulonephritis--early surgical intervention. Acta Cardiol 2001;56:399-400.

3. Odeh M, Oliven A. Acute brucellosis associated with massive proteinuria. Nephron 1996;72:688-689.

4. Elzouki AY, Akthar M, Mirza K. Brucella endocarditis associated with glomerulonephritis and renal vasculitis. Pediatr Nephrol 1996;10:748-751.

5. Haririan A, Ghadiri G, Broumand B. Brucella glomerulonophritis. Nephrol Dial Transplant 1993;8:373-374.

6. Siegelmann N, Abraham AS, Rudensky B, et al. Brucellosis with nephrotic syndrome, nephritis and IgA nephropathy. Postgrad Med J. 1992;68:834-836.

7. Ayatollahi J. Epidemiological, clinical, diagnostic and therapeutic survey of 686 cases of brucellosis. Ann Saudi Med 2004;24:398-399.

8. Hasanjani Roushan MR, Mohrez M, Smailnejad Gangi SM, et al. Epidemiological features and clinical manifestations in 469 adult patients with brucellosis in Babol, Northern Iran. Epidemiol Infect 2004;132:1109-1114.

9. Doregatti C, Volpi A, Torri Tarelli L, et al. Acute glomerulonephritis in human brucellosis. Pathologica 1985;77:519-524.

10. Volpi A, Doregatti C, Tarelli T, et al. Acute glomerulonephritis in human brucellosis. Report of a case. Nephrol Dial Transplant 1993;8:373-374.

11. Funk ND, Tabatabai LB, Elzer PH, et al. Indirect Enzyme-Linked Immunosorbent Assay for Detection of Brucella melitensis-Specific Antibodies in Goat Milk. J Clin Microbiol 2005;43:721-725.

12. Queipo-Ortuno MI, Colmenero JD, Baeza G, et al. Comparison between LightCycler Real-Time Polymerase Chain Reaction (PCR) assay with serum and PCR-enzyme-linked immunosorbent assay with whole blood samples for the diagnosis of human brucellosis. Clin Infect Dis. 2005;40:260-264.

13. Solera J, Geijo P, Largo J, et al. Grupo de Estudio de Castilla-la Mancha de Enfermedades Infecciosas. A randomized, double-blind study to assess the optimal duration of doxycycline treatment for human brucellosis. Clin Infect Dis 2004;39:1776-1782.

To love someone means to see him as God intended him.
--Feodor Dostoevsky

Fahim Zaman, MD, FACP, and Kenneth Abreo, MD

From the Division of Nephrology and Hypertension, Louisiana State University Health Sciences Center, Shreveport, LA.

Reprint requests to Fahim Zaman, MD, FACP, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71103. Email: [e-mail]

Accepted April 20, 2005.