Table of Contents  

Venyo: Brucellosis associated with kidney injury and any form of nephropathy – a review of the literature

Introduction

Brucellosis is a multisystem disease caused by members of the genus Brucella, which is commonly transmitted from animals to humans via occupational exposure or ingestion of unpasteurized dairy products. Brucellosis may present with a wide spectrum of clinical manifestations. Common symptoms of brucellosis are constitutional symptoms. Brucellosis of bones, joints and the liver is common but involvement of the kidney is rare. Brucellosis is more common in developing countries, but is sporadically encountered in the developed world.

This literature review on brucellosis-associated kidney diseases is divided into two parts: (1) an overview and (2) miscellaneous narrations and discussions from some reported cases.

Methods

Various internet databases (PubMed, Google, Google Scholar and Educus) were searched to identify case reports, case series, review papers and other articles related to ‘brucellosis of the kidney’, ‘brucellosis nephropathy’, ‘brucellosis-associated renal failure’ and ‘brucellosis glomerulonephritis’. A total of 47 references were identified and included in this literature review.

Literature review

Overview

General

Brucellosis is more common in regions with less well-established animal disease control programmes and in areas where public health initiatives have been less effective.1

Reported high-risk areas of brucellosis include a number of Mediterranean countries (Portugal, Spain, southern France, Italy, Greece, Turkey and North Africa), South and Central America, eastern Europe, Africa, Asia, the Caribbean and the Middle East.1

According to World Health Organization data, 500 000 people are diagnosed with brucellosis annually.13

Presentation

Systemic brucellosis may be associated with acute kidney injury (AKI); haemolytic–uraemic syndrome; nephrotic syndrome or with various types of nephropathy, including acute interstitial nephritis, interstitial nephritis mimicking tuberculosis of kidney, recurrent immunoglobulin A nephropathy and renal abscess; and chronic interstitial and various other types of glomerulonephritis, including mesangiocapillary glomerulonephritis, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, rapidly progressive glomerulonephritis and focal segmental glomerulonephritis. Other types of renal disease that may be associated with brucellosis include rhabdomyolysis and acute renal failure. Presentation depends on the type of renal disease.

Acute kidney injury

Systemic brucellosis associated with AKI may present with fever, general malaise, weight loss, loin and joint pains and clinical signs of dehydration as well as biochemical test evidence of renal failure.

Acute interstitial nephritis

Acute interstitial nephritis associated with brucellosis may present with haematuria, fever, proteinuria, acute malaise or general malaise.

Nephritis mimicking tuberculosis may present insidiously with non-specific symptoms, weight loss and pyrexia of unknown origin.

Diagnosis

A good clinical history of contact with or ingestion of unpasteurized dairy products is helpful in directing the clinician to consider the possibility of brucellosis.

Diagnosis of brucellosis as a cause of nephropathy would require the following:

  1. isolation of Brucella in blood culture;

  2. positive serological test for brucellosis;

  3. renal biopsy evidence of the type of nephropathy;

  4. culture of Brucella from perinephric abscess or renal abscess aspirate;

  5. culture of Brucella from a nephrectomy specimen and finding a specific type of nephropathy during histological examination.

Ultrasonography and computerized tomography (CT) are not specific for brucellosis; however, scans may show an abnormal area in the kidney from which targeted renal biopsies can be taken for pathological examination and culturing, and if there is an abscess it can be aspirated for culture.

Diagnosis of brucellosis may be divided into (1) presumptive diagnosis and (2) confirmatory diagnosis.

Presumptive diagnosis

Presumptive diagnosis includes use of the standard agglutination test (SAT) and the Rose Bengal test (RBT) to screen for brucellosis. A positive RBT test would need to be confirmed by one of the tests specified under ‘Confirmatory diagnosis’.

Confirmatory diagnosis

Confirmatory diagnosis of brucellosis includes the isolation of Brucella spp. from blood or other clinical specimen, and a positive result from a presumptive laboratory diagnosis, which has been based on the detection of agglutinating antibodies (RBT and SAT) in combination with the detection of non-agglutinating antibodies through the use of enzyme-linked immunosorbent assay (ELISA) IgG and Coombs IgG tests.

Polymerase chain reaction (PCR) and new rapid tests, such as lateral flow tests, have been developed.48

Evidence of nephropathy associated with brucellosis would depend on:

  1. the diagnosis of brucellosis by means of Brucella culture, or a positive laboratory result for Brucella (RBT, SAT, ELISA IgG test, Coombs IgG test);

  2. evidence of renal failure by means of biochemical tests that confirm renal failure associated with brucellosis; a histological examination finding any type of nephropathy associated with positive Brucella isolation from renal tissue or blood culture should be sufficient.

Treatment

The most common antibiotic treatment for brucellosis is doxycycline 100 mg twice a day for 45 days in combination with streptomycin 1 g/day for 15 days.1 An alternative to this treatment is doxycycline 100 mg twice a day for 45 days in combination with rifampicin 15 mg/kg/day (600–900 mg) for 45 days.9 Experience suggests that streptomycin may be replaced by gentamicin 5 mg/kg/day for 7–10 days; however, there has been no study directly comparing these two treatment regimens.9 The optimal treatment for neonates and children under 8 years old has not yet been determined but there is some experience of trimethoprim/sulfamethoxazole (cotrimoxazole) in combination with an aminoglycoside (streptomycin, gentamicin) or rifampicin.9 Other combinations of antibiotics have also been used.

In cases of kidney injury (renal failure) and dehydration, in addition to antibiotic treatment, rehydration and clinical monitoring of patients is required, as is monitoring urine output, repeated urinalysis and repeated serum biochemical tests for renal function estimation to assess the progress of the patient.

Renal abscess is treated by nephrectomy if it is considered likely that the lesions are renal tumours. Renal/perirenal abscesses found in association with isolation of Brucella in blood cultures or with positive Brucella serology tests can be treated by aspiration under radiological guidance (ultrasonography/CT). The patient should then be followed up by repeating the scans whilst antibiotic treatment continues.

Relapses of brucellosis can occur; thus, before stopping combined antibiotic treatment, clinicians are advised to confirm cure as follows:

  • Clinical improvement is apparent, with disappearance of symptoms.

  • There is biochemical evidence of resolution of kidney injury or improvement in renal function to near normal.

  • The results of laboratory tests used to diagnose brucellosis (RBT, SAT, ELISA IgG test, Coombs IgG test, PCR) have returned to normal.

  • If Brucella was isolated from blood cultures, the organism should be absent from two consecutive blood cultures, taken 1 month apart, after the patient has become asymptomatic.

  • If renal or perirenal abscesses have been drained, there should be further radiological evidence of complete resolution of the abscess confirmed by ultrasonography, CT or magnetic resonance imaging (MRI).

Even if there is evidence of dissolution of symptoms and of resolution of an abscess, a long period of follow-up is recommended to identify relapses early.

Outcome

Most cases of renal complications associated with brucellosis resolve/improve after careful combined antibiotic treatment and rehydration, and renal function can also be expected to improve or even return to normal.

As relapses can occur, careful patient follow-up, involving regular urinalysis, renal function tests, liver function tests and full blood count and coagulation tests, as well as repeated blood and urine cultures and Brucella serology tests, is essential.

Prevention

To avoid infection in future, patients should be educated to avoid contact with and ingestion of unpasteurized dairy products.

In Brucella-endemic areas, pasteurization of all dairy products should be advised, encouraged and monitored.

Veterinary surgeons in endemic areas should be informed and assist when a new diagnosis is made in order to help identify and treat or kill affected animals harbouring Brucella.

Miscellaneous narrations and discussions from some reported cases

Ceylan et al.10 retrospectively evaluated data from 15 patients (eight males and seven females; age 16 to 80 years) diagnosed with brucellosis with renal involvement between 1998 and 2006:

  • In almost all cases, urinalysis revealed haematuria and variable amounts of proteinuria, and, in some patients, pyuria.

  • Kidney injury was present in 14 of the 15 patients.

  • The aetiology of kidney injury was as follows: prerenal azotaemia (1); acute tubular necrosis as a sequel of non-steroidal anti-inflammatory drug use (1); anuric tubulointerstitial nephritis due to use of rifampicin (1); nephritis caused by Brucella endocarditis (3); Brucella endocarditis and tubulointerstitial nephritis-associated vasculitis (1); Brucella membranoproliferative glomerulonephritis (1); and Brucella tubulointerstitial nephritis without vasculitis (6).

  • Five patients received haemodialysis, one patient developed chronic kidney disease, two patients were lost to follow-up and 11 patients experienced complete recovery of renal function.

  • Renal biopsy and pathological examination in two patients revealed membranoproliferative glomerulonephritis with intraglomerular infiltration of histiocytes in one and chronic tubulointerstitial nephritis associated with vasculitis and features of immune complex nephritis in the other.

Ceylan et al.10 concluded that in Brucella-endemic areas, renal involvement of brucellosis can be associated with haematuria, proteinuria and kidney injury and, furthermore, many diverse aetiologies can play a role in the renal involvement associated with Brucella infection.

In 2008, Bakri et al.11 described Brucella glomerulonephritis as a rare condition, with only a few cases reported in the literature, and reported the case of a 24-year-old woman presenting with oedema and proteinuria. Blood culture showed growth of Brucella melitensis. Renal biopsy and pathological examination of the specimen showed diffuse proliferative glomerulonephritis. The patient progressed to end-stage renal disease despite antibiotic and steroid therapy.

Dagli et al.1 reported the case of a 42-year-old man who presented with a 3-week history of nausea, sweating, fever, loss of appetite, weakness and generalized joint pain. He had also been experiencing dysuria and bilateral testicular swelling for 2 days. He had been healthy previously and worked as a shepherd. On examination, he was found to have a temperature of 38.2°C and a pulse of 109 beats/minute. He also had an enlarged liver and spleen. He was tender on suprapubic palpation and his testicles looked inflamed. A number of investigations were carried out, which were reported as follows:

  • white blood cell count – 1620 leucocytes/mm3 with 61% neutrophils;

  • platelet count – 81 000/mm3;

  • haemoglobin – 11 g/dl;

  • partial thromboplastin time – 14.9 s;

  • international normalized ratio – 1.28;

  • C-reactive protein – 43.3 mg/l;

  • erythrocyte sedimentation rate – 67 mm/h;

  • blood urea nitrogen (BUN) – 98 mg/l;

  • creatinine – 3.4 mg/dl;

  • serum sodium – 135 mmol/l;

  • serum potassium – 3.7 mmol/l;

  • aspartate aminotransferase – 59 U/l;

  • alanine transferase – 65 U/l;

  • serum calcium – 1.94 mmol/l;

  • urinalysis showed haematuria;

  • 24-hour urine examination revealed a proteinuria of 600 mg;

  • urine sediment contained granular casts;

  • ultrasonography of renal tract and scrotum revealed an enlarged and inflamed scrotum and increased echogenicity of the kidney;

  • chest radiograph was normal;

  • electrocardiography showed sinus tachycardia;

  • rheumatoid factor and tuberculosis skin test were negative.

The patient refused to undergo renal biopsy. He was diagnosed with oliguria on admission based on the fact he had passed 250 ml of urine in 24 hours. As a result, he was diagnosed as also having pyrexia of unknown origin and AKI. He was hydrated and given ceftriaxone 2 g/day. On day 2 post admission, his Brucella agglutinin serological test was positive at a titre of 1:160 and his Brucella indirect haemagglutination RBT was positive. A diagnosis of brucellosis was made and treatment was switched to oral rifampicin 600 mg and doxycycline 100 mg twice daily for 8 weeks. Brucella melitensis was isolated from the patient’s urine culture after 7 days of incubation, and from the blood culture after 8 days of incubation. Dagli et al.1 further reported that after 4 days of antibiotic treatment, the patient’s pyrexia decreased and, by day 5, the patient’s BUN and serum creatinine had markedly improved to near normal. His oliguria progressively disappeared. The azotaemia and inflammation of the testes and scrotum resolved. After 8 weeks of antibiotic treatment the patient had completely recovered.

Onaran et al.12 reported the case of a 36-year-old man with a localized perinephric soft-tissue mass containing both necrotic and cystic areas. The patient had been diagnosed with brucellosis 3 months prior to his referral, the cause of which was attributed to the regular consumption of dairy products, including cottage cheese. He initially presented with fever, arthralgia and back pain. The diagnosis of brucellosis had been made based on the results of a RBT and 2-mercaptoethanol positivity with a titre of 1:80, and he had been treated with doxycycline and rifampicin for 10 weeks. Despite treatment, in the month before his referral, night sweats, weight loss and subfebrile fever had recurred. Ultrasonography and CT were performed on the abdomen, which showed a left perinephric abscess with a possible diagnosis of renal cell carcinoma or perforated renal cyst. On examination he was found to have low-grade fever and slight tenderness in the left flank region. Blood cultures and serological tests were negative for brucellosis or other causes of renal abscess. The CT scan showed a 46 mm × 48 mm cystic lesion on the upper portion of the kidney and contrast injection revealed necrosis, which had extended into the perinephric soft tissue. Surgical exploration revealed purulent material and fistula tract between the cystic lesion and the perinephric tissue. The cyst was completely excised with its capsule, and frozen-section histological examination of the specimen ruled out malignancy. Pathological examinations of the specimen, including Ziehl–Neelsen, Kinyoun, light-green periodic acid–Schiff, Braun Bren and methenamine silver staining, was non-specific and the findings were adjudged to be similar to chronic inflammatory changes. Examination of a Giemsa-stained specimen revealed foamy histiocytes filled with basophilic microorganism-like elements. Standard microbiological cultures of the specimen were undertaken, which were also negative. PCR of DNA from the excised tissue followed by a genus-specific assay confirmed the presence of Brucella. The patient’s postoperative recovery was unremarkable and he was discharged on a 6-week course of rifampicin 900 mg/day and doxycycline 200 mg/day.

A 27-year-old woman reported by Ghanei et al.8 presented with brucellosis manifesting as hepatitis, pancytopenia, peripheral arthritis and renal failure. During admission, urinalysis revealed a trace of albuminuria and pyuria (leucocyte count of 20–25 cells per high-power field). Urine culture was negative for microorganism but her urine contained 1664 mg protein per 24 hours. She had oliguria during the first few days of her admission with an average 24-hour urine volume of 200 ml, and experienced repeated episodes of epistaxis. Serological tests for systemic lupus erythematosus, collagen vascular disease, vasculitis and hepatitis were all negative. In view of the patient’s thrombocytopenia a renal biopsy was not carried out. Bone marrow aspiration and bone marrow biopsy and pathological examinations of the specimens revealed hyperplasia of the erythroid line and slightly elevated numbers of megakaryocytes with pleomorphic nuclei. echocardiograpphy excluded subacute bacterial endocarditis. Ultrasonography of the abdomen, including Doppler ultrasound, revealed normal renal arteries, hepatosplenomegaly and no evidence of ascites. CT of the abdomen revealed hepatosplenomegaly and fine lymphadenopathy around the coeliac axis. Five days after admission, the patient developed a fever with a temperature of 39.5°C, and during the second week of admission the results of a Wright 2-mercaptoethanol test were positive for brucellosis. The patient was treated with intramuscular streptomycin 1 g/day and doxycycline 100 mg twice per day. Nine days following commencement of antibiotic treatment, the fever had subsided, serum creatinine levels had decreased to 0.9 mg/dl and blood urea nitrogen was recorded as 17 mg/dl. A liver function test also showed improvement while leucopenia and thrombocytopenia gradually improved over the ensuing 2 weeks. The patient was discharged on doxycycline 100 mg twice per day for 2 months and streptomycin intramuscular injection 1 g/day for 1 month. Six weeks after discharge the patient was completely asymptomatic and hepatosplenomegaly had subsided. Renal function tests, urinalysis, 24-hour urine protein level, full blood count and liver function tests were all within the normal range. Serological tests for systemic lupus erythematosus and brucellosis were both negative.

According to Ghanei et al.,13 renal involvement in brucellosis in the form of AKI is rare, but acute interstitial nephritis, which results from direct invasion of the organism, is common.1417 Circulating immune complex can be deposited in glomeruli and membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, rapidly progressive glomerulonephritis, rhabdomyolysis, focal segmental glomerulosclerosis and immunoglobulin A nephropathy may also occur.1618

There are also reports of haemolytic–uraemic syndrome in patients with brucellosis.19,20 Renal disease involvement in brucellosis manifests can present as as haematuria, proteinuria (in nephrotic syndrome range at times) and various degrees of renal dysfunction. Following antibiotic treatment, these signs improve; however, histological findings, proteinuria and hypertension may persist.17

Ghanei et al.13 concluded that acute Brucella infection should be borne in mind in the differential diagnosis of AKI when it is accompanied by symptoms such as arthritis, especially in areas where brucellosis is endemic.

Wright et al.21 reported two cases of brucellosis (see Figures 1 to 4, which illustrate the macroscopic and microscopic features of renal brucellosis).

FIGURE 1

Macroscopic appearance of kidney post nephrectomy. Extensive loss of parenchyma is noted with replacement by caseating necrosis. Multiple collections and cysts are also apparent. Reproduced from Wright et al. Renal Parenchymal Brucellosis – a Rare Manifestation of a Common Zoonosis. Sullivan Nicolaides Pathology. Available from: www.asid.net.au/documents/item/203.21 Reproduced with permission from the Australasian Society for Infectious Diseases.

HMJ-9-3-1-fig1.jpg
FIGURE 2

Section of ureter exhibiting transmural inflammation. A non-necrotizing granuloma (arrow and insert at 100× magnification) is identified in the muscularis propria (haematoxylin and eosin stain). Reproduced from Wright et al. Renal Parenchymal Brucellosis – a Rare Manifestation of a Common Zoonosis. Sullivan Nicolaides Pathology. Available from: www.asid.net.au/documents/item/203.21 Reproduced with permission from the Australasian Society for Infectious Diseases.

HMJ-9-3-1-fig2.jpg
FIGURE 3

Section of kidney exhibiting necrotizing granulomatous inflammation in the cortex and outer medulla, chronic interstitial nephritis with lymphoid aggregates. Reproduced from Wright et al. Renal Parenchymal Brucellosis – a Rare Manifestation of a Common Zoonosis. Sullivan Nicolaides Pathology. Available from: www.asid.net.au/documents/item/203.21 Reproduced with permission from the Australasian Society for Infectious Diseases.

HMJ-9-3-1-fig3.jpg
FIGURE 4

Epithelioid histiocytes rimming a granuloma with a necrotic core. Reproduced from Wright et al. Renal Parenchymal Brucellosis – a Rare Manifestation of a Common Zoonosis. Sullivan Nicolaides Pathology. Available from: www.asid.net.au/documents/item/203.21 Reproduced with permission from the Australasian Society for Infectious Diseases.

HMJ-9-3-1-fig4.jpg

Case 1

A 48-year-old man, with a background of seronegative polyarthritis, and who was immunosuppressed and had undergone a series of investigations for mild impairment of renal function, was referred for review. Ultrasonography revealed evidence of right-sided ureteric strictures with significant pelvicalyceal dilatation. There was no history of flank or abdominal pain, fevers, night sweats, weight loss or lower urinary tract symptoms. The patient had been employed in a number of pastoral occupations, including a cattle tuberculosis eradication programme. Physical examination was unremarkable and the patient was found to be afebrile with no significant peripheral lymphadenopathy. CT of the abdomen confirmed the ultrasound findings and showed significant nodularity of the renal parenchyma, which suggested granulomatous disease, with only a rim of preserved parenchyma. The possibility of tuberculosis, including Mycobacterium bovis infection, was considered and isotope renography (99mTc-diethylenetriamine-pentaacetic acid scan) was undertaken, which showed minimal residual function in the affected kidney. Based on this finding, a right nephroureterectomy was performed. Macroscopic examination of the specimen during the operation revealed a hard nodular kidney containing widespread purulent caseous material. The specimen was sent for various examinations, including histopathology, microscopy and culture inclusive of Ziehl–Neelsen staining and mycobacterial culture. Histological examination of the specimen revealed extensive necrotizing granulomatous inflammation, which had largely replaced normal parenchyma. The largest of these lesions were several centimetres in diameter. No organisms were identified. On post-operative day 4, the tissue cultures were positive for a Gram-negative bacillus, which was identified as Brucella suis. A complement fixation (CFT) serology test was positive for antibodies to Brucella with a titre of 1:128. IgM by enzyme immunoassay (EIA) and agglutinating antibodies were not detected. Subsequent to the patient’s admission of having been involved in recreational hunting of feral swine, he was treated with a 6-week course of doxycycline and rifampicin with an initial week of concomitant gentamicin. Since treatment, the patient has remained well with stable renal function.

Case 2

A 38-year-old man was referred for specialist review because of recurring ureteric stricture. The patient had previously undergone reimplantation for ureteric strictures and did not have any significant symptoms, such as fever, rigors, night sweats or weight loss. The patient lived on a farm in a rural community and was involved in shooting and processing feral pigs for export. The physical examination was unremarkable. Histological examination of a specimen from his previous ureteric surgery revealed evidence of granulomatous disease and tuberculosis was considered even though cultures from previous operative specimens had been negative. Sterile pyuria was evident from multiple urine specimens. Ultrasonography and CT of the abdomen revealed multiple cystic structures within the kidney with replacement of the parenchyma. There was evidence of right-sided hydronephrosis with thickening of the ureter and obstruction in the distal ureter. The patient underwent right nephrectomy and gross examination of the kidney revealed cortical and medullary distortion with irregular thinning and extensive caseating necrosis, which varied from miliary-type lesions to large lesions measuring up to several centimetres in size. Microscopic examination of the specimen revealed replacement of the renal parenchyma by caseating granulomas with extensive interstitial fibrosis and inflammation. Gram staining and Ziehl–Neelsen staining of the specimen showed no evidence of microorganisms. Nevertheless, cultures of the renal tissue were positive for Brucella suis. EIA was positive for IgG and CFT was positive with a titre of 1:64. The patient was started on doxycycline and rifampicin and completed a 6-week course of the combination antibiotic treatment. The patient remained well following completion of treatment and serology tests performed 6 months post-operatively did not show any significant change.

Wright et al.21 described brucellosis as a systemic disease that can present in acute and chronic forms. Focal disease accounts for 30% of cases but involvement of every organ system has been reported. Upper renal tract involvement is rare, and interstitial nephritis, proteinuria and glomerulonephritis are recognized complications. Kidney abscess formation is rare (only a handful of cases are reported in the literature)12,22 and widespread granulomatous infiltration of the kidney with abscesses and the almost complete destruction of normal tissue would appear to be a highly unusual form of a disease that is known to have protean manifestations. Granulomatous disease is most often seen in the liver and spleen given the relative tropism of Brucella for the reticuloendothelial system, although formation of granulomas in other organs can occur.

The authors also pointed out that brucellosis can mimic extrapulmonary tuberculosis, a diagnosis that was considered in both of their reported cases. Wright et al.21 concluded that:

  • Renal parenchymal involvement in brucellosis, even though rare, can be severe and lead to destruction of the infected kidney.

  • Extensive granulomatous disease can mimic renal tuberculosis.

  • Brucella should be considered as a possible aetiological agent in this setting, especially in the presence of known epidemiological risk factors.

Li et al.23 reported the case of a 45-year-old Chinese man who presented with a 10-day history of fever, mild headache, myalgia of the lower limbs and back, sore gums, sweating and occasional cough, which was not associated with phlegm. Treatment with cephalosporins and antipyretic drugs produced no improvement. The patient denied exposure to cattle or sheep, and drinking raw milk or eating raw meat. On examination, the patient was noted to be febrile, and to have bilateral swollen red gums and tenderness in the right renal angle. A number of investigations were carried out on admission, which were reported as follows:

  • full blood count – haemoglobin 127 g/l; white blood cell count 7.99 × 109/l (50.9% neutrophils, 36.4% lymphocytes); platelets 337 × 109/l;

  • urinalysis – showed 10–15 red blood cells per high-power field and traces of protein;

  • C-reactive protein was 57 mg/l;

  • liver function and renal function tests were normal.

The patient was commenced on metronidazole 200 mg three times per day and intravenous levofloxacin 400 mg/day for 48 hours. At the end of treatment the patient continued to be febrile, and a high temperature of 39°C was noted. In view of the possibility of rickettsial disease, minocycline 100 mg twice per day was added to treatment. After another 48 hours the temperature of the patient began to decline. The result of a Brucella agglutination test was positive with a titre of 1:80. Brucella melitensis was isolated from three consecutive blood cultures taken every 2 days after admission. The patient then remembered that he had purchased the fetus of a goat to feed to his dogs. His dogs had apparently been well and behaving normally. Treatment was then changed to minocycline 100 mg twice per day and moxifloxacin (Avelox®, Bayer, Leverkusen, Germany) 400 mg/day. Within 24 hours the patient’s temperature returned to normal and a routine urine test was normal after 48 hours of treatment. CT of the abdomen showed a round, 3.2-cm-diameter, low-density lesion in the parenchyma of the upper pole of the right kidney. On day 7 of admission, ultrasound-guided aspiration was performed on the lesion and dark-red bloody fluid was observed. A sample of the fluid was obtained for bacterial culture and Brucella melitensis was isolated. Diagnoses of brucellosis and renal brucelloma were made. The patient then received a 4-month course of minocycline 100 mg twice per day in combination with moxifloxacin 400 mg/day. Follow-up CT of the abdomen showed that the abscess had considerably diminished in size (diameter of 1.0 cm) and antibiotic therapy was stopped. After discharge, the patient had routine blood and urine tests at several follow-up appointments, the results of which were normal. Nevertheless, 6 months after cessation of medication, the patient developed fever. Brucella was again isolated from the blood. His routine blood test (haematology and biochemistry) was normal. A routine urine test indicated protein with 0 to 1 red blood cell per high-power field. Ultrasonography did not reveal any lesions of the kidney. The patient was treated with minocycline 100 mg twice daily combined with rifampicin 450 mg/day for 2 months. The medication was discontinued after two consecutive blood cultures were negative at an interval of 1 month. The patient did not suffer any relapse over the ensuing 20 months. Subsequent blood, urine, liver function and Brucella agglutination tests, as well as the results of an ultrasonography, were all normal.

Brucella infection associated with renal involvement is uncommon but typically manifests as (1) acute interstitial nephritis, which tends to present with haematuria, pyuria and proteinuria; (2) chronic interstitial nephritis, the presentation of which mimics the presentation of tuberculosis; or (3) glomerulonephritis.12,23 Kidney abscess caused by brucellosis is also uncommon; as of November 2014 only five cases had been reported in the English literature.12,22 One such case was reported by Bartralot et al.,22 namely a 82-year-old woman with chronic brucellosis infection. The patient developed an abscess that involved the left kidney and left groin region. The mass was removed and culture confirmed a diagnosis of chronic renal brucellosis.22 Chronic renal brucellosis should be differentiated from malignant tumours of the kidney. Biopsy and pathological examinations of the specimens after surgical resection would be helpful with regard to the diagnosis of malignancy.23 Renal brucelloma has been cured by means of ultrasound-guided aspiration together with the use of combination antimicrobial treatment.23

Li et al.23 summarized that:

  • Kidney abscess caused by Brucella is an uncommon condition of a common disease.

  • It is possible to cure kidney abscess caused by brucellosis with antibiotics and ultrasound-guided aspiration.

  • Antibiotic treatment for renal abscess caused by brucellosis should not be discontinued until the abscess disappears and two consecutive blood cultures taken 1 month apart are negative.

Buzgan et al.24 analysed the efficacy of treatment in 1028 cases of brucellosis in Turkey and concluded that the duration of treatment in patients with bone or articular involvement should be between 6 and 12 weeks. The duration of treatment in the case of patients with involvement of the nervous system or with chronic infected shoulders should be between 12 and 24 weeks. The recurrence rate following treatment with doxycycline combined with streptomycin or doxycycline and streptomycin combined with rifampicin was low.

Söker et al.25 reported the case of a 9-year-old boy with Brucella infection manifesting as microangiopathic haemolytic anaemia, severe thrombocytopenia and AKI with coexisting gastrointestinal bleeding and visible haematuria. Examination of the patient’s peripheral blood smear revealed haemolytic anaemia, thrombocytopenia and leucopenia. Examination of the specimen acquired via bone marrow aspiration showed hypercellularity, histiocytic proliferation and haemophagocytosis with features typically associated with Brucella infection. The results of agglutination tests on cerebrospinal fluid and serum were positive for Brucella. The patient was rehydrated, treated with combination antibiotics, which included rifampicin, doxycycline and gentamicin, and given fresh-frozen plasma and platelet transfusion, following which the patient showed complete recovery. Söker et al.25 suggested that brucellosis should be investigated when haemolytic–uraemic syndrome of unknown aetiology is encountered, particularly in Brucella-endemic areas. The most common cause of AKI in young children is haemolytic–uraemic syndrome; however, its exact aetiology is not known for sure.25 Brucella-associated endothelial damage caused directly or indirectly through toxins or cytokines was the underlying cause of disease in this patient, and the authors commented that microangiopathic anaemia results from mechanical damage to the red blood cells as they traverse the altered vasculature. The authors also noted that Escherichia coli and Brucella can be transmitted by unpasteurized milk and both could have caused the haemolytic–uraemic syndrome observed.

Haemolytic–uraemic syndrome often follows an episode of gastroenteritis caused by enterohaemorrhagic strains of Escherichia coli.25 The reservoir of this organism is the intestinal tract of domestic animals and it is most often transmitted by unpasteurized milk.25 Haemolytic–uraemic syndrome-like diseases in brucellosis have not been widely reported; nevertheless, Ruggenenti and Remuzzi26 described two clinical conditions with atypical haemolytic–uraemic syndrome. One of these is characterized by severe gastrointestinal prodromes, acute-onset anuria and neurological involvement, and is associated with a high mortality rate; in the second type, prodromal diarrhoea is not a feature but progressive deterioration of renal function and neurological involvement mimics thrombotic thrombocytopenic purpura.26

According to Ruggenenti and Remuzzi,26 haemolytic–uraemic syndrome and thrombotic thrombocytopenic purpura are syndromes of microangiopathic haemolytic anaemia and thrombocytopenia in which endothelial dysfunction would appear to play an important role in the sequence of events that lead to microvascular thrombosis.

Some authors27,28 have linked haemolytic–uraemic syndrome to bacterial and viral infections, and have suggested that these agents may induce microangiopathy and coagulopathy, which result in the release of circulating endotoxins that alter the function of a number of organs. Other studies27,29 have suggested that the major role of bacterial and viral infections relates to the generation of immune complexes that can damage the endothelium of small blood vessels.

Odeh et al.30 postulated that the mechanisms via which infection may result in haemolytic–uraemic syndrome include local invasion of the surrounding tissues by the infectious agent and direct endothelial damage induced by the infectious agent.

Bergstein31 suggested that thrombocytopenia is a result of intrarenal platelet adhesion or damage.

Siegelmann et al.17 described a 43-year-old woman with systemic brucellosis due to Brucella melitensis with severe renal involvement. The clinical features included hypertension, visible haematuria, azotaemia and massive proteinuria of 10 g per 24 hours. Brucella agglutinins were present at a titre of 1:1600 and blood cultures were positive for Brucella melitensis biotype 1. The patient was treated with doxycycline 200 mg/day and rifampicin 900 mg/day orally for 6 weeks. Treatment with antibiotics resolved the azotaemia, and proteinuria decreased to less than 0.5 g per 24 hours, but hypertension and non-visible haematuria persisted. A renal biopsy was carried out during the recovery period and pathological examination of the specimen revealed IgA nephropathy with minimal mesangial changes, which is suggestive of a causal relationship between brucellosis and IgA nephropathy with a reversal nephrotic syndrome.17

Ardalan and Shoja32 reported the case of a 28-year-old man who was admitted to hospital because of rapidly progressive kidney injury. The patient had a 5-month history of anorexia, weakness and vomiting in addition to urinary frequency and nocturia. Brucellosis had been serologically proven 4 months prior to admission but the patient had failed to comply with specific antibiotic treatment provided. The patient had low-grade pyrexia and looked ill, but otherwise findings from examination were unremarkable. Laboratory tests revealed haemoglobin levels of 8.8 g/dl, serum creatinine 4 mg/dl and urea 101 mg/dl, but hepatitis and HIV serology were normal and antibodies to dsDNA and glomerular basement membrane were negative. A Brucella SAT was positive with a titre of 1:2560. Examination of urine sediment revealed many red blood cell casts. A 24-hour urine examination revealed proteinuria of 1 g/day, and ultrasonography of the renal tract showed increased echogenicity of the kidneys. Echocardiography demonstrated pulmonary stenosis. Renal biopsy and light microscopic examination of the specimen revealed mesangial cell proliferation, matrix expansion, glomerular basement membrane thickening (double-contour appearance) as well as accentuation of lobular architecture in some glomeruli. Immunofluorescence study revealed intense mesangial staining for C3 and C1q in a granular pattern that was negative for any immunoglobulins as well as kappa and lambda light chains. Based on these findings, the patient was diagnosed with mesangiocapillary glomerulonephritis and treated with rifampicin 200 mg/day and doxycycline 900 mg/day as well as intravenous prednisolone pulses of 500 mg/day for 3 days, which was followed by oral prednisolone. The patient’s general condition dramatically improved following commencement of treatment. On day 12, serum creatinine levels and findings from urinalysis returned to normal.

Brucella nephropathy may be secondary to glomerulonephritis, interstitial nephritis, renal vasculitis and granuloma or abscess formation.3336 Brucellosis may involve renal glomeruli, interstitium and/or vasculature.18,33,36 Brucella nephropathy would appear to be an underdiagnosed clinical entity and hence a high index of suspicion for Brucella nephropathy is necessary in areas where brucellosis is endemic.

In 1969, Dunba et al.36 described two patients infected with Brucella suis with severe renal involvement. The clinical features of the patients included transient azotaemia, massive proteinuria, hypertension and later urinary frequency and dysuria. Renal morphological studies showed a diffuse interstitial nephritis with focal and local glomerular lesions. In one of the patients, clinical and pathological signs of renal disease had persisted for over 3 years, which, in the opinion of the authors, suggested that brucellosis may be a precursor of chronic renal disease.

Patients affected by brucellosis are capable of excreting Brucella in their urine; however, reports of brucellosis involving the kidney are only occasional and anecdotal.37 Mild proteinuria as well as cases of systemic brucellosis with kidney injury (renal failure) may be encountered from time to time. Nevertheless, several types of nephropathy, such as interstitial nephritis, pyelonephritis, immunoglobulin A nephropathy, membranous nephropathy, massive proteinuria as well as caseating granulomatous, have been documented.18,35,3840

Renal involvement of brucellosis has been divided into three main groups: (1) acute interstitial nephritis, (2) chronic granulomatous interstitial nephritis and (3) an immune complex-mediated glomerulonephritis.37

Acute interstitial nephritis

Acute interstitial nephritis is usually associated with pyuria, urinary frequency, dysuria, haematuria and proteinuria, and tends to be encountered during the acute phase of brucellosis. Acute interstitial nephritis results from direct invasion by the bacterium.37,39 Interstitial nephritis associated with brucellosis does not appear to be caused by infection of the renal parenchyma, but it had been conjectured to be a sequel of immune response that targets the interstitium.37

Chronic interstitial nephritis

Chronic interstitial nephritis, which mimics tuberculosis of the kidney or chronic pyelonephritis, typically exhibits lymphocytic infiltrates and, rarely, granulomas.37

Immune complex-mediated glomerulonephritis

In immune-complex-mediated glomerulonephritis, circulating antigen–antibody complexes are deposited on the epithelial side of the basement membrane.37 Infection-associated glomerulonephritis has been documented in Brucella endocarditis.3 Low complement levels have been documented in the mesangiocapillary form of Brucella glomerulonephritis. Pathological examinations of kidney biopsies have demonstrated a number of lesions, including focal segmental proliferation, diffuse proliferations, caseation and mesangial proliferation. Reports of cases with lesions observed in IgA nephropathy, membranous nephropathy, as well as membranoproliferative glomerulonephritis, have been documented.18,35,3840

In brucellosis infections, immunofluorescence may reveal (1) no evidence of deposits, (2) IgG or (3) IgA, under rare circumstances.17,18,35,3844

The non-specific clinical presentations make the diagnosis of brucellosis and brucellosis nephropathy difficult. Failure to consider the possibility of brucellosis in a patient with a history suggestive of Brucella as a source of infection (e.g. farmer, slaughterhouse worker, shepherd, traveller to Brucella-endemic areas, veterinary laboratory worker, someone who has ingested unpasteurized dairy product or meat) may delay the diagnosis of brucellosis and, consequently, lead to more serious complications. It has been documented that early diagnosis and treatment tend to result in resolution of the clinical and renal function in most cases.37

A definitive diagnosis of brucellosis is established by isolation of Brucella from the blood or other tissues. In patients with active infections, a presumptive diagnosis of brucellosis may be made by demonstrating high or rising titres of specific antibodies (1:160 or higher) to Brucella. A SAT is the most widely used test,42 but an indirect ELISA and PCR are also available.45,46 The speed and technical simplicity of LightCycler® (Roche, Basel, Switzerland) PCR on serum samples makes it a useful alternative to blood cultures in patients in whom brucellosis is suspected or in those patients with negative or doubtful serological test results.37,45,46

It has been suggested that simple brucellosis infections should be treated with oral doxycycline 100 mg twice a day for 6 weeks; however, the relapse rate is around 40% for monotherapy.47 In view of this, combination therapy of doxycycline with rifampicin, gentamicin, streptomycin or trimethoprim/sulfamethoxazole is use to treat acute brucellosis.4446 With regard to the treatment of complicated brucellosis renal disease, such as renal abscess or perinephric abscess, it has been suggested that following successful ultrasound-guided aspiration of the abscess, despite clinical improvement in the patient or absence of symptoms, combined antibiotic therapy should be continued until the following criteria are met: (1) two consecutive blood cultures, taken 1 month apart, are negative for Brucella; (2) Brucella serological test results return to normal on two consecutive occasions, 1 month apart, after resolution of symptoms; (3) there should be radiological evidence (ultrasonography/CT/MRI) of complete resolution of abscesses before antibiotic treatment is stopped in order to avoid relapse.

Conclusions

A high index of suspicion is required to diagnose brucellosis. Treatment should continue for at least 6 weeks or 45 days with appropriate combined antibiotic treatment and supportive management.

Evidence from case reports indicates that, even if the patient’s condition improves, histological abnormalities, proteinuria and hypertension may persist. Resolution of proteinuria, abnormal urinary findings and correction of renal function following treatment of brucellosis would perhaps indicate an association between complete response to the infection to treatment and improvement/restoration of renal function.

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