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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2018  |  Volume : 29  |  Issue : 2  |  Page : 284-289
Association of brucellosis with renal tubular and glomerular damage in children in Turkey


1 Department of Pediatric Nephrology, Ege University, İzmir, Turkey
2 Department of Pediatric Infectious Diseases, Children's Hospital, Diyarbakir, Turkey
3 Department of Infectious Diseases, Children's Hospital, Diyarbakir, Turkey

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Date of Web Publication10-Apr-2018
 

   Abstract 

Brucellosis is a multisystem disease that may present with a broad spectrum of clinical manifestations. Until now, no studies have been performed on renal tubular disorders in patients with brucellosis. The present study aims to investigate renal tubular disorders in patients with brucellosis. This prospective case–control study includes a total of 31 brucellosis patients (Group 1) and 30 healthy controls (Group 2) matched for age and sex. Renal tubular functions of children who were diagnosed as having brucellosis in outpatient pediatric clinics were evaluated. First-morning urine samples were collected from Group 1 and Group 2 at the same time. Urea, creatinine, potassium, sodium, and phosphorus were determined in serum and urine by an autoanalyzer. Tubular reabsorption and excretion of urine electrolytes were calculated using the related formulas. Patients with brucellosis had significantly lower levels of tubular reabsorption of phosphorus and serum phosphorus than those of the control group. Furthermore, urine sodium and serum potassium levels and fractionated sodium excretion of brucellosis patients were significantly higher than healthy control group. Estimated glomerular filtration rate was remarkably higher in the patient group (P < 0.001).We concluded that tubular and glomerular functional parameters demonstrate deterioration in patients with brucellosis compared to those in healthy participants.

How to cite this article:
Conkar S, Kosker M, Cevik S, Ay M. Association of brucellosis with renal tubular and glomerular damage in children in Turkey. Saudi J Kidney Dis Transpl 2018;29:284-9

How to cite this URL:
Conkar S, Kosker M, Cevik S, Ay M. Association of brucellosis with renal tubular and glomerular damage in children in Turkey. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2018 Jun 22];29:284-9. Available from: http://www.sjkdt.org/text.asp?2018/29/2/284/229288

   Introduction Top


Brucellosis is a zoonotic disease, caused by Brucella species that can affect all systems and organs in the body, although it commonly involves the musculoskeletal system. Patients with brucellosis usually present with joint and bone pain.[1] Brucellosis affects more than 500,000 people worldwide each year. During the different stages of the disease, 4%–50% of patients present the organism in their urine.[2],[3] However, patients usually do not present with clinical signs and symptoms of renal disease. Renal brucellosis was first published by Bruce[4] in 1889 and he described “Albumin is detected in the urine in the most severe cases, but this appears to be a rare occurrence.” Dunea et al[5] categorized renal involvement of brucellosis into three clinical types: (1) chronic brucellosis with renal involvement which looks like renal tuberculosis or chronic nonspecific pyelonephritis;[6] (2) renal involvement associated with Brucella endocarditis;[7],[8] and (3) acute nephritis or acute pyelonephritis-like characteristics observed during the acute stages of brucellosis. These characteristics are generally transient.[9],[10] In this study, we aimed to investigate the effect of brucellosis on the kidney. To date, to the best of our knowledge, no studies have been performed on measuring renal tubular and glomerular functions in patients with brucellosis. The aim of this study was to investigate renal dysfunctions in patients with brucellosis.


   Methods Top


This prospective case–control study included a total of 31 brucellosis patients and 30 healthy controls matched for age and sex. A total of 31 brucellosis cases, who presented to the outpatient clinics of the Department of Pediatric Infectious Diseases and Clinical Microbiology, at the Diyarbakìr Children's Hospital, between January 2013 and September 2014, were enrolled in the study. Healthy children as a control group were selected from well-children outpatient clinics. This study has been approved by the Ethical Committee of the institution and has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Furthermore, an informed consent form was obtained from the parents of each patient before enrolling in the study.

The exclusion criteria were as follows: (1) being under 10 or above 18 years of age, (2) presence of hypertension, diabetes mellitus, heart failure, urinary tract infections, other systemic diseases, or recurrent urinary tract infections, (3) history of previous renal disease, nephrolithiasis, or malnutrition, and (4) use of nephrotoxic drugs and diuretics within the past 15 days. Patients receiving treatment for brucellosis and those with chronic brucellosis were not included in the study.

Rose Bengal plate agglutination[11],[12] or slide agglutination tests were performed as screening tests to patients who were suspected to have Brucellosis (patients with constitutional symptoms, persistent fevers, high acute phase proteins, and other clinical symptoms) at the outpatient clinics. If screening result was positive, Wright agglutination, Coombs test, and IgM/IgG titer measurement for Brucellosis by the Elisa method were performed. Rose Bengal Wright agglutination techniques, Coombs test, Elisa, and Brucella IgM/IgG were screened for the diagnosis of brucellosis infection. Serologic tests were performed on all patients. Positive serum samples were examined by serial dilution from 1/40 to 1/1240. Bactec automated blood culture system, BACTEC 9240, was used for blood and urine cultures for the isolation of Brucella species. The diagnosis of Brucellosis was established by one of the following criteria: (1) isolation of Brucella spp. from blood or other clinical samples; (2) an appropriate clinical picture, such as arthralgia, fever, sweating, chills, headache, and malaise plus detection of specific antibodies at significant titers and/or the demonstration of an at least four-fold increase in antibody titer in serum specimens obtained over two to three weeks.[11] C-reactive protein, erythrocyte sedimentation rate, and leukocyte counts were measured from acute phase reactants. Leukocytosis was defined as >11×103 cells/mm. Furthermore, age, gender, systolic and diastolic blood pressures, heart rate, weight, height, body mass index, and presence of other chronic illnesses were recorded.

Assessment of renal functions

First-morning urine samples were collected from the patient and control groups and used for pH, microscopy, and urine dipstick analysis. Urine dipstick test was performed by an automatic urine analyzer BT URI-10®, and after centrifugation, urine sediment was evaluated through a microscope by a pediatric nephrologist. For urine sediment analysis, 10 mL of urine was centrifuged for 5 min at 400 × g, and sediment from the bottom of the tube was placed on a microscope slide and coverslip. Sediment analysis was done with a light microscopy at 400 × per high power field (HPF). At least one bacterium per HPF was considered as bacteriuria and >5 leukocytes per HPF was considered as pyuria. Hematuria was defined as more than five red blood cells per HPF. Urine and serum levels of potassium, sodium, phosphorus, and creatinine were measured by an autoanalyzer (Roche Cobas 6000, Roche-Hitachi Diagnostics, Mannheim, Germany). Tubular reabsorption and excretion of urine electrolytes were calculated using the related formulas. Glomerular filtration rate was estimated by the Schwartz formula[13]. Urinary albumin-to-creatinine ratio (Ua/Uc) was calculated.[14] Furthermore, the following parameters were measured from the blood: complete blood count, plasma creatinine (Pcr), urea (PUrea), sodium (PNa+), potassium (PK+), and phosphorus (PP). Serum complement C3 levels were measured in all cases. Serum C3 levels were measured by the turbidi- metric method (Alfa Wasserman Diagnostics, Italy).


   Statistical Analysis Top


All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) software version 10.0 for Windows (SPSS Inc., Chicago, IL, USA). The Shapiro–Wilks test was used for the evaluation of the normal distribution of data. Continuous variables were presented as a mean ± standard deviation. Kruskal–Wallis variance analysis, Bonferroni corrections, Mann–Whitney U-test, and the one-way ANOVA test were performed for comparison of continuous data. Intergroup comparisons of categorical parameters were made using the Chi-square test. Pearson's linear regression analysis was carried out. P <0.05 was considered as statistically significant.


   Results Top


Thirty-one patients who were diagnosed as brucellosis on an outpatient basis between January 2013 and September 2014 and 30 healthy children as a control group were enrolled in the study. The mean age was 12.7 ± 2.97 years in the patient group and 13.03 ± 3.18 years in the control group (P = 0.68). Most common symptoms were arthralgia (73.7%), fever (72.2%), and fatigue (71.2%). Most common clinical findings were fever (28.8%), hepatomegaly (20.6%), splenomegaly (14.5%), and peripheral arthritis (14.3%). There were no significant differences regarding age, gender, mean arterial blood pressure, and body weight between the patient and the control groups (P >0.05) [Table 1].
Table 1: Comparison of demographic data for the patient and control groups.

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Laboratory findings for the diagnosis of the disease of the patient group are summarized in [Table 2]. C-reactive protein levels were increased in 67.7% of the cases. The standard tube agglutination test was positive in 29 cases (93.5%) [Table 2].
Table 2: Positive laboratory findings in the patient group.

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Estimated glomerular filtration rate (GFR) was significantly higher in the patient group (147.93 ± 34.24 mL/min/1.73 m2) than the control group (103.46 ± 10.38 mL/min/ 1.73 m2) (P = 0.001). There were no other remarkable differences between the patient and control groups. The mean spot urine protein/creatinine ratio was similar in both groups (P >0.05). Furthermore, urinary pH was similar in the patient (6.04 ± 0.55) and control group (5.96 ± 0.31; P = 0.48). Four patients had pyuria (12.9%) and three patients had hematuria (9.6%).

Comparison of renal tubular functions and glomerular functions among groups are shown in [Table 3]. Patients with brucellosis had significantly lower levels of tubular reabsorption of phosphorus (TPR) (P = 0.03) and serum phosphorus than those of the controls (P = 0.001). The C3 levels of all cases were normalized. There was no statistically significant difference between C3 levels in the two groups (P = 0.38) [Table 3].
Table 3: Comparison of renal tubular and glomerular functions among groups.

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In addition, urine sodium and serum potassium levels and fractionated sodium excretion (FENa) of brucellosis patients were significantly higher than the control group (P = 0.04, P = 0.001, and P = 0.001, respectively). Serum potassium was significantly higher than patients as compared to controls. Low serum potassium levels in Brucella patients were thought to be due to tubular potassium loss. None of the patients underwent renal biopsy. No chronic kidney failure developed in any of the follow-ups.


   Discussion Top


Brucellosis is an anthropozoonosis with a worldwide distribution. It is associated with high morbidity in both animals and humans and causes a heavy economic burden, as well as creating a serious public health problem in many developing countries.[15] Brucellosis is still endemic in Turkey along with the Middle East and Latin America. This disease has been widespread in Turkey for years, and according to data from the Ministry of Health, a total of 14,572 cases of human brucellosis were reported in 2003.[16] In Turkey, the spread of the disease usually results from consuming unpasteurized or unboiled dairy products, particularly fresh cheese or cream butter.[17],[18],[19],[20] In our study, nearly all patients displayed the common symptoms of brucellosis, such as fever, sweating, headache, and malaise, lasting for weeks or months. In most of the cases, establishing the diagnosis was not difficult as the area was endemic for brucellosis. In Turkey, the Brucella agglutination test and cultures are performed routinely for patients exhibiting fever in the absence of another clear diagnosis.

Although Brucella infection with kidney involvement is a rare, it could manifest as acute interstitial nephritis, chronic interstitial nephritis, or glomerulonephritis.[19] A case of nephrotic syndrome due to minimal alteration of the disease during acute brucellosis has been reported.[20] A related study revealed that brucellosis cases with end-stage renal disease exhibiting joint and bone pain were particularly seen in endemic regions. Patients with the disease may develop severe organ involvement.[21] Likewise, another study demonstrated that, in all areas endemic to brucellosis, the infection can be linked to hematuria, proteinuria, and renal failure.[22]

We hypothesized that tubular and glomerular functional parameters might be affected in brucellosis patients. To the best of our knowledge, our study is the first to make a comparison of renal functional parameters between brucellosis patients and healthy participants. The results of our study show that, in patients with brucellosis, tubular and glomerular dysfunction may be related to the disease. Urinary excretion of sodium may be elevated in patients with brucellosis due to proximal tubular damage. In our study, TPR values were lower in the patient group. There have been no studies revealing significant differences between brucellosis patients and healthy subjects with respect to TPR values. On the other hand, there have been studies showing an increase in FENa levels, which indicates poor renal function.[23] In our study, we also showed that renal tubular functions were deteriorated as indicated by increased FENa and decreased TPR. Brucellosis may also cause acute tubular necrosis and interstitial nephritis. The mechanism that leads to tubular and glomerular dysfunction in brucellosis is complex and includes mechanic and immune factors such as cytokine release and acute phase response.

Our study showed significantly higher e-GFR levels in patients with brucellosis. We believe that increased e-GFR was due to the disease itself. Drug-related renal effects were excluded as renal function measurements were performed before the treatment for brucellosis. Since the patient group consisted of only patients with brucellosis and patients with other chronic and systemic diseases were excluded from the study, there were no renal effects associated with other systemic diseases. Furthermore, patients were not hospitalized, did not receive intravenous fluids, and were not malnourished. We found that tubular and glomerular functions were affected in patients with brucellosis. To the best of our knowledge, our study is the first study in the literature to show brucellosis-related tubular and glomerular damage. We believe that tubular damage in brucellosis cases results from the e-GFR increase and this damage alters phosphorus and sodium reabsorption in the glomerular tubules. Brucella species are intracellular pathogens and may cause direct glomerular and tubular damage; further investigations are needed to prove this hypothesis.

We did not evaluate urinary levels of retinol-binding protein, alpha-1 macroglobulin, and beta-2 microglobulin or urine osmolality for better evaluation of tubular functions. However, we advocate that other tests which were included in this study were convenient to assess glomerular and tubular function. The small number of patients included in this study is another limitation of this study.


   Conclusion Top


In areas endemic to brucellosis, this infection may be associated with renal tubular and glomerular dysfunction. Several factors may cause renal involvement related to Brucella infection and our study shows that there is a need for further investigations on this issue.

Acknowledgment

The authors declare that the development of the manuscript was not supported by an honorarium, a grant, or any other sources of support, including sponsorship or any material sources of support.

 
   References Top

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Magill GB, Killough JH. Oxytetracycline-streptomycin therapy in brucellosis due to Brucella melitensis. AMA Arch Intern Med 1953:91:204-11.  Back to cited text no. 3
    
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Bruce D. Observations on Malta fever. Br Med J 1889:1:1101-5.  Back to cited text no. 4
    
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Clark AL. Urinary tract infections accompanying brucellosis. J Urol 1939;42:249-56.  Back to cited text no. 6
    
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De La Chapelle CE. Vegetative endocarditis due to Brucella mellitensis. Am Heart J 1929; 4:732-9.  Back to cited text no. 7
    
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Cazeneuve Z. Les troubles renauxdans la fievere mediteraneane: Crises d’hematuries a la periods critique de l’afection. Bull Soc Pathol 1911: 4:94.  Back to cited text no. 9
    
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King HE. Hypertension in acute renal insufficiency: Report of a case. Proc Mayo Clin 1939;14:187.  Back to cited text no. 10
    
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Young EJ. Serologic diagnosis of human brucellosis: Analysis of 214 cases by agglutination tests and review of the literature. Rev Infect Dis 1991;13:359-72.  Back to cited text no. 11
    
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Alton GG, Jones LM, Pietz DE. Laboratory Techniques in Brucellosis. 2nd ed. Geneva: World Health Organization; 1975.  Back to cited text no. 12
    
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Schwartz GJ, Muñoz A, Schneider MF, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol 2009;20:629-37.  Back to cited text no. 13
    
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Barratt TM, McLaine PN, Soothill JF. Albumin excretion as a measure of glomerular dysfunction in children. Arch Dis Child 1970;45:496-501.  Back to cited text no. 14
    
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Ozisik L, Akman B, Huddam B, et al. Isolated Brucella peritonitis in a CAPD patient. Am J Kidney Dis 2006;47:e65-6.  Back to cited text no. 15
    
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Akdeniz H, Irmak H, Demiroz P. Evaluation of brucellosis cases in Van region of Eastern Anatolia: A 3-year experience. Nagoya Med J 1998;42:101-10.  Back to cited text no. 16
    
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Ceylan E, Irmak H, Buzğan T, et al. Brucellosis prevalence among human and animal populations in some villages of the Van province. Van Tıp Dergisi 2003;10:1-5.  Back to cited text no. 17
    
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Sözen TH, Topçu AW, Söyletir G, Doğanay M, editors. Infectious Diseases and Microbiology. 2nd ed. Istanbul: Nobel Tıp Kitapevleri; 2002. p. 636-42.  Back to cited text no. 18
    
19.
Onaran M, Sen I, Polat F, et al. Renal brucelloma: A rare infection of the kidney. Int J Urol 2005;12:1058-60.  Back to cited text no. 19
    
20.
Sabanis N, Gavriilaki E, Paschou E, et al. Renal manifestations of human brucellosis: First report of minimal change disease. Saudi J Kidney Dis Transpl 2016;27:590-4.  Back to cited text no. 20
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21.
Ceylan K, Karahocagil MK, Soyoral Y, et al. Renal involvement in Brucella infection. Urology 2009;73:1179-83.  Back to cited text no. 21
    
22.
Jafari HM, Vahidshahi K, Kosaryan M, et al. Major beta-thalassemia, use of desferiexamine and renal proximal tubular damage. Bratisl Lek Listy 2011;112:278-81.  Back to cited text no. 22
    
23.
Cetin T, Oktenli C, Ozgurtas T, et al. Renal tubular dysfunction in beta-thalassemia minor. Am J Kidney Dis 2003;42:1164-8.  Back to cited text no. 23
    

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Correspondence Address:
Dr. Secil Conkar
Department of Pediatric Nephrology, Ege University, İzmir
Turkey
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DOI: 10.4103/1319-2442.229288

PMID: 29657194

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