Behçet's disease (BD) theoretically affects all sizes and types of blood vessels and results in multi-organ involvement.1 Renal BD has not been fully characterized, although kidneys are histologically rich in blood vessels and receive approximately 20% of the cardiac output.2,3 The main causes of renal BD reportedly include AA type amyloidosis, glomerulonephritis, renal vascular involvement, and interstitial nephritis.2,3 The clinical manifestations of renal BD range from asymptomatic hematuria and/or proteinuria to end-stage renal disease.2 Akpolat, et al.2 have demonstrated that renal involvement in BD seems to be more frequent than has been reported, and most renal BD patients have an indolent disease course. Histopathologically, minor glomerular changes and microscopic vascular disease are most commonly observed in renal BD patients with a mild clinical course.2

In this study, we retrospectively reviewed the clinical characteristics of 2007 Korean BD patients and analyzed the results of their urinalyses. Herein we also discuss the findings of light microscopy, immunofluorescence tests, and electron microscopy in 12 BD patients who underwent renal biopsy.

Two thousand and seven patients (584 males and 1423 females (1 : 2.4); median age, 42 years; age ranging, 13 to 82 years) who were registered at the BD Specialty Clinic of Severance Hospital between January 2009 and December 2010 and fulfilled the diagnostic criteria for BD were enrolled in this study. The criteria used for BD diagnosis are outlined by the International Study Group for BD.4 A diagnosis of hematuria was made on the basis of microscopic examination of urine sediment, with a count of five erythrocytes/high power field (1 field, 400× magnification) appearing more than two times in one year or three times in six months considered positive.5 Among the 2007 BD patients, 12 patients underwent renal biopsies, and two nephrologists made the diagnosis of renal disease through biopsy confirmation, taking into account the findings of light microscopy, immunofluorescence tests, and electron microscopy.

Patient medical records were reviewed in order to investigate the clinical characteristics of BD, the results of the urinalyses, and other laboratory test results. Lab tests included complete blood count, blood glucose level, renal and liver function tests, erythrocyte sedimentation rate (ESR; normal range, ≤20 mm/hour), C-reactive protein (CRP; normal range, ≤0.8 mg/dL), anti-streptolysin O titer, rheumatoid factor, antinuclear antibodies, sexually transmitted infection work-up, and HLA B51 genotype. Additionally, patients with hematuria and/or proteinuria underwent intravenous pyelogram, ultrasonographic examination of the abdomen and pelvis, cytologic examination of the urine, and lab tests including complement levels and the quantitative evaluation of serum immunoglobulins.

Chi-square tests, Fisher's exact tests, and Mann-Whitney U tests were applied to assess differences between the clinical features of BD patients with hematuria and/or proteinuria and those with normal urinalyses. The strength of associations among urinary abnormalities, demographics, clinical symptoms, and laboratory characteristics are expressed as odds ratios (ORs) and 95% confidence intervals (CI). Logistic regression models were used, and variables with p<0.15 in the univariate analysis were included in the multivariate analysis. All analyses were performed using SAS software version 9.1.3 (SAS Institute Inc., Cary, NC, USA). Differences were considered statistically significant when the p-value was less than 0.05.

Since Oshima, et al.6 first reported hematuria and proteinuria associated with BD, AA-type amyloidosis, glomerulonephritis, and renal vascular disease have been accepted as renal manifestations of BD.2,3 According to a previous report,3 the types of renal involvement among 253 cases of renal BD patients were determined to be amyloidosis (n=108; 42.7%), glomerulonephritis (n=88; 34.8%), renal macroscopic/microscopic vascular disease (n=55; 21.7%), and interstitial nephritis (n=5; 2.0%). The authors suggested that BD patients with vascular involvement have a high risk of amyloidosis, which is the most common cause of renal failure in BD patients.3 Also, routine urinalysis and measurement of serum creatinine level have been proposed for early diagnosis of renal BD.3 In addition, Kavala, et al.7 reported that 16.1% (n=34) of BD patients (n=211) were revealed to have renal involvement as microalbuminuria in 11.1% (n=22) and proteinuria in 5.6% (n=12). The authors described that central nervous system involvement and disease duration of ≥10 years was significantly associated with the risk of microalbuminuria.

In the present study, we retrospectively reviewed the medical records of a total of 2007 BD patients and analyzed the patients' data using univariate and multivariate logistic regression analyses to determine the clinical significance of renal involvement in BD. Among the 2007 BD patients, hematuria was identified in 412 patients (20.5%) while proteinuria was noted in 29 patients (1.4%). The univariate analysis showed that the BD patients with hematuria were predominantly female and older, had higher ESR levels, and more frequently experienced genital ulcerations compared to BD patients without hematuria. BD patients with proteinuria had higher ESR levels compared to BD patients without proteinuria. Multivariate analysis revealed that age, sex, and ESR were significantly associated with hematuria in BD patients, whereas only ESR was associated with proteinuria in BD patients. Male gender has been considered a risk factor for all types of renal involvement in BD patients.2 However, our study demonstrated that female gender was a risk factor for hematuria in BD patients, but not for proteinuria. We suspect that regional differences in the male to female ratio of BD patients might contribute to the marked female predominance in cases of hematuria.

Many types of glomerulonephritis have been reported to be associated with BD;2,3,7-10 however, the exact pathogenesis remains unclear. The suggested pathogenesis of glomerulonephritis in BD patients includes the deposition of immune complexes, IgA, and anti-neutrophilic cytoplasmic antibodies.11-13 Cumulative analyses by Akpolat, et al.2,3 demonstrated that only 6 (6.8%) of 88 BD patients with pathology-proven glomerulonephritis had IgA nephropathy.8-10 Our study demonstrated that IgA nephropathy was the most common pathologic findings among 12 BD patients who underwent renal biopsies. IgA nephropathy is the most common form of glomerulonephritis, with a prevalence ranging from 10% in North American renal biopsies to 30-40% in the Asian-Pacific area.14,15

Several types of glomerular lesions can be found in BD and these lesions are probably the most common manifestation of renal disease observed in BD patients.2 Although current treatment options for renal BD are not evidence-based, corticosteroids, colchicine, azathioprine, and cyclophosphamide have been used for the treatment of glomerular lesions in BD.3 In our study, a majority of the 12 BD patients who underwent renal biopsies had indolent courses of renal diseases with systemic colchicine treatment with or without concomitant corticosteroids and azathioprine. It has been suggested that colchicine may prevent extracellular matrix and amyloid accumulation as well as various renal injuries via its anti-inflammatory action, which occurs through the inhibition of enhanced monocyte chemotactic protein-1 and intercellular adhesion molecule-1 expression.3,16 However, routine administration of colchicine for BD patients with hematuria, proteinuria, or biopsy-proven glomerular lesions requires further investigation.

In this study, we analyzed risk factors associated with hematuria and proteinuria in 2007 Korean BD patients and demonstrated that IgA nephropathy was the most common pathologic diagnosis in 12 renal BD patients who underwent renal biopsies. Our study group previously reported the clinical characteristics of 30 BD patients diagnosed with aneurysms or pseudoaneurysms in major arterial systems.17 One patient with multiple saccular aneurysms of the renal arteries was already included in the previous report17 therefore, this patient was excluded in the present study. The high prevalence of hematuria or IgA nephropathy in BD patients may be the result of regional differences in the manifestations of BD or coincidental findings of BD and hematuria or IgA nephropathy. Based on our data, we recommend routine urinalysis and serum renal function tests as well as early consultation with a nephrologist for the diagnosis of renal BD, especially in older female patients with hematuria, high ESR levels, and frequent genital ulcers or BD patients with proteinuria and high ESR levels. In addition, we believe that our data can be effectively used as a clinical reference for further investigations into the pathogenetic similarities and differences between BD and IgA nephropathy in the Asian-Pacific BD population.