Tacrolimus for the treatment of systemic lupus erythematosus with pure class V nephritis.

OBJECTIVES: The treatment of pure membranous (class V) lupus nephropathy remains unsatisfactory. We studied the efficacy and safety of tacrolimus in the treatment of membranous nephritis secondary to SLE. METHODS: We recruited 18 consecutive SLE patients (tacrolimus group) with recently confirmed biopsy-proven class V lupus nephritis. They were treated with a tailing dose of oral prednisolone and tacrolimus 0.1-0.2 mg/kg/day for 6 months, followed by maintenance prednisolone and AZA. The rate of resolution of proteinuria and SLEDAI were compared with 19 historical controls treated with oral cyclophosphamide or AZA (control group). All patients were followed for 12 months. RESULTS: Baseline clinical characteristics were comparable between the groups. For the tacrolimus group, the complete and partial remission rates were 27.8 and 50.0%, respectively at 12 weeks; for the control group, they were 15.8 and 47.4%, respectively (overall chi-square test, P = 0.5). However, tacrolimus group had faster resolution of proteinuria than the control group by the general linear model with repeated measures (P = 0.032). At 12 weeks, proteinuria was reduced by 76.2 +/- 17.0% for the tacrolimus group and 47.1 +/- 51.1% for the control group (P = 0.028). Serial change in renal function and SLEDAI score did not differ between the groups. During the study period, four patients of the tacrolimus group, and 11 of the control group, developed lupus flare (P = 0.027). There was no serious adverse effect in the tacrolimus group. CONCLUSIONS: A 6-month course of tacrolimus is a safe and effective treatment of pure class V (membranous) lupus nephritis. As compared with conventional cytotoxic treatment, tacrolimus possibly results in a faster resolution of proteinuria, and a lower risk of lupus flare within 1 yr. The long-term effect and optimal regimen of tacrolimus require further study.

Chromosomal telomere shortening of kidney cells in IgA nephropathy by the measurement of DNA in urinary sediment.

BACKGROUND: The histology and function of the kidney deteriorates with age and progressive renal failure, but the mechanisms involved in renal ageing are not known. In vitro studies suggest that telomere shortening is important in replicative senescence, and is accelerated by stress factors that increase replication. We investigated whether IgA nephropathy, a prototype chronic kidney disease, is associated with localized intrarenal cellular ageing. METHODS: We studied the mean length of terminal restriction fragments (TRF), a measure of average telomere size, in the DNA of peripheral blood mononuclear cells and urinary sediment of 15 patients with IgA nephropathy. RESULTS: The mean TRF lengths in peripheral blood is 7043.8 +/- 1 182.8 base pairs, and in urinary sediment is 6 749.7 +/- 636.5 base pairs. The mean TRF lengths of urinary DNA significantly correlate with the serum creatinine (r = -0.525, p = 0.044) and estimated glomerular filtration rate (GFR) (r = 0.651, p = 0.009). The mean TRF lengths of urinary DNA had an insignificant inverse correlation with patient age (r = -0.364, p = 0.2), and do not correlate with the degree of glomerulosclerosis (r = 0.004, p = 0.9) or tubulointerstitial scarring in renal biopsy (r =-0.032, p = 0.9). After 30 months of follow-up, the rate of decline of estimated GFR has an inverse correlation with the mean TRF lengths of urinary DNA (r = -0.699, p = 0.004). The TRF lengths of peripheral blood DNA do not correlate with any clinical or histological parameter or the rate of renal function decline. CONCLUSIONS: Although this is a pilot study, our observation indicates that the TRF lengths of genomic DNA extracted from urinary sediment is related to the degree of renal impairment. However, a long telomere length of genomic DNA in urinary sediment is associated with a more rapid decline of renal function. Our findings might be relevant to the pathogenesis of progressive renal failure.

Tacrolimus in resistant primary membranous nephropathy--a report of 3 cases.

AIM: To study the efficacy and safety of tacrolimus in primary membranous nephropathy. METHOD: We describe 3 patients with primary membranous nephropathy who were either resistant to or could not tolerate steroid with or without cytotoxic agents. They were treated with tacrolimus 0.2 mg/kg/day for 6 months. The dosage of tacrolimus was adjusted to keep a whole blood tacrolimus level of 5-10 ng/ml. RESULTS: One patient had almost complete disappearance of proteinuria while the other 2 had at least 50% reduction in proteinuria. Proteinuria increased again in 2 of the patients after tacrolimus was stopped, but in neither of them proteinuria returned to the pretreatment level 6 months after tacrolimus was stopped. CONCLUSION: We conclude that tacrolimus may have a modest efficacy in the treatment of resistant membranous nephropathy.

Urinary mRNA expression of ACE and ACE2 in human type 2 diabetic nephropathy.

AIMS/HYPOTHESIS: The interplay of ACE and type 2 ACE (ACE2) has been recognised as playing an important role in the tissue renin-angiotensin system within the kidney. In the present study, we measured urinary mRNA expression of ACE and ACE2 in patients with type 2 diabetic nephropathy. METHODS: We studied 50 patients with diabetic nephropathy: 26 were being treated by ACE inhibitor (ACEI) alone (ACEI group), the other 24 by ACEI and angiotensin-receptor blocker (ARB) (ACEI+ARB group). mRNA expression of ACE and ACE2 was measured by real-time quantitative RT-PCR at 0 and 12 weeks. All patients were then followed for 56 weeks. RESULTS: Proteinuria correlated significantly with urinary ACE (r=0.454, p=0.001) and ACE2 expression (r=0.651, p<0.001). Urinary ACE2 expression correlated with estimated GFR (r= -0.289, p=0.042). In the ACEI group, there was a significant inverse correlation between the rate of GFR decline and urinary ACE2 expression at baseline (r= -0.423, p=0.031) as well as at 12 weeks (r= -0.395, p=0.046). In contrast, there was no significant correlation between the rate of GFR decline and urinary ACE2 expression at baseline or at 12 weeks in the ACEI+ARB group. The rate of GFR decline did not correlate with the baseline urinary ACE expression of either group. CONCLUSION/INTERPRETATION: There was a relationship between urinary mRNA expression of ACE2 and the degree of proteinuria. The physiological implication and possibility of clinical application of quantifying urinary ACE2 expression require further study.

Epithelioid hemangioendothelioma of the oral cavity.

OBJECTIVE: To investigate the clinicopathological characteristics and biologic behaviour of epithelioid hemangioendothelioma in the oral cavity. MATERIALS AND METHODS: The clinical features and pathological findings of nine cases with intraoral epithelioid hemangioendothelioma were reviewed, including immunohistochemistry study. RESULTS: This series comprised seven males and two females aged 6-53 years (mean 28 years). The sites of the tumour included the tongue (n = 4), lip (n = 1), the gingiva and alveoli of the maxilla (n = 1), the gingiva and alveoli of the mandible (n = 1), buccal mucosa (n = 1), and the floor of the mouth (n = 1). A painless solitary mass was the most common presentation and was found in eight cases. On pathology, the tumour grew in short strands, cords or nests of polygonal to slightly spindled epithelioid cells in fibro-myxoid stroma, with formation of intracytoplasmic lumina. Tumour cells were immunoreactive to CD34, FVIIIRAg, and vimentin. Focal-positive cytokeration were observed in three cases. Immunoreactivity for S-100 protein, epithelial membrane antigen (EMA) and human herpesvirus (HHV)-8 was negative in all cases. Two cases recurred after surgical excision, but no patient developed local or distant metastasis. CONCLUSIONS: Wide local excision with long-term follow-up seems to be the treatment of choice for intraoral epithelioid hemangioendothelioma because of their unpredictable biological behaviour and recurrence potential.

Expression of T-bet, a type 1 T-helper cell transcription factor, in the urinary sediment of lupus patients predicts disease flare.

BACKGROUND: Systemic lupus erythematosus (SLE) is characterized by the aberrant activation of T-lymphocytes. Since T-bet is the principal transcription factor for the differentiation of type-1 helper T-lymphocyte, we study the impact of urinary T-bet mRNA expression in clinically quiescent SLE patients on the risk of subsequent disease flare. METHODS: We studied 60 quiescent SLE patients. Urinary mRNA expression of T-bet was studied by the real-time quantitative polymerase chain reaction. Patients were followed for 4 yrs for disease flare. RESULTS: We studied 60 patients; 57 were female. The mean age was 38.8 +/- 11.2 yrs. Their baseline SLE disease activity index score was 1.63 +/- 1.64. During the follow-up, 28 patients (46.6%) developed lupus flare, of which 17 (28.3%) had severe flare. Receiver operating characteristic curves showed that urinary T-bet expression three times above the average level of healthy control had 64.3% sensitivity and 84.4% specificity of predicting all lupus flare. Using this cut-off, patients with a high urinary T-bet expression had a significantly higher risk of all lupus flare and severe flare than the patients with a low T-bet expression (log-rank test, P < 0.001 for both). With multivariate Cox proportional hazard model to adjust for potential confounding variables, urinary T-bet expression and patient's sex were the only independent predictors of all lupus flare and severe flare. It could be estimated that 1-fold increase in urinary T-bet expression would result in 8.4% excess risk of all lupus flare [95% confidence interval (CI), 4.1-13.0%, P < 0.001] and 12.9% excess risk of severe flare (95% CI 7.4-18.7%, P < 0.001). CONCLUSIONS: A high urinary T-bet expression was an independent predictor of lupus flare. Measurement of urinary T-bet may provide valuable information for the risk stratification of SLE patients.

Pancreatic islet beta-cell deficit and glucose intolerance in rats with uninephrectomy.

This study was performed to examine the effect of chronic renal impairment and renin-angiotensin system (RAS) activation induced by unilateral nephrectomy (UNX) on the development of pancreatic islet beta-cell deficit and glucose intolerance. Sprague-Dawley rats were randomized into three groups: untreated UNX (n=10), UNX treated with the angiotensin-converting enzyme inhibitor lisinopril (n=8) and sham operation (n=10). Blood glucose, serum insulin, renal function and histological changes of kidney and pancreas were examined 8 months postoperation. Compared with the sham rats, UNX rats developed renal impairment, insulin deficiency and glucose intolerance. Histological staining revealed an islet beta-cell deficit associated with increased immunoreactivity for angiotensin and angiotensin type 1 receptor in UNX rats. Treatment with lisinopril significantly improved renal dysfunction, hyperglycemia, insulin secretion and islet RAS expression. These data suggest that chronic renal impairment and RAS activation may contribute to islet beta-cell loss and glucose intolerance. RAS blockade may therefore prevent these disorders.

Urinary mononuclear cell and disease activity of systemic lupus erythematosus.

Mononuclear cells play a cardinal role in the pathogenesis of systemic lupus erythematosus (SLE). A high urine cytology score has been reported to be associated with lupus nephritis in relapse. The objective of this study was to examine the urinary mononuclear cell population of patients with lupus nephritis, and explore its correlation with lupus disease activity. We studied 12 patients with active lupus nephritis, 17 patients with lupus nephritis in remission, 12 SLE patients with no history of renal disease and 13 healthy subjects. Clinical disease activity was quantified by the SLE Disease Activity Index (SLEDAI). Mononuclear cell species in the urinary sediment were examined by immunocytochemistry. Patients with active lupus nephritis had significantly more mononuclear cells in the urinary sediment. The number of CD3+ cell was significantly elevated in the active lupus nephritis than the others (P < 0.001), while there was no significant difference in the number of CD20+ and CD56+ cell among patient groups. The total urinary mononuclear cell correlated significantly with the overall SLEDAI score (r = 0.58, P < 0.001) as well as the renal score (r = 0.57, P < 0.001). The number of urinary CD3+, but not CD20+ or CD56+, cell significantly correlated with the overall SLEDAI score (r = 0.46, P = 0.003) as well as the renal score (r = 0.40, p = 0.011). In nine patients with renal biopsy, the histological activity index correlated with the total urinary mononuclear cell (r = 0.75, P = 0.02), CD3+ (r = 0.69, P = 0.04) and CD20+ cell (r = 0.69, P = 0.04). We conclude that urinary mononuclear cell was markedly elevated in patients with active lupus, and the urinary mononuclear cell count correlated significantly with the SLEDAI score and histological activity. CD3+ and CD20+ cells are the major component of urinary mononuclear cell in SLE patients and their number correlates with lupus disease activity.

Imbalance of Th1/Th2 transcription factors in patients with lupus nephritis.

OBJECTIVE: Systemic lupus erythematosus (SLE) is characterized by the aberrant activation of T lymphocytes. Since T-bet and GATA-3 are the principal transcription factors for the differentiation of type-1 and type-2 helper T lymphocytes, respectively, we studied their mRNA expression in the urinary sediment of SLE patients and compared this with their urinary and intra-renal protein expression. METHODS: We studied 100 SLE patients and 10 healthy subjects. Urinary mRNA expression of T-bet and GATA-3 were studied by the real-time quantitative polymerase chain reaction. Intra-renal and urinary expressions of T-bet and GATA-3 were studied by immunohistochemistry and western blotting, respectively. RESULTS: The urinary mRNA and protein expressions of T-bet were significantly higher in SLE patients with active nephritis than those with inactive disease (mRNA: P < 0.001; protein: P = 0.004). The urinary mRNA expression of T-bet correlated with the SLE disease activity index (SLEDAI) score (r = 0.55, P < 0.001) and the histological activity index (r = 0.48, P = 0.03). On the other hand, the urinary mRNA and protein expressions of GATA-3 were significantly lower in SLE patients with active nephritis (mRNA: P < 0.001; protein: P = 0.006), and GATA-3 mRNA expression inversely correlated with the SLEDAI score (r = 0.38, P < 0.001). For the 22 SLE patients with kidney biopsy, tubular expressions of T-bet and GATA-3 significantly correlated with the histological activity index (T-bet: r = 0.57, P = 0.006; GATA-3: r = -0.79, P < 0.001). CONCLUSIONS: Patients with active lupus nephritis have increased T-bet and depressed GATA-3 expression in the urinary sediment and kidney tissue, indicating a predominant Th1 type of T-lymphocyte activation.