Bonnie Ching-Ha Kwan

Lipoprotein Metabolism and Lipid Management in Chronic Kidney Disease

Dyslipidemia is an established cardiovascular (CV) risk factor in the general population. In chronic kidney disease (CKD), however, epidemiologic studies ([1][1]–[3][2]) and clinical trials ([4][3]–[12][4]) have raised uncertainties regarding the impact of dyslipidemia on clinical outcomes and,

Serum and Urinary Cell–free MiR-146a and MiR-155 in Patients with Systemic Lupus Erythematosus

Objective. Recent studies showed that micro-RNA play important roles in the pathogenesis of autoimmune diseases. We studied the levels of miR-146a and miR-155 in the serum and urinary supernatant of patients with systemic lupus erythematosus (SLE). Methods. The serum and urinary supernatant levels of miR-146a and miR-155 were determined by real-time quantitative polymerase chain reaction in 40 patients with SLE and 30 healthy controls. Results. Compared to controls, serum miR-146a and miR-155 levels were lower, and the urinary level of miR-146a was higher, in SLE. Estimated glomerular filtration rate (eGFR) correlated with both serum miR-146a (r = 0.519, p = 0.001) and miR-155 (r = 0.384, p = 0.014). Serum miR-146a inversely correlated with proteinuria (r = −0.341, p = 0.031) and the SLE Disease Activity Index (r = −0.465, p = 0.003). Serum miR-146a and miR-155 levels also correlated with red blood cell count, platelet count, and lymphocyte count. After treatment with calcitriol for 6 months, serum miR-146a level of SLE patients increased significantly (p < 0.001), and its change inversely correlated with the level of calcium-phosphate product (r = −0.466, p = 0.003). Conclusion. The results suggested that serum miR-146a and miR-155 participate in the pathophysiology of SLE and might be used as biomarkers of SLE.

Endotoxemia is related to systemic inflammation and atherosclerosis in peritoneal dialysis patients.

BACKGROUND AND OBJECTIVES Systemic inflammatory state is a hallmark of peritoneal dialysis (PD) patients, but its etiology remains obscure. Because circulating microbial products are an important cause of systemic immune activation in other conditions such as HIV infection, it was hypothesized that endotoxemia is a cause of systemic inflammatory state and atherosclerosis in PD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Plasma lipopolysaccharide (LPS) levels in 30 consecutive new PD patients were measured. The result was compared with serum C-reactive protein (CRP) level, peritoneal transport status, history of pre-existing cardiovascular diseases, and carotid intima media thickness (IMT) by Doppler ultrasound. RESULTS Among the 30 PD patients, there were 17 men. The average age was 53.7 +/- 15.1 yr. The average endotoxin concentration of PD patients was 0.44 +/- 0.18 EU/ml, which was significantly higher than that of patients with chronic kidney disease secondary to Ig-A nephropathy (IgAN) (0.035 +/- 0.009 EU/ml, P < 0.0001) and the controls (0.013 +/- 0.007 EU/ml, P < 0.0001). In PD patients, plasma LPS concentration had a significant correlation with serum CRP (r = 0.415, P = 0.025) and serum albumin level (r = -0.394, P = 0.034). In contrast, plasma LPS level did not correlate with Charlsons Comorbidity Index, peritoneal transport characteristics, or nutritional indices. Patients with pre-existing cardiovascular disease (CVD) had higher plasma LPS level than those without CVD (0.53 +/- 0.19 versus 0.36 +/- 0.16 EU/ml, P = 0.016). Plasma LPS level correlated with carotid IMT (r = 0.438, P = 0.016). CONCLUSIONS It was found that endotoxemia was probably common in PD patients, and the degree of circulating endotoxemia might be related to the severity of systemic inflammation and features of atherosclerosis. This result suggests that endotoxemia may have a contributory role to the systemic inflammatory state and accelerated atherosclerosis in PD patients.

Expression of microRNAs in the Urine of Patients With Bladder Cancer

UNLABELLED We quantified the urine sediment and supernatant levels of microRNA (miRNA) targets related to epithelial-mesenchymal transition in 51 patients with bladder cancer and in 24 controls. We found that patients with bladder cancer had depressed levels of the miR-200 family, miR-192, and miR-155 in urinary sediment. The urinary level of these miRNAs may be developed as noninvasive markers for bladder cancer. BACKGROUND MicroRNAs (miRNA) have been implicated to play an important role in the pathogenesis of a variety of cancers. We studied the levels of miRNAs related to epithelial-mesenchymal transition (EMT) in the urine of patients with bladder cancer. METHOD The expression of the miR-200 family, miR-205, miR-192, miR-155, and miR-146a in the urine sediment and supernatant of 51 patients with bladder cancer and in 24 controls was determined by real-time quantitative polymerase chain reaction. RESULTS Compared with controls, the patients with bladder cancer had a lower expression of the miR-200 family, miR-192, and miR-155 in the urinary sediment; lower expression of miR-192; and higher expression of miR-155 in the urinary supernatant. The expression of the miR-200 family, miR-205, and miR-192 in the urine sediment significantly correlated with urinary expression of EMT markers, including zinc finger E-box-binding homeobox 1, vimentin, transforming growth factor β1, and Ras homolog gene family, member A. Furthermore, the levels of miR-200c and miR-141 in the urine sediment became normalized after surgery. CONCLUSION We found that the urinary miR-200 family, miR-155, miR-192, and miR-205 levels are depressed in patients with bladder cancer. The level of these miRNA targets in urine has the potential to be developed as noninvasive markers for bladder cancer.

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.

Intrarenal expression of miRNAs in patients with hypertensive nephrosclerosis.

BACKGROUND MicroRNAs (miRNAs) are non-coding, single-stranded RNA molecules that play important roles in a number of physiological and pathological processes. Previous studies showed that miRNAs targeting transcription factors ZEB1 and ZEB2 may repress epithelial-mesenchymal transition (EMT). METHODS We studied 34 consecutive patients with biopsy-proven hypertensive nephrosclerosis. Intrarenal expression of miR-200 family, miR-205, and miR-192 were determined. We also studied normal renal tissue from 20 patients with nephrectomy for kidney cancer as controls. RESULTS The level of intrarenal of miR-200a, miR-200b, miR-141, miR-429, miR-205, and miR-192 were significantly higher in patients with hypertensive nephrosclerosis than controls. Proteinuria correlated with intrarenal expression of miR-200a (r = 0.594, P < 0.001), miR-200b (r = 0.395, P = 0.004), miR-141 (r = 0.377, P = 0.007), miR-429 (r = 0.346, P = 0.013), miR-205 (r = 0.636, P < 0.001), and miR-192 (r = 0.306, P = 0.029). Estimated glomerular filtration rate (GFR) correlated with intrarenal expression of miR-200a (r = -0.374, P = 0.007) and miR-205 (r = -0.400, P = 0.005). Intrarenal expression of ZEB1 inversely correlated with intrarenal expression of miR-429, whereas expression of ZEB2 inversely correlated with miR-200a, miR-200b, and miR-429. CONCLUSIONS The results show that intrarenal expression of miR-200a, miR-200b, miR-141, miR-429, miR-205, and miR-192 were increased in hypertensive nephrosclerosis, and the degree of upregulation correlated with disease severity. The results suggested that these miRNA species may play important roles in the pathogenesis of hypertensive nephrosclerosis.

Urinary miR-21, miR-29, and miR-93: Novel Biomarkers of Fibrosis

Background: MicroRNAs (miRNAs) play important roles in the progression of renal fibrosis. We studied the urinary levels of miR-21, miR-29 family and miR-93, which are downstream mediators of the transforming growth factor-β1 (TGF-β1), in patients with immunoglobulin A (IgA) nephropathy. Methods: We studied the urinary miRNA levels of 43 IgA nephropathy patients and 13 healthy controls. Results: The IgA nephropathy group had significantly lower urinary miR-29b and miR-29c, but higher miR-93 levels than controls. Proteinuria significantly correlated with urinary levels of miR-29b (r = –0.388, p = 0.003) and miR-29c (r = –0.409, p = 0.002). Glomerular filtration rate significantly correlated with urinary levels of miR-21 (r = 0.338, p = 0.028), miR-29b (r = 0.333, p = 0.031) and miR-29c (r = 0.304, p = 0.050). Urinary miR-93 level significantly correlated with glomerular scarring (r = –0.392, p = 0.010). Urinary miRNA level of SMAD3, but not TGF-β1, correlated with urinary miR-21 (r = 0.624, p < 0.001), miR-29b (r = 0.566, p < 0.001), miR-29c (r = 0.619, p < 0.001) and miR-93 (r = 0.332, p = 0.032). Conclusions: Urinary miR-29b and miR-29c levels correlated with proteinuria and renal function, while urinary miR-93 level correlated with glomerular scarring. More importantly, urinary levels of these miRNA targets significantly correlated with urinary SMAD3 level. Our results suggest that these miRNA targets are regulated by the TGF-β1/SMAD3 pathway and they may play important roles in the development of progressive renal fibrosis in IgA nephropathy.

Oral Calcitriol for the Treatment of Persistent Proteinuria in Immunoglobulin A Nephropathy: An Uncontrolled Trial

BACKGROUND Laboratory research and previous retrospective study suggest that vitamin D and its analogues have profound effects on immune system function and glomerular mesangial cell proliferation. We conducted an open-label study to evaluate the antiproteinuric effect of calcitriol on proteinuria in patients with immunoglobulin A (IgA) nephropathy. STUDY DESIGN Open-label prospective uncontrolled trial. SETTING & PARTICIPANTS 10 patients (3 men) with biopsy-proven IgA nephropathy and persistent proteinuria despite angiotensin-converting enzyme-inhibitor or angiotensin receptor blocker therapy in a tertiary referral center. INTERVENTION Calcitriol, 0.5 microg, twice weekly for 12 weeks. OUTCOME MEASURES Changes in proteinuria, renal function, serum transforming growth factor beta (TGF-beta) and angiotensin II levels. RESULTS After calcitriol treatment, there was a significant overall decrease in proteinuria with time by using a general linear model with repeated measures (P = 0.03). There was a progressive decrease in urine protein-creatinine ratio from 1.98 +/- 0.74 to 1.48 +/- 0.81 g/g (P = 0.007) during the first 6 weeks that persisted throughout the study period. No significant change in blood pressure or renal function was noted. There was a simultaneous decrease in serum TGF-beta level, and percentage of decrease in serum TGF-beta level significantly correlated with percentage of change in proteinuria (Spearman r = 0.643; P = 0.02). Serum angiotensin II level did not change throughout the study. One patient experienced transient hypercalcemia that normalized after a dosage decrease. No other major adverse effect was reported. LIMITATIONS This small study is uncontrolled and does not examine the long-term effect of calcitriol therapy. CONCLUSION Twice-weekly oral calcitriol has a modest antiproteinuric effect in patients with IgA nephropathy and persistent proteinuria despite angiotensin-converting enzyme-inhibitor or angiotensin receptor blocker therapy. Additional studies are needed to confirm the renal protecting effect of calcitriol in patients with chronic proteinuric kidney diseases.

Intrarenal expression of microRNAs in patients with IgA nephropathy

MicroRNAs (miRNAs) are noncoding, single-stranded RNA molecules that have important roles in a number of physiological and pathological processes. Previous studies have proved that miRNAs targeting ZEB1 and ZEB2 may repress epithelial-to-mesenchymal transition. In this work, we studied the intrarenal expression of miR-200 family, miR-205 and miR-192 in patients with immunoglobulin A (IgA) nephropathy. We studied 43 patients with biopsy-proven IgA nephropathy (IgA group). The intrarenal expression of miRNAs was quantified and compared with that of 15 patients with noninflammatory glomerulosclerosis (GS group) and 20 patients with nephrectomy for kidney cancer as controls (CTL group). The level of intrarenal miR-200c was downregulated, whereas the levels of intrarenal miR-141, miR-205 and miR-192 were upregulated in IgA but not GS group. Proteinuria significantly correlated with the intrarenal expression of miR-200c (r=−0.324, P=0.011) and glomerular filtration rate (GFR) significantly correlated with the intrarenal expression of miR-205 (r=−0.280, P=0.030). The degree of tubulointerstitial scarring correlated with miR-205 expression (r=0.389, P=0.021), whereas glomerulosclerosis correlated with miR-192 expression (r=−0.311, P=0.045). The rate of GFR decline significantly correlated with the intrarenal expression of miR-192 (r=0.373, P=0.015). The intrarenal expression of E-cadherin significantly correlated with the intrarenal expression of miR-200c (r=0.392, P=0.002). The results show that intrarenal expression of miR-200c, miR-141, miR-205 and miR-192 was diversely regulated and correlated with disease severity and progression in patients with IgA nephropathy. These miRNA species may be important in the pathogenesis and progression of IgA nephropathy.

Elevated Levels of miR-146a and miR-155 in Kidney Biopsy and Urine from Patients with IgA Nephropathy

Background: Previous studies suggested miR-146a and miR-155 play important roles in innate and adaptive immune responses. We studied intra-renal and urinary levels of miR-146a and miR-155 in patients with immunoglobulin A nephropathy (IgAN). Methods: Intra-renal and urinary levels of miR-146a and miR-155 are quantified in 43 patients with IgAN; the result was compared to 20 nephrectomy specimens and urine sediment of 13 healthy volunteers. Results: The levels of intra-renal and urinary levels of miR-146a and miR-155 of IgAN are significantly higher than controls. Estimated glomerular filtration rate inversely correlates with intra-renal level of miR-146a and miR-155; proteinuria positively correlates with intra-renal level of miR-146a and miR-155, as well as urinary level of miR-146a and miR-155. Intra-renal level of miR-155 significantly correlates with tubulointerstitial scarring. Urinary level of miR-146a inversely correlates with urinary expression of interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α and positively correlates with urinary expression of regulated upon activation, normal T-cell expressed, and secreted (RANTES). Urinary level of miR-155 inversely correlates with urinary expression of IL-1β and TNF-α and positively correlates with urinary expression of forkhead box P3 (FOXP3) and RANTES. Conclusion: We conclude that intra-renal and urinary levels of miR-146a and miR-155 were significantly elevated in IgAN, and the degree of upregulation correlates with clinical and histological severity of the disease. Our results suggested miR-146a and miR-155 might play an important role in the pathophysiology of IgAN.