Urinary Long Non-Coding RNA Levels as Biomarkers of Lupus Nephritis.

BACKGROUND: Emerging evidence suggests that long non-coding RNA (lncRNA) plays important roles in the regulation of gene expression. We determine the role of using urinary lncRNA as a non-invasive biomarker for lupus nephritis. METHOD: We studied three cohorts of lupus nephritis patients (31, 78, and 12 patients, respectively) and controls (6, 7, and 24 subjects, respectively). The urinary sediment levels of specific lncRNA targets were studied using real-time quantitative polymerase chain reactions. RESULTS: The severity of proteinuria inversely correlated with urinary maternally expressed gene 3 (MEG3) (r = -0.423, p = 0.018) and ANRIL levels (r = -0.483, p = 0.008). Urinary MEG3 level also inversely correlated with the SLEDAI score (r = -0.383, p = 0.034). Urinary cancer susceptibility candidate 2 (CASC2) levels were significantly different between histological classes of nephritis (p = 0.026) and patients with pure class V nephritis probably had the highest levels, while urinary metastasis-associated lung carcinoma transcript 1 (MALAT1) level significantly correlated with the histological activity index (r = -0.321, p = 0.004). Urinary taurine-upregulated gene 1 (TUG1) level was significantly lower in pure class V lupus nephritis than primary membranous nephropathy (p = 0.003) and minimal change nephropathy (p = 0.04), and urinary TUG1 level correlated with eGFR in class V lupus nephritis (r = 0.706, p = 0.01). CONCLUSIONS: We identified certain urinary lncRNA targets that may help the identification of lupus nephritis and predict the histological class of nephritis. Our findings indicate that urinary lncRNA levels may be developed as biomarkers for lupus nephritis.

Kidney microRNA-21 Expression and Kidney Function in IgA Nephropathy.

RATIONALE & OBJECTIVE: Previous studies have suggested that microRNA-21 (miR-21) plays an important role in kidney fibrosis. We examined the relationship between intrarenal miR-21 level and rate of kidney function loss in immunoglobulin A nephropathy (IgAN). STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 40 patients with IgAN and 10 with hypertensive nephrosclerosis as controls. PREDICTORS: miR-21 levels in kidney biopsy specimen and urinary sediment, quantified as ratio to the housekeeping gene. OUTCOMES: Kidney event-free survival and rate of kidney function decline. ANALYTIC APPROACH: Time-to-event and correlation analysis. RESULTS: The IgAN group had significantly higher intrarenal miR-21 expression compared with the hypertensive nephrosclerosis group (1.71 [IQR, 0.99-2.77] vs 0.31 [IQR, 0.25-1.32]; P < 0.0001), but urinary miR-21 levels were similar. Intrarenal miR-21 expression had significant but modest correlation with severity of glomerulosclerosis (r = 0.293; P = 0.05) and tubulointerstitial fibrosis (r = 0.341; P = 0.03). Patients with high intrarenal miR-21 expression had significantly higher risk for developing kidney end points compared with those with low expression (log-rank test, P = 0.017). Univariate Cox analysis showed that intrarenal miR-21 expression significantly predicted the development of kidney end points (unadjusted HR, 1.586; 95% CI, 1.179-2.134; P = 0.002). However, the result was just short of statistical significance after adjusting for the severity of histologic damage (P = 0.06). There was also a significant correlation between intrarenal miR-21 expression and the slope of kidney function decline by univariate analysis (r = -0.399; P = 0.02). LIMITATIONS: Small sample size; uncertain cellular origin of miR-21. CONCLUSIONS: We found that intrarenal miR-21 expression is increased in patients with IgAN, modestly correlated with the severity of histologic damage, and predictive of subsequent kidney function loss.

Causes of nephrotic syndrome and nephrotic-range proteinuria are different in adult Chinese patients: A single centre study over 33 years.

AIM: The reported causes of nephrotic syndrome (NS) varies between different countries. Less is known about the causes of nephrotic-range proteinuria (NPU). We aimed to evaluate the underlying causes of NS and NPU. METHODS: This was a single-centre, retrospective study of adult patients who underwent renal biopsy between 1983 and 2015 in a tertiary referral hospital in Hong Kong. We determined the distribution of histopathological diagnoses with regard to the age subgroups and time periods. RESULTS: Among 7456 patients who underwent renal biopsy, 982 and 838 patients had NS and NPU, respectively. The most common diagnosis in NS was minimal change disease (MCD) (33.3%), followed by membranous nephropathy (MN) (23.6%) and lupus nephritis (LN) (12.8%); whereas the most common diagnosis in NPU was LN (27.4%), followed by immunoglobulin A nephropathy (IgAN) (21.4%) and diabetic nephropathy (DN) (9.3%). In the NS group, MCD was the most common diagnosis in young adults while MN was the leading cause in the elderly. On the other hand, LN was the most common pathology in the NPU group until the age of 60. Over the past three decades, there was a trend of decrease in the proportion of IgAN in both NS and NPU group, while a combined pathology of hypertensive nephrosclerosis and diabetic nephropathy (HTNS and DN) increased significantly. CONCLUSIONS: The causes of NS and NPU in Chinese adults were different and may represent two distinct pathological identities. The spectrum of renal histopathology among these two groups changed significantly over time.

Urinary sediment mRNA level of extracellular matrix molecules in adult nephrotic syndrome.

BACKGROUND: Glomerular and tubulointerstitial fibrosis play important roles in the progression of chronic kidney disease. We determine whether urinary mRNA levels of extracellular matrix proteins reflect the degree of kidney fibrosis and predict renal function decline in adult nephrotic patients. METHODS: We studied 56 adult nephrotic patients and 20 controls. Urinary mRNA levels of collagen I A1 chain (COL1A1), collagen IV A3 chain (COL4A3), and fibronectin were measured. RESULTS: Urinary sediment mRNA levels of COL1A1 and fibronectin were significantly higher in nephrotic patients as compared to the control, irrespective to the pathological diagnosis. Urinary COL1A1 mRNA level correlates with proteinuria, glomerular and interstitial fibrosis, and inversely with estimated glomerular filtration rate (GFR); urinary fibronectin mRNA level significantly correlates with glomerular and interstitial fibrosis, and inversely with estimated GFR. After 42.4 ± 12.6 months follow-up, the rate of GFR decline inversely correlates with urinary mRNA level of COL1A1 (r = -0.273, p = 0.044). Multivariate analysis confirmed that urinary COL1A1 mRNA level is an independent predictor of serum creatinine doubling or progressing to end stage renal disease; for each 10-fold increase in urinary COL1A1 mRNA level, there is 15.1% excess in risk (95% confidence interval, 1.9% to 30.4%, p=0.022). CONCLUSIONS: Urinary COL1A1 mRNA level is elevated in nephrotic patients irrespective to the pathological diagnosis, and it correlates with proteinuria, histological scarring, and inversely with renal function. Furthermore, urinary COL1A1 mRNA level predicts renal function loss during follow-up. Our results suggest that urinary COL1A1 mRNA level may be used for risk stratification of adult nephrotic syndrome.

Prostate Health Index and %p2PSA Predict Aggressive Prostate Cancer Pathology in Chinese Patients Undergoing Radical Prostatectomy.

PURPOSE: To investigate the performance of prostate health index (PHI) and percentage prostate-specific antigen (PSA) isoform [-2]proPSA (%p2PSA) in predicting pathologic outcomes at radical prostatectomy (RP) in a Chinese population. METHODS: We performed a prospective study of 135 prostate cancer patients with RP. The accuracy of preoperative %p2PSA (= p2PSA/free PSA) and PHI [= (p2PSA/free PSA) × âˆšPSA] in predicting pathologic outcomes of RP including pT3 disease, pathologic Gleason score (pGS) ≥7, Gleason score (GS) upgrade at RP, tumor volume >0.5 ml, and Epstein criteria for significant tumor were calculated using multivariate analyses and area under the curve. The base model in multivariate analysis included age, PSA, abnormal digital rectal examination, and biopsy GS. RESULTS: PHI was significantly higher in patients with pT3 or pGS ≥ 7 (p < 0.001), pT3 disease (p = 0.001), pGS ≥ 7 (p < 0.001), GS upgrade (p < 0.001), tumor volume >0.5 ml (p < 0.001), and Epstein criteria for significant tumor (p = 0.001). %p2PSA was also significantly higher in all the above outcomes. The risk of pT3 or pGS ≥ 7 was 16.1 % for PHI < 35 and 60.8 % for PHI > 35 (sensitivity 84.2 %, specificity of 60.3 %), and the risk of tumor volume >0.5 ml was 25.5 % for PHI < 35 and 72.6 % for PHI > 35 (sensitivity 79.1 %, specificity 67.2 %). In multivariate analysis, adding %p2PSA or PHI to the base model significantly improved the accuracy (area under the curve) in predicting pT3 or pGS ≥ 7 (by 7.2-7.9 %), tumor volume >0.5 ml (by 10.3-12.8 %), and Epstein criteria for significant tumor (by 13.9-15.9 %). Net clinical benefit was observed in decision curve analyses for prediction of both tumor volume >0.5 ml, and pT3 or pGS ≥ 7. CONCLUSIONS: Both PHI and %p2PSA predict aggressive and significant pathologies in RP in Chinese men. This enabled identification of nonaggressive cancers for better counseling on active surveillance or treatment.

Podocyte mRNA in the urinary sediment of minimal change nephropathy and focal segmental glomerulosclerosis.

BACKGROUND: Podocyte depletion is a characteristic feature of progressive renal failure. We hypothesize that studying the podocyte mRNA level in urinary sediment may provide diagnostic and prognostic information in adult nephrotic syndrome. METHODS: We studied 25 patients with minimal change nephropathy (MCN), 25 with focal segmental glomerulosclerosis (FSGS), and 17 healthy controls. The mRNA levels of nephrin, podocin, and synaptopodin in urinary sediment were quantified. RESULTS: There were significant differences in the urinary sediment nephrin and podocin, but not synaptopodin, mRNA levels between diagnosis groups. Post-hoc analysis further showed that urinary nephrin mRNA levels of the MCN group were lower than those in the control and FSGS groups, although the difference between MCN and FSGS groups did not reach statistical significance. The degree of proteinuria inversely correlated with urinary nephrin mRNA levels in the MCN (r = -0.526, p = 0.007) as well as in the FSGS group (r = -0.521, p = 0.008). For the FSGS group, the rate of renal function decline significantly correlated with baseline urinary synaptopodin mRNA levels (r = -0.496, p = 0.012). CONCLUSIONS: Urinary nephrin and podocin mRNA levels were reduced in patients with MCN and probably FSGS, and the magnitude of reduction correlated with the degree of proteinuria. Urinary synaptopodin mRNA levels correlated with the subsequent rate of renal function decline in patients with FSGS. Our result indicates that urine sediment podocyte mRNA levels provide novel insights in the pathophysiology of nephrotic syndrome and could be useful for risk stratification.

Functional and histological improvement after everolimus rescue of chronic allograft dysfunction in renal transplant recipients.

BACKGROUND: We tested the strategy of mTOR inhibitors with calcineurin inhibitor minimization in renal transplant recipients with known chronic allograft dysfunction. METHODS: In this open-label, single-arm study, renal transplant patients were recruited after biopsy-confirmed chronic allograft dysfunction in the absence of acute rejection episode within 2 months, with proteinuria <0.8 g/day, and serum creatinine <220 µmol/L or estimated glomerular filtration rate >40 mL/min/1.73 m(2). They were converted to everolimus (aiming for trough everolimus level 3-8 ng/mL) with cyclosporine minimization, to assess the effect on renal function, rate of glomerular filtration rate decline, and longitudinal transplant biopsy at 12 months. RESULTS: Seventeen Chinese patients (median transplant duration, 4.2 years) were recruited; no patients discontinued study medication. The mean slope of the glomerular filtration rate over time was -4.31±6.65 mL/min/1.73 m(2) per year in the year before everolimus, as compared with 1.29±5.84 mL/min/1.73 m(2) per year in the 12 months of everolimus therapy, a difference of 5.61 mL/min/1.73 m(2) per year (95% confidence interval [CI], 0.40-10.8) favoring everolimus therapy (P=0.036). Serial renal biopsy histology showed significant decrease of tubular atrophy (15.7%±11.3% versus 7.1%±7.3%, P=0.005) and interstitial fibrosis (14.8%±11.5% versus 7.2%±8.2%, P=0.013). Intrarenal expression of TGF-ß1 mRNA showed a nonsignificant decrease after everolimus treatment. CONCLUSION: In renal transplant recipients with biopsy-confirmed chronic allograft dysfunction, we found a significant beneficial effect of everolimus rescue therapy and calcineurin inhibitor minimization strategy on the improvement of glomerular filtration rate decline rate. In secondary analysis, everolimus was shown to slow down the disease progression by reducing the tubular atrophy and interstitial fibrosis scoring.

Intrarenal and Urinary Th9 and Th22 Cytokine Gene Expression in Lupus Nephritis.

OBJECTIVE: We studied the urinary sediment mRNA level of Th9- and Th22-related cytokines in patients with systemic lupus erythematosus (SLE). METHODS: We quantified urinary mRNA levels of interleukin (IL) 9, IL-10, IL-22, and their corresponding transcription factors in 73 patients with active lupus nephritis, 13 patients with hypertensive nephrosclerosis (HTN), and 25 healthy subjects. RESULTS: There was no detectable IL-9 mRNA in all samples. Patients with proliferative lupus nephritis had significantly lower urinary IL-22 mRNA levels than those with nonproliferative nephritis (2.2 ± 5.4 vs 8.6 ± 20.0 copies, p = 0.019), and urinary IL-22 mRNA level inversely correlated with the histological activity index (r = -0.427, p < 0.0001). In contrast, patients with lupus nephritis had significantly higher urinary IL-10 mRNA levels than patients with HTN (7.8 ± 18.5 vs 1.9 ± 4.0 copies, p = 0.012), and urinary IL-10 mRNA levels correlated with its intrarenal mRNA levels (r = 0.337, p = 0.004) and SLE disease activity index (r = 0.277, p = 0.018). Urinary IL-10 mRNA level was significantly lower among patients who achieved complete remission than those with partial remission or no response (4.1 ± 6.5 vs 14.1 ± 28.0 copies, p = 0.036). CONCLUSION: Urinary IL-22 mRNA level is decreased in patients with SLE with proliferative nephritis, while urinary IL-10 mRNA levels correlates with its intrarenal mRNA level and disease activity. Urinary IL-10 mRNA levels may also predict treatment response. These results suggest that urinary mRNA levels of IL-10 and IL-22 might be used as biomarkers for assessing disease activity and risk stratification in lupus nephritis.

Urinary mRNA levels of ELR-negative CXC chemokine ligand and extracellular matrix in diabetic nephropathy.

BACKGROUND: Inflammation and fibrosis play important roles in the progression of diabetic nephropathy. We determine the urinary mRNA levels of ELR-CXC chemokine ligand and extracellular matrix in diabetic nephropathy. METHODS: We studied 26 patients with biopsy-proven diabetic nephropathy, 15 with hypertensive nephrosclerosis and 10 healthy controls. Urinary mRNA levels of CXCL9, CXCL10, CXCL11, collagen I A1 chain, collagen IV A3 chain and fibronectin were measured. Patients were followed for 36.9 ± 7.4 months to determine the rate of glomerular filtration rate (GFR) decline. RESULTS: Urinary mRNA levels of CXCL10 and CXCL11 are decreased, and those of collagen I A1 chain and fibronectin are increased in diabetic nephropathy. Baseline estimated GFR correlates with urinary mRNA level of CXCL9 (r = 0.583, p = 0.002) and CXCL11 (r = 0.703, p < 0.0001), respectively. The rate of GFR decline significantly correlates with urinary CXCL9 (r = -0.618, p = 0.0008) and CXCL11 mRNA levels (r = -0.726, p < 0.0001). Multivariate linear regression analysis confirms that urinary CXCL9 mRNA level is independently associated with the rate of GFR decline, while the correlation with urinary CXCL11 mRNA level has borderline significance. CONCLUSION: Urinary CXCL9 and CXCL11 mRNA levels correlate with baseline renal function. The rate of renal function decline correlates with urinary CXCL9 mRNA level. Our results suggest that urinary CXCL9 mRNA levels may be used for risk stratification of diabetic nephropathy.

Long-term outcome of biopsy-proven minimal change nephropathy in Chinese adults.

BACKGROUND: Minimal change nephropathy is a common cause of primary nephrotic syndrome in adults. However, there are few studies of its clinical course, response to treatment, and long-term outcome. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 340 consecutive adult patients with nephrotic syndrome and biopsy-proven minimal change nephropathy treated in a university hospital from 1984 until 2004. FACTORS: Treatment response groups: primary steroid resistance, frequent relapse (≥4 relapses within 1 year), infrequent relapse (≥1 relapse but not frequent relapse), and no relapse (reference group); disease pattern. OUTCOME: Medical problems after diagnosis; patient survival; renal survival. RESULTS: Median time to remission was 10 (IQR, 8-12) weeks; 179 (52.6%) had no relapse, 42 (12.4%) had infrequent relapses, 86 (25.3%) were frequent relapsers or steroid dependent, and 33 (9.7%) had primary steroid resistance. After a median follow-up of 174.7 (IQR, 119.7-235.0) months, 32 patients developed end-stage renal disease and 62 died (25 after progression to end-stage renal disease). Cox regression analysis showed that age and treatment response groups were the independent predictors of patient survival. Compared to the no-relapse group, the infrequent-relapse group had significantly better patient survival (adjusted HR, 0.19; 95% CI, 0.08-0.44; P<0.001), whereas the primary-steroid-resistance group had significantly worse patient survival (adjusted HR, 5.87; 95% CI, 1.83-18.85; P<0.001). Renal survival was excellent except in the primary-steroid-resistance group. LIMITATIONS: Retrospective study. CONCLUSIONS: A substantial proportion of adult patients with minimal change nephropathy continue to have disease flares more than 10 years after the initial presentation, and medical problems after diagnosis are common.

Urinary sediment miRNA levels in adult nephrotic syndrome.

BACKGROUND: MicroRNAs are a group of non-coding RNA molecules that play important roles in the pathogenesis of various kidney diseases. We investigate the urinary sediment miRNA levels of adult patients with nephrotic syndrome. METHODS: We study 20 patients with diabetic glomerulosclerosis (DGS), 21 with minimal change nephropathy (MCN) or focal glomerulosclerosis (FGS), 23 with membranous nephropathy (MGN), and 10 healthy controls. Urinary sediment miRNA levels are quantified. RESULTS: Urinary sediment miR-29a, miR-192, and miR-200c levels were significantly different between diagnosis groups. Post hoc analysis showed that urinary miR-638 level was significantly lower in all causes of nephrotic syndrome than healthy controls, while the DGS group had lower urinary miR-192 level than other diagnosis groups. In contrast, the MCN/FGS group had higher urinary miR-200c level than other diagnosis groups. For each specific pathology group, urinary level of several miRNA targets significantly correlated with kidney function and histological scarring. CONCLUSIONS: Urinary miR-29a, miR-192 and miR-200c levels have characteristic alterations among patients with different causes of nephrotic syndrome. Our results suggest that urinary miRNA levels have the potential of being developed as the diagnosis tool and marker of disease severity in adult nephrotic syndrome.

Urinary biomarkers for the prediction of reversibility in acute-on-chronic renal failure.

BACKGROUND: There is no reliable clinical test to predict the reversibility of acute-on-chronic renal failure. We study whether urinary biomarkers could be used as a noninvasive prognostic marker in patients with acute-on-chronic renal failure. METHODS: We studied 39 adult patients with pre-existing chronic renal impairment presenting to us with acute-on-chronic renal failure. Urinary neutrophil gelatinase-associated lipocalin (NGAL) level was measured. The mRNA of kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), alpha-1-microglobulin (α1M), sodium/hydrogen exchanger-3 (NHE3), beta-2 microglobulin (ß2M), and N-acetyl-ß-D-glucosaminidase (NAG) in urinary sediment were quantified. RESULTS: Urinary NGAL level significantly correlated with the serum creatinine at presentation (r=0.762, p<0.0001) but not baseline serum creatinine. Urinary sediment ß2M expression significantly correlated with baseline glomerular filtration rate (GFR) (r=−0.400, p=0.012). Urinary α1M and NHE3 expressions were significantly higher in ischemic acute tubular necrosis than other causes of acute kidney injury (p<0.0001 and p=0.006, respectively). Urinary α1M expression significantly correlated with the degree of improvement in renal function (r=0.387, p=0.026), as well as the estimated GFR 6 months later (r=0.386, p=0.027). CONCLUSION: In patients with acute-on-chronic renal failure, urinary NGAL level correlates with the severity of renal failure, while urinary α1M expression correlates with the degree of renal function recovery. Quantification of urinary α1M mRNA may be developed as an non-invasive tool for risk stratification of this group of patients.

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-ß(1) (TGF-ß(1)), 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-ß(1), 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-ß(1)/SMAD3 pathway and they may play important roles in the development of progressive renal fibrosis in IgA nephropathy.

Relationship of intrarenal gene expression and the histological class of lupus nephritis -- a study on repeat renal biopsy.

OBJECTIVE: To study the role of tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK)/Fn14 and the interferon-inducible protein (IP-10)/CXCR3 axis in lupus nephritis (LN). METHODS: We studied 113 patients with LN who had had repeat renal biopsies. Glomerular and tubulointerstitial messenger RNA expression of TWEAK, Fn14, IP-10, and CXCR3 were quantified. RESULTS: Glomerular Fn14 expression decreased when changed from proliferative or mixed nephritis to membranous nephropathy (p = 0.016), and increased when changed from membranous to proliferative or mixed nephritis (p = 0.0006). On the other hand, tubulointerstitial TWEAK expression decreased when changed from proliferative or mixed nephritis to membranous nephropathy (p = 0.004), and increased when changed from membranous nephropathy to proliferative nephritis (p = 0.010). Tubulointerstitial IP-10 expression decreased when changed from proliferative or mixed nephritis to membranous nephropathy (p < 0.0001). Histological activity index correlated significantly with the glomerular expression of Fn14 (r = 0.421, p < 0.0001) and tubulointerstitial expression of TWEAK (r = 0.413, p < 0.0001) and IP-10 (r = 0.472, p < 0.0001). CONCLUSION: Glomerular Fn14 and tubulointerstitial TWEAK and IP-10 expression appeared to have consistent changes in relation to the histological class of LN and correlated with the histological activity index. Our findings suggest a specific role of these genes in the pathogenesis of LN.

Glomerular and tubulointerstitial miR-638, miR-198 and miR-146a expression in lupus nephritis.

AIM: MicroRNAs (miRNAs) play important roles in the pathogenesis of autoimmune diseases. We studied the intra-renal expression of miRNA targets that were reported to be differentially expressed in peripheral blood or urine between lupus nephritis (LN) patients and normal controls. METHODS: We quantified the expression of in glomerulus and tubulointerstitium of miR-146a, miR-155, miR-198 miR-638 and miR-663 in 42 patients with LN and 10 healthy controls. RESULTS: As compared with controls, LN patients had lower glomerular expression of miR-638 (P < 0.001) but higher tubulointerstitial expression of this target (P = 0.001). Both glomerular and tubulointerstitial expression of miR-198 were higher in LN patients than controls (P < 0.001). For miR-146a, LN patients only had higher expression in glomerulus (P = 0.005) but not in tubulointerstitium. Tubulointerstitial miR-638 expression was significantly correlated with proteinuria (r = 0.404; P = 0.022) and disease activity score (r = 0.454; P = 0.008), while glomerular miR-146a expressions were correlated with estimated GFR (r = 0.453; P = 0.028) and histological activity index (r = 0.494; P = 0.027). CONCLUSION: We found that intra-renal expression of miR-638, miR-198 and miR-146a are differentially expressed between LN patients and normal controls. Furthermore, the degree of change in glomerular miR-146a and tubulointerstitial miR-638 expression correlated with clinical disease severity. The results suggested that these miRNA targets may play a role in the pathogenesis of lupus nephritis.

Monitoring of urinary messenger RNA levels for the prediction of flare in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is characterized by disease flares and remission. We hypothesize that in clinically quiescent SLE patients, the mRNA level of target genes in the urinary sediment is an early indicator of disease flare. METHODS: From a cohort of 134 adult SLE patients prospectively followed for 56 weeks, we identified 19 patients with a single disease flare. The mRNA level of eight pre-defined target genes in their urinary sediment before disease flare was compared to 19 matched controls with no disease flare during the same period. RESULTS: Urinary mRNA level remained static in the control group during the study period. Before disease flare, there was a significant increase in the mRNA level of monocyte chemotactic protein (MCP)-1 and forkhead box P3 (FOXP3), and decrease in interleukin (IL)-17 and GATA-3, in the urinary sediment. The mRNA level of FOXP3 in urinary sediment increases 8 weeks prior to a flare, which precedes the corresponding change in serum complement and anti-DNA antibody titer, while that of MCP-1, IL-17, and GATA3 began to change 4 weeks prior to a flare. The same pattern of change in urinary mRNA level was observed in patients with mild-to-moderate or severe flare, and those with renal or non-renal flare. The SLE Disease Activity Index (SLEDAI) score at the time of flare significantly correlated with the change in urinary level of IL-17 (r=-0.462, p=0.046) and GATA-3 (r=-0.455, p=0.05), but not MCP-1 or FOXP3, prior to the flare. CONCLUSION: Monitoring of MCP-1, IL-17, GATA-3 and FOXP3 mRNA level in urinary sediment may provide an early clue for detecting disease flare in SLE patients.

Repeat renal biopsy in lupus nephritis: a change in histological pattern is common.

BACKGROUND: The role of longitudinal change in sequential renal biopsies of lupus nephritis (LN) patient remains elusive. METHODS: Clinical and pathological documents of 156 LN patients with repeat renal biopsies (412 times) were collected from a database. RESULTS: The percent of transformation of the biopsy class from reference biopsies to repeat biopsies was 75%. For the reference biopsies that showed pure proliferative, pure membranous, and mixed nephritis, the histological pattern in the repeat biopsies changed in 57.8, 50.0, and 60.4%, respectively. As compared to reference biopsy, repeat biopsy had a higher degree of tubulointerstitial scarring (p < 0.001), chronicity index (p < 0.001) and serum creatinine (p < 0.001). In addition, baseline serum creatinine was significantly lower (p = 0.004), and the time lapse between the two biopsies was significantly longer (p < 0.001) amongst patients who had a change in the histological pattern upon repeat renal biopsy than those whose histological pattern remained the same. CONCLUSION: The present study suggests that a change in the histological class of LN is common in systemic lupus erythematosus patients with lupus flare, and the histology during disease flare could not be predicted by baseline clinical, biochemical, or pathological parameters. Our results indicate that when there is lupus flare with renal involvement, repeat renal biopsy is often necessary to guide the treatment.

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)-1ß, 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-1ß 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.

Gene expression of TWEAK/Fn14 and IP-10/CXCR3 in glomerulus and tubulointerstitium of patients with lupus nephritis.

AIM: The role of the tumour necrosis factor-like weak inducer of apoptosis (TWEAK)/Fn14 and interferon-inducible protein (IP-10)/CXCR3 axis in the pathogenesis of lupus nephritis were studied. METHODS: The mRNA expression of TWEAK, Fn14, IP-10 and CXCR3 were quantified in the glomerulus and tubulointerstitium of 42 patients with lupus nephritis (LN group) and 10 healthy controls. RESULTS: As compared to controls, LN patients had higher glomerular expression of TWEAK and Fn14, but glomerular CXCR3 expression was lower in the LN group. Similarly, the LN group had higher tubulointerstitial expression of TWEAK and Fn14, but lower tubulointerstitial expression of CXCR3, than controls. Glomerular TWEAK expression of class V nephritis was significantly higher than class IV nephritis. Glomerular expression of CXCR3 significantly correlated with proteinuria (r = -0.532; P = 0.019), whereas tubulointerstitial CXCR3 significantly correlated with serum creatinine (r = -0.447; P = 0.029). CONCLUSION: In patients with lupus nephritis, there is an increase in intra-renal expression of TWEAK and Fn14, and a decrease in CXCR3 expression. Intra-renal expression of CXCR3 correlates with proteinuria and renal function. Our findings suggest that the TWEAK/Fn14 and IP-10/CXCR3 axis may contribute to the pathogenesis of lupus nephritis.