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.

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.

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.

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 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.

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.

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.

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.

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.

Expression of ACE and ACE2 in patients with hypertensive nephrosclerosis.

BACKGROUND: The interplay between intrarenal angiotensin-converting enzyme (ACE) and type 2 ACE (ACE2) might play important roles in the pathogenesis of hypertensive nephrosclerosis (HTN), but human data are limited. METHODS: Renal biopsy specimens of 41 patients with HTN and 10 transplant donors as controls (CTL) were studied. The glomerular and tubulointerstitial mRNA expression of ACE and ACE2 was measured by laser microdissection and real-time quantitative polymerase chain reaction. The corresponding protein level was determined by immunohistochemistry. RESULTS: Neither the glomerular nor tubulointerstitial mRNA expression of ACE or ACE2 correlated with the corresponding protein level by immunohistochemistry. The tubulointerstitial levels of ACE and ACE2 were significantly lower in HTN than CTL, while the glomerular ACE and ACE2 levels were similar between the groups. The tubulointersitial ACE and ACE2 levels significantly correlated with the estimated glomerular filtration rate (GFR) and inversely with the degree of histological damage. The glomerular ACE and ACE2 levels significantly correlated with the rate of GFR decline. The ratio of glomerular ACE and ACE2 level correlated with the estimated GFR and the degree of glomerulosclerosis. CONCLUSION: Our results suggest that intrarenal ACE and ACE2 may play an important role in the pathogenesis and progression of HTN. Studies based on the mRNA expression of ACE and ACE2 should be cautiously interpreted.

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.

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.

Intra-renal and urinary mRNA expression of podocyte-associated molecules for the estimation of glomerular podocyte loss.

BACKGROUND: Podocyte loss plays an important role in the pathogenesis of diabetic nephropathy, but counting the number of glomerular podocyte in renal biopsy specimen is a labor-intensive task. We study whether intra-renal and urinary messenger RNA expression of podocyte-associated molecules could be used to estimate glomerular podocyte number in patients with diabetic nephropathy. METHOD: We studied 21 consecutive patients with biopsy-proven diabetic nephropathy. The intra-renal and urinary mRNA expression of nephrin, podocin, and synaptopodin were measured by real-time quantitative polymerase chain reaction. Podocyte number was determined in micro-dissected glomerulus. The degree of histological scarring was quantified by morphometric analysis. RESULTS: Glomerular podocyte number correlated with intra-renal expression of nephrin (r=0.510, p=0.044), podocin (r=0.605, p=0.013), and synaptopodin (r=0.480, p=0.060). Glomerular podocyte number also significantly correlated with urinary expression of synaptopodin (r=0.595, p=0.019) but not other targets. Baseline renal function correlated with intra-renal expression of nephrin (r=0.617, p=0.005), synaptopodin (r=0.474, p=0.040), and podocin (r=0.443, p=0.057). The degree of tubulointerstitial scarring also inversely correlated with intra-renal expression of nephrin (r=-0.462, p=0.047), podocin (r=-0.458, p=0.049), and synaptopodin (r=-0.500, p=0.029) but not with urinary gene expression. CONCLUSION: Intra-renal expression of podocyte-associated molecules correlated with glomerular podocyte number, renal function, and tubulointerstitial scarring. The results suggest that intra-renal, but not urinary expression of podocyte-associated molecules, might be used to assess the degree of podocyte loss in diabetic nephropathy.

The gene expression of type 17 T-helper cell-related cytokines in the urinary sediment of patients with systemic lupus erythematosus.

OBJECTIVE: We studied the role of type 17 Th cells (TH17) in the pathogenesis of SLE. METHODS: We quantified the mRNA expression of IL-17, -23, -27 and retinoic-acid-related orphan receptor (ROR)-gamma, the regulator for the development and function of TH17, in the urinary sediment of 23 subjects with active lupus nephritis, 25 subjects with a history of lupus nephritis in remission, 30 SLE patients with no history of renal involvement and 8 healthy subjects. RESULTS: All three groups of lupus patients had a higher urinary expression of TH17-related cytokines than the controls. However, urinary expression of IL-17 and -27 was found to be inversely correlated with the SLEDAI score (r = -0.252 and -0.258, respectively; P < 0.05 for both). For patients with active lupus nephritis, the histological activity index of kidney biopsy was also found to be inversely correlated with the urinary expression of ROR-gamma (r = -0.447; P = 0.032), IL-17 (r = -0.454; P = 0.029) and IL-23 (r = -0.455; P = 0.029). Urinary expression of IL-17, -23, -27 and ROR was also found to be inversely correlated with the urinary expression of IFN-gamma and T-bet, the key transcription factor of type 1 Th cells. After 6 months of treatment, urinary IL-27 expression rose significantly in patients with complete response (from 2.07 +/- 1.62 to 3.70 +/- 1.69; P = 0.028) but remained unchanged in those with partial or no response (from 2.60 +/- 1.87 to 2.52 +/- 1.94; P = 0.9). CONCLUSIONS: The urinary expression of TH17-related genes is increased in SLE patients. The degree of up-regulation, however, is inversely related to systemic and renal lupus activity, as well as urinary expression of TH1-related genes. Urinary expression of TH17-related genes increased again after successful immunosuppressive treatment of active disease. Our findings suggest a regulatory role of TH17-related cytokines in pathogenesis of lupus nephritis.

Discrepancy between intrarenal messenger RNA and protein expression of ACE and ACE2 in human diabetic nephropathy.

BACKGROUND: The intrarenal angiotensin-converting enzyme (ACE) and type 2 ACE (ACE2) play important roles in the pathogenesis of diabetic nephropathy, but human data are limited. We studied glomerular and tubulointerstitial mRNA and the protein expression of ACE and ACE2 in patients with diabetic nephropathy. METHODS: We studied renal biopsy specimens of 22 patients with diabetic nephropathy and 11 transplant donors as normal controls. Intrarenal mRNA expression of ACE and ACE2 was measured by laser microdissection and real-time quantitative polymerase chain reaction; expression at the protein level was determined by immunostaining. RESULTS: Glomerular and tubulointerstitial mRNA expression levels of ACE and ACE2 were significantly higher in patients with diabetic nephropathy than in normal controls (p < 0.001 for all comparisons). Glomerular ACE and ACE2 protein levels of patients with diabetic nephropathy were significantly higher than those of kidney donors (4.90 +/- 2.55% vs. 2.64 +/- 0.98%, p = 0.022, and 7.40 +/- 3.36% vs. 4.37 +/- 2.36%, p = 0.017, respectively). The tubulointerstitial ACE at the protein level, however, was similar between diabetic patients and controls (8.76 +/- 4.18% vs. 10.44 +/- 6.61%, p = 0.453), and the tubulointerstitial ACE2 at the protein level was significantly lower in diabetic nephropathy (16.48 +/- 7.68% vs. 23.23 +/- 7.65%, p = 0.025). CONCLUSION: The mRNA expression of ACE and ACE2 increased in both the glomerular and tubulointerstitial area of diabetic nephropathy. However, the tubulointerstitial ACE expression at the protein level remained unchanged, while that of ACE2 actually decreased. Our results suggest a posttranscriptional modulation of tubulointerstitial ACE and ACE2 expression. Experimental data of intrarenal mRNA expression of ACE and ACE2 should be interpreted with caution.

Messenger RNA expression of podocyte-associated molecules in the urinary sediment of patients with diabetic nephropathy.

BACKGROUND: Podocyte loss plays an important role in the pathogenesis of diabetic nephropathy. We hypothesize that messenger RNA expression of podocyte-associated molecules in urinary sediment may provide important clinical information in patients with diabetic nephropathy. METHOD: We studied 21 patients with biopsy-proven diabetic nephropathy and 9 healthy controls. The mRNA expression of nephrin, podocin, synaptopodin, Wilms' tumor-1 (WT-1) and alpha-actinin-4 in urinary sediment were measured by real-time quantitative polymerase chain reaction. The degree of histological damage was quantified by morphometric analysis. Patients were then followed for an average of 25.63 +/- 10.76 months. The rate of glomerular filtration rate (GFR) decline was calculated by the least-square regression. RESULTS: There were significant differences in nephrin, podocin, synaptopodin, alpha-actinin-4 (p < 0.01 for all comparisons) and WT-1 (p = 0.028) expression between patients and normal controls. Urinary nephrin expression was significantly correlated with proteinuria (r = 0.502, p = 0.020); urinary synaptopodin was significantly correlated with proteinuria (r = 0.585, p = 0.005), serum creatinine (r = 0.516, p = 0.017) and estimated GFR (r = -0.560, p = 0.008), and urinary WT-1 expression was significantly correlated with the degree of tubulointerstitial fibrosis (r = 0.558, p = 0.009). There was no significant correlation between GFR decline and urinary expression of target genes. CONCLUSION: Urinary mRNA expressions of nephrin, podocin, synaptopodin, WT-1 and alpha-actinin-4 are higher in patients with diabetic nephropathy than in normal controls. Urinary nephrin and synaptopodin expressions are correlated with baseline clinical parameters such as proteinuria or renal function, while WT-1 expression is related to the degree of histological damage. Our results suggest that urinary mRNA expression of podocyte-associated molecules may be used for risk stratification of diabetic nephropathy.

Prevalence and implications of isolated microscopic hematuria in asymptomatic Chinese pregnant women.

BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. However, the actual prevalence of microscopic hematuria and IgAN is unknown in the Chinese population. METHODS: We screened 7,828 consecutive pregnant women for microscopic hematuria in the antenatal clinic of a tertiary referral center. Persistent microscopic hematuria was defined as urine Hemastix (Bayer Diagnostics, Hong Kong) of 1+ for red cells in two clinic visits. Subjects were referred to the renal clinic for specialist evaluation, including measurement of blood pressure, serum creatinine, urine bacterial culture, and quantification of proteinuria. RESULT: There were 207 women (2.64%) with microscopic hematuria. Mean age was 31.8 +/- 5.0 years. In 101 patients (48.8%), there was proteinuria >0.1 g/day by quantitative assay. Hematuria was found to resolve before or shortly after delivery in 126 (60.9%) and 68 women (32.9%), respectively. Five patients (2.4%) had urinary tract infection proved by repeated urine culture, 1 had papillary necrosis, and 1 had duplex collecting system. Three patients were confirmed to have IgAN by renal biopsy; all had normal blood pressure and serum creatinine, but dysmorphic red cells in urine microscopy, and proteinuria of over 0.5 g/day that persisted after delivery. Renal biopsy on another woman showed no specific pathology. Two women were lost to follow-up, both with normal renal function and no detectable proteinuria. The overall prevalence of IgAN was 38 cases per 100,000 population (95% confidence interval: 8-112 cases). CONCLUSION: Microscopic hematuria is not uncommon in pregnant women, and IgAN is present in a small proportion of these patients. Further study is needed to determine whether screening for microscopic hematuria would allow early diagnosis and improve the prognosis of these patients.

Undifferentiated sex cord-stromal tumor in a young adult.

Undifferentiated sex cord-stromal tumor in post-puberty male is extremely rare. There were only three reported cases in the literature. We reported a 19-year-old patient presented with an asymptomatic right testicular nodule with normal level of serum marker for germ cell tumor. Excisional biopsy and subsequent orchidectomy was preformed and the final pathology supported the diagnosis of undifferentiated sex cord-stromal tumor. He was then put on regular surveillance with no adjuvant therapy given. He remained disease free 18 months after the operation. A summary of the literatures and discussion on the management of this rare tumor was provided.

mRNA expression of target genes in the urinary sediment as a noninvasive prognostic indicator of CKD.

BACKGROUND: Study of messenger RNA (mRNA) expression of target genes in urinary sediment was suggested as a noninvasive marker of renal damage in patients with chronic kidney diseases (CKDs). We studied the relationship between urinary mRNA expression of target genes and risk for renal function deterioration in patients with CKD. METHODS: We studied 131 patients with CKD with kidney biopsy. mRNA expression of 11 target genes in urinary sediment was measured by means of quantitative polymerase chain reaction. Patients then were followed up for 27.4 +/- 10.1 months. The primary end point is doubling of serum creatinine concentration or end-stage renal disease. RESULTS: Thirty-six patients (27.5%) reached the primary end point during follow-up. Univariate analysis showed that sex, age, proteinuria, estimated glomerular filtration rate, histological diagnosis, degree of tubulointerstitial scarring, percentage of glomerulosclerosis, and urinary mRNA expression of hepatocyte growth factor (HGF) were predictors of the primary end point. At 24 months, event-free survival rates were 90.9% and 64.3% for patients with low and high urinary HGF expression, respectively (log rank test, P = 0.002). After adjusting for other confounding factors by using a Cox proportional hazard model, urinary HGF expression remained an independent predictor of the primary end point, and a 1-fold increase in expression was associated with a 4.0% (95% confidence interval, 0.5 to 7.5; P = 0.024) increase in risk. CONCLUSION: In the target genes examined, urinary HGF expression is an independent prognostic indicator of CKD after adjusting for confounding clinical and histological factors. Measurement of urinary HGF mRNA expression may be a useful noninvasive tool for risk stratification of patients with CKD.

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.