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.

Urinary mi-106a for the diagnosis of IgA nephropathy: Liquid biopsy for kidney disease.

BACKGROUND: Urinary micro-RNA (miRNA) level may serve as non-invasive disease markers for immunoglobulin A nephropathy (IgAN), but urinary miRNA targets identified in previous studies may represent kidney scarring rather than being specific for IgAN. We aim to identify urinary miRNA targets for the diagnosis of IgAN by including hypertensive nephrosclerosis (HTN) as a control group. Methods In the development cohort, we performed complete miRNA profiling of urinary sediment in 33 patients with IgAN, 9 with HTN, and 9 healthy controls (CTL). Potential miRNA targets were quantified by a separate validation cohort of 72 IgAN, 34 HTN, and 20 healthy controls. Results In the development cohort, we identified 6 miRNA targets with urinary levels significantly increased in IgAN as compared to both HTN and CTL. In the validation study, all 6 miRNA targets remained increased than the other groups, although the result of miR-345 did not reach statistical significance. The area-under-curve of the receiver operating characteristic (ROC) curve for urinary mi-106a level for the diagnosis of IgAN was 0.742 (p < 0.0001), and the diagnostic performance was not further improved by having additional miRNA targets. At the cut-off ≥ 800 copy per 1000 copies of housekeeping gene, urinary miR-106a has 100% sensitivity and 14.8% specificity in detecting IgA nephropathy. Conclusions We identified 6 miRNA targets whose urinary levels are significantly elevated in IgAN, and urinary miR-106a level has an excellent sensitivity for the identification of IgAN. Further validation studies are needed to confirm its role in disease screening.

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.

Images of the month: Crystalglobulin-induced nephropathy.

We report a patient with chronic diabetes and was referred for recent onset proteinuria. Light microscopy of the renal biopsy specimen showed mildly expanded mesangium with mesangial hypercellularity and segmental sclerosis, features compatible with diabetic glomerulosclerosis. However, crystalglobulin-induced nephropathy with crystal deposit was identified on electron microscopy. Renal biopsy is often performed for diabetic patients who present with proteinuria and light microscopy often shows features of diabetic glomerulosclerosis. Additional information may occasionally be revealed on electron microscopy, altering the subsequent plan of management.

An International Collaborative Consensus Statement on En Bloc Resection of Bladder Tumour Incorporating Two Systematic Reviews, a Two-round Delphi Survey, and a Consensus Meeting.

BACKGROUND: There has been increasing interest in en bloc resection of bladder tumour (ERBT) as an oncologically noninferior alternative to transurethral resection of bladder tumour (TURBT) with fewer complications and better histology specimens. However, there is a lack of robust randomised controlled trial (RCT) data for making recommendations. OBJECTIVE: We aimed to develop a consensus statement to standardise various aspects of ERBT for clinical practice and to guide future research. DESIGN, SETTING, AND PARTICIPANTS: We developed the consensus statement on ERBT using a modified Delphi method. First, two systematic reviews were performed to investigate the clinical effectiveness of ERBT versus TURBT (effectiveness review) and to identify areas of uncertainty in ERBT (uncertainties review). Next, 200 health care professionals (urologists, oncologists, and pathologists) with experience in ERBT were invited to complete a two-round Delphi survey. Finally, a 16-member consensus panel meeting was held to review, discuss, and re-vote on the statements as appropriate. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Meta-analyses were performed for RCT data in the effectiveness review. Consensus statements were developed from the uncertainties review. Consensus was defined as follows: (1) ≥70% scoring a statement 7-9 and ≤15% scoring the statement 1-3 (consensus agree), or (2) ≥70% scoring a statement 1-3 and ≤15% scoring the statement 7-9 (consensus disagree). RESULTS AND LIMITATIONS: A total of 10 RCTs were identified upon systematic review. ERBT had a shorter irrigation time (mean difference -7.24 h, 95% confidence interval [CI] -9.29 to -5.20, I2 = 85%, p < 0.001) and a lower rate of bladder perforation (risk ratio 0.30, 95% CI 0.11-0.83, I2 = 1%, p = 0.02) than TURBT, both with moderate certainty of evidence. There were no significant differences in recurrences at 0-12, 13-24, or 25-36 mo (all very low certainty of evidence). A total of 103 statements were developed, of which 99 reached a consensus. A summary of statements is as follows: ERBT should always be considered for treating non-muscle-invasive bladder cancer; ERBT should be considered feasible even for bladder tumours larger than 3 cm; number and location of bladder tumours are not major limitations in performing ERBT; the planned circumferential margin should be at least 5 mm from any visible bladder tumour; after ERBT, additional biopsy of the tumour edge or tumour base should not be performed routinely; for the ERBT specimen, T1 substage, and circumferential and deep resection margins must be assessed; it is safe to give a single dose of immediate intravesical chemotherapy, perform second-look transurethral resection, and give intravesical bacillus Calmette-Guérin (BCG) therapy after ERBT; and in studies of ERBT, both per-patient and -tumour analysis should be performed for different outcomes as appropriate. Important outcomes for future ERBT studies were also identified. A limitation is that as consensus statements are brief, concise and binary in nature, areas of uncertainty that are complex in nature may not be addressed adequately. CONCLUSIONS: We have provided the most comprehensive review of the evidence base to date using a meta-analysis where appropriate and applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and mobilised the international urology community to develop a consensus statement on ERBT using transparent and robust methods. The consensus statement will provide interim guidance for health care professionals who practice ERBT and inform researchers regarding ERBT-related studies in the future. PATIENT SUMMARY: En bloc resection of bladder tumour (ERBT) is a surgical technique aiming to resect a bladder tumour in one piece. We included an international panel of experts to agree on the best practice of ERBT, and this will provide guidance to clinicians and researchers in the future.

Urinary miRNA profile for the diagnosis of IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Urinary micro-RNA (miRNA) level is increasingly reported to as non-invasive markers of various kidney diseases. We aim to identify urinary miRNA targets for the diagnosis of IgAN. METHODS: In the development cohort, we performed complete miRNA profiling of urinary sediment in 22 patients with IgAN and 11 healthy controls (CTL). Potential miRNA targets were quantified by a separate validation cohort of 33 IgAN patients and 9 healthy controls. RESULTS: In the development cohort, we identified 39 miRNA targets that have significantly different expression between IgAN and CTL (14 up-regulated, and 25 down-regulated). Among the 8 miRNA targets chosen for validation study, urinary miR-204, miR-431 and miR-555 remained significantly reduced, and urinary miR-150 level was significantly increased in the IgAN as compared to CTL. The area-under-curve of the receiver operating characteristic (ROC) curve for urinary mi-204 level for the diagnosis of IgAN was 0.976, and the diagnostic performance of combining additional miRNA targets was not further improved. At the cut-off 1.70 unit, the sensitivity and specificity of urinary miR-204 was 100 and 55.5%, respectively, for diagnosing IgAN. CONCLUSIONS: Urinary miR-150, miR-204, miR-431 and miR-555 levels are significantly different between IgAN and healthy controls; urinary miR-204 level alone has the best diagnostic accuracy.

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.

Ultrasound-guided synovial Tru-cut biopsy: indications, technique, and outcome in 111 cases.

OBJECTIVE: To investigate the diagnostic performance of ultrasound-guided synovial biopsy. METHODS: Clinical notes, pathology and microbiology reports, ultrasound and other imaging studies of 100 patients who underwent 111 ultrasound-guided synovial biopsies were reviewed. Biopsies were compared with the final clinical diagnosis established after synovectomy (n = 43) or clinical/imaging follow-up (n = 57) (mean 30 months). RESULTS: Other than a single vasovagal episode, no complication of synovial biopsy was encountered. One hundred and seven (96 %) of the 111 biopsies yielded synovium histologically. Pathology ± microbiology findings for these 107 conclusive biopsies comprised synovial tumour (n = 30, 28 %), synovial infection (n = 18, 17 %), synovial inflammation (n = 45, 42 %), including gouty arthritis (n = 3), and no abnormality (n = 14, 13 %). The accuracy, sensitivity, and specificity of synovial biopsy was 99 %, 97 %, and 100 % for synovial tumour; 100 %, 100 %, and 100 % for native joint infection; and 78 %, 45 %, and 100 % for prosthetic joint infection. False-negative synovial biopsy did not seem to be related to antibiotic therapy. CONCLUSION: Ultrasound-guided Tru-cut synovial biopsy is a safe and reliable technique with a high diagnostic yield for diagnosing synovial tumour and also, most likely, for joint infection. Regarding joint infection, synovial biopsy of native joints seems to have a higher diagnostic yield than that for infected prosthetic joints. KEY POINTS: • Ultrasound-guided Tru-cut synovial biopsy has high accuracy (99 %) for diagnosing synovial tumour. • It has good accuracy, sensitivity, and high specificity for diagnosis of joint infection. • Synovial biopsy of native joints works better than biopsy of prosthetic joints. • A negative synovial biopsy culture from a native joint largely excludes septic arthritis. • Ultrasound-guided Tru-cut synovial biopsy is a safe and well-tolerated procedure.

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.

Histopathological correlations of islet amyloidosis with apolipoprotein E polymorphisms in type 2 diabetic Chinese patients.

OBJECTIVE: Islet amyloidosis and arteriosclerosis are histopathological hallmarks in type 2 diabetes. Apolipoprotein E (ApoE) is a common component of amyloidosis. ApoE [Latin Small Letter Open E]4 allele is associated with arteriosclerosis and cerebral amyloidosis in Alzheimer disease. We examined the correlations of ApoE polymorphisms with islet amyloidosis in type 2 diabetes. METHODS: Genomic DNA samples were obtained from 117 autopsy cases with type 2 diabetes and 209 nondiabetic cases. ApoE genotypes and amylin gene mutations were determined by polymerase chain reaction-ligase detection reaction analysis. Islet amyloidosis and arteriosclerosis were evaluated by staining of thioflavin T, amylin, ApoE, and amyloid P component. RESULTS: In the diabetic group, 33.3% in group [Latin Small Letter Open E]2 ([Latin Small Letter Open E]2[Latin Small Letter Open E]2, [Latin Small Letter Open E]2[Latin Small Letter Open E]3), 23.6% in group [Latin Small Letter Open E]3 ([Latin Small Letter Open E]3[Latin Small Letter Open E]3), and 62.5% in group [Latin Small Letter Open E]4 ([Latin Small Letter Open E]4[Latin Small Letter Open E]4, [Latin Small Letter Open E]3[Latin Small Letter Open E]4) had islet amyloidosis. After adjustment for confounders, group [Latin Small Letter Open E]4 had an odds ratio of 7.0 (95% confidence interval, 1.3-38.0; P = 0.023) in having islet amyloidosis compared to group [Latin Small Letter Open E]3. Diabetic cases with islet amyloidosis had more severe arteriosclerosis (P = 0.0111), arteriolar hyalinosis (P = 0.0369), and interstitial fibrosis (P = 0.0188) than those without amyloidosis. Immunoreactivity of both ApoE and amyloid P component was detected in islet amyloid deposits and arteriosclerotic lesions. CONCLUSIONS: In type 2 diabetes, islet amyloidosis and arteriosclerosis share common pathophysiological features with ApoE [Latin Small Letter Open E]4 as a probable linking factor.

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.

Micro-RNA expression in the urinary sediment of patients with chronic kidney diseases.

BACKGROUND: Evidence indicates that microRNAs (miRNA) play a role in the pathogenesis of chronic kidney diseases (CKD). We explored the possibility of using urinary miRNA as non-invasive biomarkers for CKD. METHODS: We quantified miRNA expression in urinary sediment of 56 CKD patients who underwent kidney biopsy. Patients were followed for 16.2 ± 15.5 months. RESULTS: Patients with diabetic glomerulosclerosis had lower urinary miR-15 expression, while those with IgA nephropathy had higher urinary miR-17 expression, than other diagnosis groups. Baseline proteinuria had significant inverse correlation with urinary expression of miR-15, miR-192, and miR-216a; baseline renal function correlated with urinary expression of miR-15, miR-17, miR-192, and miR-217. The rate of renal function decline correlated with urinary expression of miR-21 (r=0.301, p=0.026) and miR-216a (r=0.515, p < 0.0001). Patients with a high urinary expression of miR-21 and miR-216a had better dialysis-free survival than those with low expression (log rank test, p=0.005 and p=0.003, respectively). CONCLUSIONS: Urinary miR-21 and miR-216a expression correlated with the rate of renal function decline and risk of progression to dialysis-dependent renal failure. Our results suggest that urinary miRNA profiling has the potential of further development as biomarkers of CKD.