Chiang Gs

Overexpression of Interleukin-13 Induces Minimal-Change–Like Nephropathy in Rats

IL-13 has been implicated in the pathogenesis of minimal-change nephrotic syndrome. This study aimed to investigate the role of IL-13 on the development of proteinuria and expression of podocyte-related genes that are associated with nephrotic syndrome. IL-13 was overexpressed in Wistar rats through transfection of a mammalian expression vector cloned with the rat IL-13 gene, into the quadriceps by in vivo electroporation. Serum IL-13, albumin, cholesterol, and creatinine and urine albumin were measured serially. Kidneys were harvested after day 70 for histology and electron microscopy. Glomerular gene expression of nephrin, podocin, dystroglycan, B7-1, and IL-13 receptor subunits were examined using real-time PCR with hybridization probes and expressed as an index against beta-actin. Protein expression of these molecules was determined by immunofluorescence staining. The IL-13-transfected rats (n = 41) showed significant albuminuria, hypoalbuminemia, and hypercholesterolemia when compared with control rats (n = 17). No significant histologic changes were seen in glomeruli of IL-13-transfected rats. However, electron microscopy showed up to 80% of podocyte foot process fusion. Glomerular gene expression was significantly upregulated for B7-1, IL-4Ralpha, and IL-13Ralpha2 but downregulated for nephrin, podocin, and dystroglycan. Immunofluorescence staining intensity was reduced for nephrin, podocin, and dystroglycan but increased for B7-1 and IL-4Ralpha in IL-13-transfected rats compared with controls. In conclusion, these results suggest that IL-13 overexpression in the rat could lead to podocyte injury with downregulation of nephrin, podocin, and dystroglycan and a concurrent upregulation of B7-1 in the glomeruli, inducing a minimal change-like nephropathy that is characterized by increased proteinuria, hypoalbuminemia, hypercholesterolemia, and fusion of podocyte foot processes.

Randomized trial of Alemtuzumab for prevention of graft rejection and preservation of renal function after kidney transplantation.

Background. A randomized, multicenter, controlled trial was undertaken to evaluate the safety and efficacy of Alemtuzumab, a powerful lytic agent for both T and B lymphocytes, in the prophylaxis of rejection in renal transplantation (RTx). Methods. Thirty patients were randomized to receive Alemtuzumab together with low-dose cyclosporine (CsA) monotherapy (CAMPATH, n=20) or to full doses of CsA with azathioprine and corticosteroids (Standard, n=10). CsA was administered at doses to achieve whole-blood trough CsA levels of 90 to 110 ng/mL and 180 to 225 ng/mL in CAMPATH and Standard groups, respectively. Results. Per protocol, CsA trough levels were lower in patients assigned to CAMPATH post-RTx (median trough level of 119 vs. 166 ng/mL at 6 months, CAMPATH vs. Standard; 95% confidence interval, −92 to −34). At 6 months post-RTx, serum creatinine, graft and patient survivals, incidence of biopsy proven acute rejection (25% vs. 20%, CAMPATH vs. Standard), overall treatment failure, and severe and moderate infections were comparable. Whereas all patients receiving Standard therapy required maintenance corticosteroids at 6 months, of the 17 of 20 patients with functioning grafts in CAMPATH, 15 (88%, 95% confidence interval, 53%–97%) were steroid free. Conclusion. These results suggest that Alemtuzumab is an effective induction agent that permits low-dose steroid-free immunosuppression in RTx.

Correlation of Nuclear Morphometry with Pathologic Parameters in Ductal Carcinoma In Situ of the Breast

Morphometric features of nuclear perimeter, nuclear area, feret ratio, and feret circle were studied in a series of 64 cases of ductal carcinoma in situ (DCIS) of the breast in Singapore women. The results were compared with pathologic parameters of tumor size, nuclear grade, necrosis, cell polarization, and architectural pattern. There was statistically significant correlation between nuclear perimeter and area with all the pathologic parameters, with the strongest association observed for nuclear grade (P < .0001). Higher grade nuclei as assessed histologically were associated with larger nuclear area (44.14 μm2 in low-grade lesions, 47.77 μm2 in intermediate-grade lesions, and 72.05 μm2 in high-grade lesions) and perimeter (25.94 μm in low-grade nuclei, 27.12 μm in intermediate-grade nuclei, and 33.66 μm in high-grade nuclei). DCIS lesions with necrosis and absence of polarization also revealed increased nuclear area and perimeter (P < .05). Comedo architecture was associated with larger nuclear area and perimeter (65.97 μm2, 31.7 μm) than the papillary subtype (42.17 μm2, 25.29 μm), with the mixed morphologic pattern disclosing intermediate values (54.83 μm2, 29.43 μm). There was direct correlation for tumor size with nuclear area and perimeter (P < .01). No similar relationship was found between pathologic parameters and feret ratio or circle, indicating that nuclear roundness or lack of it did not factor as a significant component in the pathologic assessment.

Anti-vascular endothelial cell antibodies in patients with IgA nephropathy: frequency and clinical significance.

This study examined the frequency of anti-vascular endothelial cell (VEC) antibodies (Ab) in 72 patients with IgA nephropathy (IgAN), and their possible relationship to clinical and histological parameters of the disease. An enzyme immunoassay was developed to measure the binding of sera to endothelial cells grown to a confluent monolayer. Thirty-two percent of IgAN patients had serum anti-VEC activity as compared to 4% of controls (P = 0.004) and 9% of patients with other primary glomerulonephritis (P = 0.017). This was shown to be due to anti-HLA class I Abs in 6 of the 23 IgAN patients, and in the 1 control positive for anti-VEC activity. Hence 17 IgAN patients had anti-VEC Abs, predominantly of the IgA subclass. Stimulation of the endothelial cells with interferon-gamma and interleukin 1 did not increase the binding of these Abs. There was no correlation with circulating immune complex (IC) levels, and removal of ICs in positive sera by ultracentrifugation did not decrease anti-VEC binding. Significant correlations were found between anti-VEC Abs and proteinuria greater than 1 g/day (P = 0.044), as well as IgA anti-VEC Abs and C3 or IgA deposition in renal arterioles (P = 0.048). These IgA Abs may be an important marker of pathogenetic activity in IgAN.

Global evolutionary trend of the prevalence of primary glomerulonephritis over the past three decades.

Objective: The prevalence of primary glomerulonephritis in Singapore is compared with that of 28 other countries to review changing trends in the evolution of primary glomerulonephritis in Asia and other countries. Method: 2,586 renal biopsies in Singapore over the past 3 decades were reviewed and compared with data from 28 other countries. Results: In the 1st decade most Asian countries have mesangial proliferative glomerulonephritis as the most common form of primary glomerulonephritis, and in the 3rd decade there has been a dramatic increase in focal and segmental glomerulosclerosis reflecting aging and obesity in keeping with more developed countries. IgA nephritis remains the commonest glomerulonephritis in many countries. Membranous glomerulonephritis continues to be more prevalent in Western countries while mesangial proliferative glomerulonephritis remains prevalent in many Asian countries. Conclusion: Apart from geographical and genetic influences, socioeconomic factors may play a role in the evolution of the biopsy pattern in some countries. Worldwide, the prevalence of focal segmental glomerulosclerosis continues to increase. In third world countries some of the commoner forms of glomerulonephritis are related to infections, in contrast to developed countries where the antigenic exposure may be related to diet, allergens and other industrial agents.

Molecular characterization of hepatitis B virus surface antigen mutants in Singapore patients with hepatocellular carcinoma and hepatitis B virus carriers negative for HBsAg but positive for anti-HBs and anti-HBc

Background and Aims : Mutations on the a‐determinant of hepatitis B virus surface antigen (HBsAg), capable of escaping detection and vaccination, are identified in HBsAg‐positive/anti‐HBs‐positive vaccinated infants. We studied the prevalence of these mutants in HBsAg‐negative/anti‐HBc‐positive chronic HBV carriers and patients with hepatocellular carcinoma (HCC).

Pathologic-radiologic correlations in screen-detected ductal carcinoma in situ of the breast: findings of the Singapore breast screening project.

Mammography detected 34 (25%) cases of ductal carcinoma in situ (DCIS) of the breast out of a total of 135 cancers diagnosed in 28,231 participating women during the Singapore breast screening project. Radiologic findings in these 34 women with DCIS were calcifications only in 25 (74%); mass only in 2 (6%); and mass with calcifications in the remaining 7 (20%) cases. Calcifications were classified mammographically as powderish in 2 (6%), crushed stone‐like in 16 (50%) and casting in 14 (44%) cases. Pathologic assessment revealed 11 (32%) cases with pure comedo, 16 (47%) mixed, 3 (9%) cribriform, 2 (6%) papillary, 1 (3%) micropapillary and 1 (3%) solid patterns. Histologic nuclear grade was low in 6 (18%), intermediate in 9 (26%) and high in 19 (56%). Necrosis was observed in 26 (77%) cases and absent in the rest. Pathologic‐radiologic correlations yielded a significant association between the mammographic and pathologic lesional size, with the degree of agreement improved when there was histologic necrosis. A trend for radiologic crushed stone‐like and casting‐type calcifications to be associated with DCIS with necrosis and of higher nuclear grade was noted. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 231–236 (2000).

Protein Selectivity: A Prognostic Index in IgA Nephritis

Among 98 patients with IgA nephritis who had protein selectivity studies performed, 54% had nonselective proteinuria and the remaining 46% had selective proteinuria. Patients with nonselective proteinuria had a higher incidence of glomerulosclerosis. At the end of a 4-year follow-up period, patients with nonselective proteinuria had lower creatinine clearance, higher incidence of hypertension and chronic renal failure when compared to patients with selective proteinuria. Six out of eleven patients (55%) in the study who had the nephrotic syndrome had selective proteinuria. Among these 6 patients, 1 had spontaneous remission and 5 responded to steroid or cyclophosphamide therapy. The remaining 5 patients with nonselective proteinuria did not respond to therapy. In the patients who had selectivity studies repeated, the data showed that the selectivity index (SI) can fluctuate depending on the clinical course of the patients. SI can therefore be used to monitor the progress of patients on long-term follow-up. Protein selectivity appears to be a useful prognostic index in IgA nephritis. For patients with the nephrotic syndrome it may serve as a guide to therapy.

Factors associated with proteinuria in renal transplant recipients treated with sirolimus

Although sirolimus (SRL) use in renal allograft recipients (RTX) is associated with improved renal function, proteinuria develops in a significant proportion. 48 SRL‐treated RTX were evaluated for development of proteinuria and stratified by level of proteinuria after SRL therapy. The Proteinuria Group (n = 25, 52.1%) had new‐onset proteinuria or >25% increase in proteinuria following SRL conversion; the Nonproteinuria Group had stable proteinuria <0.5 g/day throughout. There was a higher proportion of male RTX and female donors to male recipients in the Proteinuria Group, (24% vs. 10%, P = 0.008). Calcineurin inhibitor‐ and statin usage were significantly higher in the Nonproteinuria Group (8% vs. 17%, P = 0.046; 28% vs. 83%, P < 0.001 respectively) whereas biopsy‐proven acute rejection was higher in the Proteinuria Group (68% vs. 33%, P = 0.037). SDS‐PAGE analysis of urine from 23 RTX in the Proteinuria Group demonstrated glomerular proteinuria in 100% and tubular proteinuria in 87%. While male gender and gender mismatch may impact on glomerular proteinuria through inadequate nephron dose and subsequent hyperfiltration, concurrent cyclosporine use may mitigate the development of proteinuria in SRL‐treated patients, through afferent arteriolar vasoconstriction. Glomerular injury occurring following acute rejection may further contribute to glomerular proteinuria. Statins, through their anti‐inflammatory and anti‐fibrotic effects, may protect against development of proteinuria.

Isoelectric focusing and selectivity index in IgA nephrotic syndrome.

Proteinuria in 13 patients with IgA nephritis with nephrotic syndrome (IgANS) was analysed by isoelectric focusing (IEF) and compared with 12 patients with minimal change nephrotic syndrome (MCNS) (n = 8) or focal global sclerosis nephrotic syndrome (FGS) (n = 4) to determine the pattern of proteinuria on IEF and to assess the value of IEF and protein selectivity index (SI) as predictors of response to therapy with predisolone or cyclophosphamide. Steroid/cyclophosphamide responsive patients with IgANS had SC:UA (cationic serum albumin with anionic urine albumin) or SA:UC (anionic serum albumin with cationic urine albumin) IEF patterns and steroid/cyclophosphamide unresponsive patients with IgANS had an SC:UC (cationic serum albumin with cationic urine albumin) IEF pattern. The majority of patients with MCNS or FGS who had an SA:UC IEF pattern were steroid responsive. SI was a better predictor of steroid/cyclophosphamide responsiveness in patients with IgANS (r = 0.78, p < 0.002 compared to IEF, r = 0.64, p < 0.02).