Tacrolimus for the treatment of systemic lupus erythematosus with pure class V nephritis.

OBJECTIVES: The treatment of pure membranous (class V) lupus nephropathy remains unsatisfactory. We studied the efficacy and safety of tacrolimus in the treatment of membranous nephritis secondary to SLE. METHODS: We recruited 18 consecutive SLE patients (tacrolimus group) with recently confirmed biopsy-proven class V lupus nephritis. They were treated with a tailing dose of oral prednisolone and tacrolimus 0.1-0.2 mg/kg/day for 6 months, followed by maintenance prednisolone and AZA. The rate of resolution of proteinuria and SLEDAI were compared with 19 historical controls treated with oral cyclophosphamide or AZA (control group). All patients were followed for 12 months. RESULTS: Baseline clinical characteristics were comparable between the groups. For the tacrolimus group, the complete and partial remission rates were 27.8 and 50.0%, respectively at 12 weeks; for the control group, they were 15.8 and 47.4%, respectively (overall chi-square test, P = 0.5). However, tacrolimus group had faster resolution of proteinuria than the control group by the general linear model with repeated measures (P = 0.032). At 12 weeks, proteinuria was reduced by 76.2 +/- 17.0% for the tacrolimus group and 47.1 +/- 51.1% for the control group (P = 0.028). Serial change in renal function and SLEDAI score did not differ between the groups. During the study period, four patients of the tacrolimus group, and 11 of the control group, developed lupus flare (P = 0.027). There was no serious adverse effect in the tacrolimus group. CONCLUSIONS: A 6-month course of tacrolimus is a safe and effective treatment of pure class V (membranous) lupus nephritis. As compared with conventional cytotoxic treatment, tacrolimus possibly results in a faster resolution of proteinuria, and a lower risk of lupus flare within 1 yr. The long-term effect and optimal regimen of tacrolimus require further study.

Urinary mRNA expression of ACE and ACE2 in human type 2 diabetic nephropathy.

AIMS/HYPOTHESIS: The interplay of ACE and type 2 ACE (ACE2) has been recognised as playing an important role in the tissue renin-angiotensin system within the kidney. In the present study, we measured urinary mRNA expression of ACE and ACE2 in patients with type 2 diabetic nephropathy. METHODS: We studied 50 patients with diabetic nephropathy: 26 were being treated by ACE inhibitor (ACEI) alone (ACEI group), the other 24 by ACEI and angiotensin-receptor blocker (ARB) (ACEI+ARB group). mRNA expression of ACE and ACE2 was measured by real-time quantitative RT-PCR at 0 and 12 weeks. All patients were then followed for 56 weeks. RESULTS: Proteinuria correlated significantly with urinary ACE (r=0.454, p=0.001) and ACE2 expression (r=0.651, p<0.001). Urinary ACE2 expression correlated with estimated GFR (r= -0.289, p=0.042). In the ACEI group, there was a significant inverse correlation between the rate of GFR decline and urinary ACE2 expression at baseline (r= -0.423, p=0.031) as well as at 12 weeks (r= -0.395, p=0.046). In contrast, there was no significant correlation between the rate of GFR decline and urinary ACE2 expression at baseline or at 12 weeks in the ACEI+ARB group. The rate of GFR decline did not correlate with the baseline urinary ACE expression of either group. CONCLUSION/INTERPRETATION: There was a relationship between urinary mRNA expression of ACE2 and the degree of proteinuria. The physiological implication and possibility of clinical application of quantifying urinary ACE2 expression require further study.

Pancreatic islet beta-cell deficit and glucose intolerance in rats with uninephrectomy.

This study was performed to examine the effect of chronic renal impairment and renin-angiotensin system (RAS) activation induced by unilateral nephrectomy (UNX) on the development of pancreatic islet beta-cell deficit and glucose intolerance. Sprague-Dawley rats were randomized into three groups: untreated UNX (n=10), UNX treated with the angiotensin-converting enzyme inhibitor lisinopril (n=8) and sham operation (n=10). Blood glucose, serum insulin, renal function and histological changes of kidney and pancreas were examined 8 months postoperation. Compared with the sham rats, UNX rats developed renal impairment, insulin deficiency and glucose intolerance. Histological staining revealed an islet beta-cell deficit associated with increased immunoreactivity for angiotensin and angiotensin type 1 receptor in UNX rats. Treatment with lisinopril significantly improved renal dysfunction, hyperglycemia, insulin secretion and islet RAS expression. These data suggest that chronic renal impairment and RAS activation may contribute to islet beta-cell loss and glucose intolerance. RAS blockade may therefore prevent these disorders.

Ventricular bigeminy during phenylephrine infusion used to maintain normotension during caesarean section under spinal anaesthesia.

A 31-year-old primiparous, healthy woman presented for emergency caesarean section. Following the siting of a spinal anaesthetic, seconds after starting a phenylephrine infusion, she developed ventricular bigeminy. She reverted to sinus rhythm spontaneously when the phenylephrine infusion was stopped at delivery. The possible proarrhythmic and antiarrhythmic effects of phenylephrine are discussed. We suggest that this was most probably a stretch-induced ventricular arrhythmia due to increased ventricular afterload.

Epithelioid hemangioendothelioma of the oral cavity.

OBJECTIVE: To investigate the clinicopathological characteristics and biologic behaviour of epithelioid hemangioendothelioma in the oral cavity. MATERIALS AND METHODS: The clinical features and pathological findings of nine cases with intraoral epithelioid hemangioendothelioma were reviewed, including immunohistochemistry study. RESULTS: This series comprised seven males and two females aged 6-53 years (mean 28 years). The sites of the tumour included the tongue (n = 4), lip (n = 1), the gingiva and alveoli of the maxilla (n = 1), the gingiva and alveoli of the mandible (n = 1), buccal mucosa (n = 1), and the floor of the mouth (n = 1). A painless solitary mass was the most common presentation and was found in eight cases. On pathology, the tumour grew in short strands, cords or nests of polygonal to slightly spindled epithelioid cells in fibro-myxoid stroma, with formation of intracytoplasmic lumina. Tumour cells were immunoreactive to CD34, FVIIIRAg, and vimentin. Focal-positive cytokeration were observed in three cases. Immunoreactivity for S-100 protein, epithelial membrane antigen (EMA) and human herpesvirus (HHV)-8 was negative in all cases. Two cases recurred after surgical excision, but no patient developed local or distant metastasis. CONCLUSIONS: Wide local excision with long-term follow-up seems to be the treatment of choice for intraoral epithelioid hemangioendothelioma because of their unpredictable biological behaviour and recurrence potential.

Expression of T-bet, a type 1 T-helper cell transcription factor, in the urinary sediment of lupus patients predicts disease flare.

BACKGROUND: Systemic lupus erythematosus (SLE) is characterized by the aberrant activation of T-lymphocytes. Since T-bet is the principal transcription factor for the differentiation of type-1 helper T-lymphocyte, we study the impact of urinary T-bet mRNA expression in clinically quiescent SLE patients on the risk of subsequent disease flare. METHODS: We studied 60 quiescent SLE patients. Urinary mRNA expression of T-bet was studied by the real-time quantitative polymerase chain reaction. Patients were followed for 4 yrs for disease flare. RESULTS: We studied 60 patients; 57 were female. The mean age was 38.8 +/- 11.2 yrs. Their baseline SLE disease activity index score was 1.63 +/- 1.64. During the follow-up, 28 patients (46.6%) developed lupus flare, of which 17 (28.3%) had severe flare. Receiver operating characteristic curves showed that urinary T-bet expression three times above the average level of healthy control had 64.3% sensitivity and 84.4% specificity of predicting all lupus flare. Using this cut-off, patients with a high urinary T-bet expression had a significantly higher risk of all lupus flare and severe flare than the patients with a low T-bet expression (log-rank test, P < 0.001 for both). With multivariate Cox proportional hazard model to adjust for potential confounding variables, urinary T-bet expression and patient's sex were the only independent predictors of all lupus flare and severe flare. It could be estimated that 1-fold increase in urinary T-bet expression would result in 8.4% excess risk of all lupus flare [95% confidence interval (CI), 4.1-13.0%, P < 0.001] and 12.9% excess risk of severe flare (95% CI 7.4-18.7%, P < 0.001). CONCLUSIONS: A high urinary T-bet expression was an independent predictor of lupus flare. Measurement of urinary T-bet may provide valuable information for the risk stratification of SLE patients.

Urinary mononuclear cell and disease activity of systemic lupus erythematosus.

Mononuclear cells play a cardinal role in the pathogenesis of systemic lupus erythematosus (SLE). A high urine cytology score has been reported to be associated with lupus nephritis in relapse. The objective of this study was to examine the urinary mononuclear cell population of patients with lupus nephritis, and explore its correlation with lupus disease activity. We studied 12 patients with active lupus nephritis, 17 patients with lupus nephritis in remission, 12 SLE patients with no history of renal disease and 13 healthy subjects. Clinical disease activity was quantified by the SLE Disease Activity Index (SLEDAI). Mononuclear cell species in the urinary sediment were examined by immunocytochemistry. Patients with active lupus nephritis had significantly more mononuclear cells in the urinary sediment. The number of CD3+ cell was significantly elevated in the active lupus nephritis than the others (P < 0.001), while there was no significant difference in the number of CD20+ and CD56+ cell among patient groups. The total urinary mononuclear cell correlated significantly with the overall SLEDAI score (r = 0.58, P < 0.001) as well as the renal score (r = 0.57, P < 0.001). The number of urinary CD3+, but not CD20+ or CD56+, cell significantly correlated with the overall SLEDAI score (r = 0.46, P = 0.003) as well as the renal score (r = 0.40, p = 0.011). In nine patients with renal biopsy, the histological activity index correlated with the total urinary mononuclear cell (r = 0.75, P = 0.02), CD3+ (r = 0.69, P = 0.04) and CD20+ cell (r = 0.69, P = 0.04). We conclude that urinary mononuclear cell was markedly elevated in patients with active lupus, and the urinary mononuclear cell count correlated significantly with the SLEDAI score and histological activity. CD3+ and CD20+ cells are the major component of urinary mononuclear cell in SLE patients and their number correlates with lupus disease activity.

Imbalance of Th1/Th2 transcription factors in patients with lupus nephritis.

OBJECTIVE: Systemic lupus erythematosus (SLE) is characterized by the aberrant activation of T lymphocytes. Since T-bet and GATA-3 are the principal transcription factors for the differentiation of type-1 and type-2 helper T lymphocytes, respectively, we studied their mRNA expression in the urinary sediment of SLE patients and compared this with their urinary and intra-renal protein expression. METHODS: We studied 100 SLE patients and 10 healthy subjects. Urinary mRNA expression of T-bet and GATA-3 were studied by the real-time quantitative polymerase chain reaction. Intra-renal and urinary expressions of T-bet and GATA-3 were studied by immunohistochemistry and western blotting, respectively. RESULTS: The urinary mRNA and protein expressions of T-bet were significantly higher in SLE patients with active nephritis than those with inactive disease (mRNA: P < 0.001; protein: P = 0.004). The urinary mRNA expression of T-bet correlated with the SLE disease activity index (SLEDAI) score (r = 0.55, P < 0.001) and the histological activity index (r = 0.48, P = 0.03). On the other hand, the urinary mRNA and protein expressions of GATA-3 were significantly lower in SLE patients with active nephritis (mRNA: P < 0.001; protein: P = 0.006), and GATA-3 mRNA expression inversely correlated with the SLEDAI score (r = 0.38, P < 0.001). For the 22 SLE patients with kidney biopsy, tubular expressions of T-bet and GATA-3 significantly correlated with the histological activity index (T-bet: r = 0.57, P = 0.006; GATA-3: r = -0.79, P < 0.001). CONCLUSIONS: Patients with active lupus nephritis have increased T-bet and depressed GATA-3 expression in the urinary sediment and kidney tissue, indicating a predominant Th1 type of T-lymphocyte activation.

Chromosomal telomere shortening of kidney cells in IgA nephropathy by the measurement of DNA in urinary sediment.

BACKGROUND: The histology and function of the kidney deteriorates with age and progressive renal failure, but the mechanisms involved in renal ageing are not known. In vitro studies suggest that telomere shortening is important in replicative senescence, and is accelerated by stress factors that increase replication. We investigated whether IgA nephropathy, a prototype chronic kidney disease, is associated with localized intrarenal cellular ageing. METHODS: We studied the mean length of terminal restriction fragments (TRF), a measure of average telomere size, in the DNA of peripheral blood mononuclear cells and urinary sediment of 15 patients with IgA nephropathy. RESULTS: The mean TRF lengths in peripheral blood is 7043.8 +/- 1 182.8 base pairs, and in urinary sediment is 6 749.7 +/- 636.5 base pairs. The mean TRF lengths of urinary DNA significantly correlate with the serum creatinine (r = -0.525, p = 0.044) and estimated glomerular filtration rate (GFR) (r = 0.651, p = 0.009). The mean TRF lengths of urinary DNA had an insignificant inverse correlation with patient age (r = -0.364, p = 0.2), and do not correlate with the degree of glomerulosclerosis (r = 0.004, p = 0.9) or tubulointerstitial scarring in renal biopsy (r =-0.032, p = 0.9). After 30 months of follow-up, the rate of decline of estimated GFR has an inverse correlation with the mean TRF lengths of urinary DNA (r = -0.699, p = 0.004). The TRF lengths of peripheral blood DNA do not correlate with any clinical or histological parameter or the rate of renal function decline. CONCLUSIONS: Although this is a pilot study, our observation indicates that the TRF lengths of genomic DNA extracted from urinary sediment is related to the degree of renal impairment. However, a long telomere length of genomic DNA in urinary sediment is associated with a more rapid decline of renal function. Our findings might be relevant to the pathogenesis of progressive renal failure.

Assessment of maternal anxiety levels before and after amniocentesis.

INTRODUCTION: To assess anxiety levels in mothers before and after undergoing amniocentesis. The secondary aim was to see how counselling by nurse-counsellors affected maternal anxiety levels. METHODS: A prospective study was carried out from February 2000 to August 2000 at the Kandang Kerbau Women's and Children's Hospital in Singapore. We used standard statistical analysis and Spielberger's state-trait anxiety inventory (STAI), that consisted of 40 items, to assess anxiety levels. Anxiety levels were assessed at different stages: before and after counselling; before amniocentesis and after amniocentesis; when results were disclosed; and after the routine 20-week screening ultrasound scan was acknowledged four to six weeks later. English-speaking women were recruited for the study as the STAI questionnaire has only been validated for an English-speaking population. 195 at-risk mothers (advanced maternal age, abnormal nuchal translucency on ultrasound scan, previous abnormal baby and high-risk maternal serum screening results) and patients requesting for amniocentesis between 15 to 20 weeks gestation were recruited. RESULTS: 156 mothers agreed to amniocentesis. 38 mothers declined amniocentesis. S-anxiety levels declined significantly after counselling by trained nurse-counsellors in all mothers counselled. S-anxiety levels were highest and significantly higher compared to all other times just prior to amniocentesis despite counselling. Anxiety levels were the lowest and significantly lower compared to all other times at the last assessment stage. CONCLUSION: High level of anxiety prior to amniocentesis despite counselling is understandable due to the invasive nature of the procedure. There is no long-lasting post-procedural anxiety to the mother.

Does maternal serum screening for Down syndrome induce anxiety in younger mothers?

INTRODUCTION: To assess anxiety levels in mothers with low-risk pregnancies before and after offering routine serum screening. METHODS: A prospective study was carried out at the Kandang Kerbau Women's and Children's Hospital in Singapore from February 2000 to August 2000. We used standard statistical analysis and Spielberger's state-trait anxiety inventory (STAI) which consists of 40 items to assess anxiety. Anxiety levels were assessed at several stages: before serum screening counselling, after counselling but before serum screening, before the routine 20-week obstetrical screening ultrasound scan, and after ultrasound scan results were acknowledged four to six weeks later. As the STAI questionnaire has only been validated for an English-speaking population, only English-speaking women were recruited for the study. The subjects included 111 women between 15 to 20 weeks gestation that were randomly selected (without any risk factors) for serum screening counselling. RESULTS: Anxiety levels did not decline significantly after counselling by a trained nurse-counsellor. They were highest prior to counselling and were significantly higher compared to all other times in which anxiety was assessed. Anxiety levels were lowest after the serum screening and routine 20-week screening ultrasound scan results were acknowledged. They were also significantly lower compared to all other times in which anxiety was assessed. CONCLUSION: Anxiety before serum screening was not abnormally high and routine serum screening offered by trained nurse counsellors did not significantly increase maternal anxiety in mothers with low risk pregnancies.

Cytochemical and ultrastructural changes in the osteoclast-like giant cells of giant cell tumor of bone following bisphosphonate administration.

Giant cell tumor of bone (GCT) is a local aggressive neoplasm of bone characterized by expansive osteolytic lesions at the epiphysis of long bones. Bisphosphonates have been used to prevent bone resorption in secondary osteolytic tumors because of their strong anti-osteoclastic action. The authors studied the apoptosis and ultrastructural changes induced in osteoclast-like giant cells of GCT, following treatment with the aminobisphosphonate pamidronate in 16 patients with GCT of bone. Transmission electron microscopy (TEM) was used to identify ultrastructural changes, indicative of apoptosis, in the cytoplasm and the nucleus of the giant cells. Significant changes were observed in tumor samples from all 16 patients. In the cytoplasm these changes were characterized by abundant large tubular vesicles containing a central electrodense core scattered through the cytoplasm. In addition, mitochondria in the sections from pamidronate-treated patients appeared to be edematous when compared with sections from untreated patients. Nuclear changes in the giants cells were characterized by the formation of dense chromatin material scattered throughout the nucleus. The TUNEL labeling assay indicated that the mean pretreatment apoptotic index of 7.8% increased to 53% following pamidronate treatment. This was statistically significant (p<.001) and correlated well with the ultrastructural changes noted on TEM. The formation of abundant tubular vesicles in giant cells following bisphosphonate treatment may reflect disturbed vesicular trafficking and may affect the bone resorbing activity of giant cells.

Mesangial lupus nephritis in Chinese is associated with a high rate of transformation to higher grade nephritis.

Mesangial lupus nephritis was thought to be a mild form of lupus nephritis. However, case reports suggest that this type of nephritis could be associated with a high rate of transformation to more serious classes. We retrospectively reviewed the clinical features, clinical response at one year following treatment, as well as the long-term outcome of patients with mesangial lupus nephritis identified on their first renal biopsy. The possible clinical parameters that may predict poor outcome were examined. Nineteen patients with a median duration of follow-up of 9.6 (2.5-11.4) years were identified. At one year after biopsy, eight patients achieved complete remission, two patients achieved partial remission and nine patients had no response. Of the 10 responders, four relapsed after a median duration of 53 (42-97) months. Nine out of 10 patients (six nonresponders and four responders who relapsed) who underwent a second biopsy showed transformation to a higher grade nephritis. The long-term outcome remained favourable in nine patients. Responders and patients who were given angiotensin-converting enzyme inhibitors were associated with favourable long-term outcome. Our data highlight that renal biopsy should be repeated early in Chinese patients with mesangial nephritis who failed to respond to treatment in order to identify those who may require intense immunosuppressive therapy.

Tacrolimus in resistant primary membranous nephropathy--a report of 3 cases.

AIM: To study the efficacy and safety of tacrolimus in primary membranous nephropathy. METHOD: We describe 3 patients with primary membranous nephropathy who were either resistant to or could not tolerate steroid with or without cytotoxic agents. They were treated with tacrolimus 0.2 mg/kg/day for 6 months. The dosage of tacrolimus was adjusted to keep a whole blood tacrolimus level of 5-10 ng/ml. RESULTS: One patient had almost complete disappearance of proteinuria while the other 2 had at least 50% reduction in proteinuria. Proteinuria increased again in 2 of the patients after tacrolimus was stopped, but in neither of them proteinuria returned to the pretreatment level 6 months after tacrolimus was stopped. CONCLUSION: We conclude that tacrolimus may have a modest efficacy in the treatment of resistant membranous nephropathy.

Birth prevalence of Down syndrome in Singapore from 1993 to 1998.

OBJECTIVE: To examine the livebirth prevalence rate of Down Syndrome in Singapore from 1993 to 1998. DESIGN: Index cases for the National Birth Defects Register were obtained from all neonatal nurseries in Singapore, all hospital discharge summaries, cytogenetic and pathology reports from all pathology laboratories in Singapore and from the compulsory reporting of all termination of pregnancy cases and stillbirths delivered. SETTING: Information for the Register was obtained from case notes retrieved from the medical record offices, antenatal clinics, cytogenetic laboratories, pathology departments and the Registry of Births and Deaths. SUBJECTS: All foetuses with Trisomy 21 diagnosed prenatally together with livebirths and stillbirths with Down Syndrome diagnosed at or after birth were identified from the Registry database. MAIN OUTCOME MEASURES: Prevalence of Down Syndrome RESULTS: From 1993 to 1998, there were 295 Down Syndrome livebirths, four stillbirths and 197 Down Syndrome foetuses aborted. There has been an increasing number of Down Syndrome foetuses diagnosed antenatally ending in termination and this is accompanied by a falling trend in the Down Syndrome livebirth rate in the same years from 1.17 to 0.89 per 1000 total live births. This is despite an expected increase in Down Syndrome livebirth rate obtained by modelling maternal Down Syndrome age-related risks on the maternal age distribution over the years. CONCLUSIONS: The livebirth prevalence of Down Syndrome in Singapore has fallen over the years from 1.17/1000 livebirths in 1993 to 0.89/1000 livebirths in 1998 due to antenatal diagnosis and selective termination.

Recurrent IgA nephropathy in renal transplant allografts.

Previous reports of renal transplantation for patients with underlying immunoglobulin A (IgA) nephropathy suggested a recurrence rate greater than 50% for transplant IgA nephropathy. Initially regarded as a benign condition, more recent data showed that recurrent transplant IgA nephropathy may be a significant contributor to graft loss. We performed a retrospective analysis in a single center of 48 kidney transplant recipients, all of Chinese origin, with biopsy-proven IgA nephropathy as the cause of end-stage renal failure to determine the recurrence rate of IgA nephropathy in the transplant allograft and subsequent clinical course in Chinese patients. Median duration of follow-up was 52 months (range, 18 to 155 months). Fourteen patients (29%) had biopsy-confirmed recurrent transplant IgA nephropathy after a median of 52 months (interquartile range, 23 to 82 months) posttransplantation. Recurrent transplant IgA nephropathy was associated with greater serum IgA levels (P = 0.01). The presence of HLA-A2 in transplant recipients (P = 0.002) appeared to protect them from developing recurrent IgA nephropathy in the transplant allograft. Twenty-nine percent of patients with recurrent transplant IgA nephropathy had progressive deterioration of graft function. The progressive graft dysfunction (GD) rate was greater in patients with a transplant from a living related donor (LRD; 21%) compared with those with a transplant from a cadaveric or living unrelated donor (URD; 3%; P = 0.062). Although the cumulative graft survival rate was 100% at 5 years for transplants from both LRDs and URDs, the 10-year graft survival rate was only 63% for a graft from an LRD versus 93% for a URD (log-rank test, P = 0.19). A review of other reported series of recurrent transplant IgA nephropathy also showed an apparently greater incidence of GD for a graft from an LRD (28%) compared with a URD (15%). Our data suggest that although recurrent transplant IgA nephropathy is highly prevalent among the Chinese population, the risk for disease recurrence is not particularly increased compared with other ethnic groups. The trend toward a greater risk for GD for living related compared with unrelated allografts in patients with IgA nephropathy needs to be confirmed with further prospective study.

In vitro studies of aquaporins 1 and 3 expression in cultured human proximal tubular cells: upregulation by transferrin but not albumin.

Dysregulated renal water handling is a cardinal feature of nephrotic syndrome that has been shown in animal models of experimental nephrosis to mediate renal aquaporin (AQP) expression. However, data on the effect of proteinuria on the proximal tubule, which is heavily vested with AQP1 and therefore may participate in water homeostasis, are limited. To investigate this, we exposed primary human proximal tubular epithelial cells (PTECs) to two key proteinuric components shown to perturb tubule function: human serum albumin and transferrin. Using reverse-transcriptase polymerase chain reaction and immunocytochemical techniques, PTECs in the quiescent state were found to express AQP3 in addition to AQP1 gene and protein, which was also validated in a human proximal tubule cell line, HK-2. Immunohistochemical staining localized AQP1 synthesis to the apical and basolateral membranes and AQP3 synthesis to the basolateral membrane of proximal tubule epithelium. Transferrin in doses reaching nephrotic range upregulated PTEC transcription and translation of both AQP1 and AQP3 in a time- and dose-dependent manner. After 24 hours of stimulation, transferrin led to a 2.4- and 2.2-fold increase in AQP1 and APQ3 messenger RNA expression, whereas protein synthesis surged by 40.7% +/- 2.48% and 24.2% +/- 0.9% compared with control, respectively. These effects were not observed with albumin challenge and were not caused by osmolality fluctuation with transferrin treatment. In summary, our novel finding of AQP3 in PTECs indicates a role for AQP3 in proximal tubule water reabsorption. The pathophysiological significance of heightened AQP1 and AQP3 expression in PTECs on protein challenge as occurs in the nephrotic state requires further investigation.

The natural history of immunoglobulin a nephropathy among patients with hematuria and minimal proteinuria.

PURPOSE: To determine the natural history of immunoglobulin (Ig) A nephropathy among patients who presented with hematuria and minimal proteinuria, and factors associated with the development of adverse clinical events, such as proteinuria. SUBJECTS AND METHODS: In Hong Kong, all patients who present with isolated hematuria are referred for renal biopsy after urologic diseases are ruled out. We reviewed the clinical course of 72 consecutive patients with histologically confirmed IgA nephropathy who presented with hematuria and minimal proteinuria (0.4 g/day or less). All patients were normotensive and had normal renal function at presentation. Adverse events were defined as proteinuria greater than 1 g per day, hypertension, or impaired renal function (serum creatinine level 120 micromol/L or estimated creatinine clearance < 70 mL per minute). RESULTS: The mean (+/- SD) age at presentation was 27 +/- 8 years; 56 (78%) were female. Nine patients (13%) had grade 2 histologic lesions. During a median follow-up of 7 years, 32 patients (44%) developed adverse events: 24 (33%) developed proteinuria of 1 g per day or more, 19 (26%) became hypertensive, and 5 (7%) developed impaired renal function. Another 30 patients (42%) had persistently abnormal urinalysis examinations. Only 10 patients (14%) had complete resolution of hematuria. The median time for progression from proteinuria (> l g/day) to renal impairment was 84 months (range 56 to 132). In a multivariate analysis, age at presentation (relative risk [RR] per 10 years of age = 2.0; 95% confidence interval [CI], 1.2 to 3.4) and histologic grade (grade 2 versus grade 1, RR = 4.5; 95% CI, 1.7 to 12) were independent predictors of developing an adverse event. CONCLUSIONS: IgA nephropathy that presents with hematuria and minimal proteinuria is usually a progressive disease. Life-long follow-up with regular monitoring of blood pressure and proteinuria is recommended.

Severe bone marrow failure associated with the use of alternating steroid with chlorambucil in lupus membranous nephropathy in Chinese.

Severe pancytopenia associated with the use of alternating steroid with chlorambucil regimen was described in six patients with nephrotic syndrome secondary to lupus membranous nephropathy (WHO class V). We believe this is the first report describing the life-threatening degree of marrow toxicity associated with this regimen of alternating steroid with chlorambucil in a Chinese population. Our data suggests that the susceptibility to marrow toxicity with the use of chlorambucil may only be applicable to Chinese patients with underlying systemic lupus erythematosus as a similar degree of toxicity has neither been reported in lupus patients of other ethnic groups nor in non-lupus patients of Chinese origin.

Plasminogen activator inhibitor-1 gene polymorphism 4G/4G genotype and lupus nephritis in Chinese patients.

BACKGROUND: Abnormal regulation in the coagulation and fibrinolytic system may play an important role in mediating glomerular damage in lupus nephritis. Indeed, glomerular thrombosis occurs frequently in lupus nephritis and predicts the future development of glomerular sclerosis. In the murine model of active lupus nephritis, plasminogen activator inhibitor-1 (PAI-1) gene was overexpressed throughout the kidney, both within the glomeruli and also in tubules and vessels. The level of PAI-1 expression in the tissues appeared to correlate with the progression of lupus nephritis. Recently, a single base pair insertion/deletion 4G/5G polymorphism of the PAI-1 gene has been identified and shown to alter plasma PAI-1 activity. This study was therefore conducted to determine the association of the 4G/5G polymorphism of the PAI-1 gene with the development and severity of lupus nephritis. METHODS: The PAI-1 gene polymorphism of 118 systemic lupus erythematosus (SLE) patients and 103 healthy controls who were gender and age matched was determined using standard polymerase chain reaction. PAI-1 genotype results were studied in relationship to the development and severity of lupus nephritis. RESULTS: Allele frequencies of 4G/5G allele were 0.59/0.41 in lupus patients and 0.59/0.41 in controls (P = 1.000). No significant difference was noted in the genotype distribution between SLE patients with and without nephritis. However, lupus nephritis patients with the 4G4G genotype showed significantly heavier proteinuria (5.0 vs. 3.7 g/day; P = 0.023) when compared with patients with 4G5G and 5G5G genotypes. Also, 73.3% patients with 4G4G had an activity index > or =8 versus 37.3% patients with 4G5G and 5G5G (P = 0.003). Extensive necrotizing lesions were seen in 51.7% patients with 4G4G as compared with 23.5% patients with 4G5G and 5G5G (P = 0.014). The association of the 4G4G gene polymorphism with a higher nephritis activity and more severe necrotizing lesions persisted when only class III and class IV nephritis patients were studied. On the other hand, no significant association was noted between the PAI-1 gene polymorphism and the chronicity of the nephritis. CONCLUSION: These findings suggest that the 4G/5G polymorphism of the PAI-1 gene is associated with the activity but not the chronicity of lupus nephritis. The presence of the 4G4G genotype does not increase the risk of developing SLE or lupus nephritis, but predicts the development of higher nephritis activity and more extensive necrotizing lesions.