TEAD1 and c-Cbl are novel prostate basal cell markers that correlate with poor clinical outcome in prostate cancer.

Prostate cancer is the most frequently diagnosed male cancer, and its clinical outcome is difficult to predict. The disease may involve the inappropriate expression of genes that normally control the proliferation of epithelial cells in the basal layer and their differentiation into luminal cells. Our aim was to identify novel basal cell markers and assess their prognostic and functional significance in prostate cancer. RNA from basal and luminal cells isolated from benign tissue by immunoguided laser-capture microdissection was subjected to expression profiling. We identified 112 and 267 genes defining basal and luminal populations, respectively. The transcription factor TEAD1 and the ubiquitin ligase c-Cbl were identified as novel basal cell markers. Knockdown of either marker using siRNA in prostate cell lines led to decreased cell growth in PC3 and disrupted acinar formation in a 3D culture system of RWPE1. Analyses of prostate cancer tissue microarray staining established that increased protein levels of either marker were associated with decreased patient survival independent of other clinicopathological metrics. These data are consistent with basal features impacting on the development and clinical course of prostate cancers.

Effects of nonsteroidal anti-inflammatory drugs on postoperative renal function in adults with normal renal function.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) can play a major role in the management of acute pain in the peri-operative period. However, there are conflicting views on whether NSAIDs are associated with adverse renal effects. OBJECTIVES: The primary objective of this review was to determine the effects of NSAIDs on postoperative renal function in adults with normal preoperative renal function. SEARCH STRATEGY: Electronic searches for relevant randomised and quasi-randomised controlled trials in Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE were performed. Attempts were also made to identify trials from citation lists of relevant trials, review articles and clinical practice guidelines. Handsearching of conference abstracts published in major anaesthetic journals was also performed. Date of most recent search: May 2006 SELECTION CRITERIA: The inclusion criteria were randomised or quasi-randomised comparisons of individual NSAIDs with either each other or placebo for treatment of postoperative pain, with relevant postoperative renal outcome measures, in adult surgical patients with normal renal function. DATA COLLECTION AND ANALYSIS: The data were extracted independently by two authors. The primary outcome measure was creatinine clearance within the first two days after surgery. Secondary outcome measures included serum creatinine, urine volume, urinary sodium level, urinary potassium level, fractional excretion of sodium, fractional excretion of potassium and need for dialysis. Weighted mean differences for continuous outcomes and relative risk (RR) and risk difference (RD) for dichotomous outcomes were estimated with 95% confidence intervals (CI). MAIN RESULTS: Twenty-three trials (1459 patients) fulfilled the selection criteria for this review. NSAIDs reduced creatinine clearance by 16 mL/min (95%CI 5 to 28) and potassium output by 38 mmol/day (95%CI 19 to 56) on the first day after surgery compared to placebo. There was no significant difference in serum creatinine on the first day (0 umol/L, 95%CI -3 to 4) compared to placebo. No significant reduction in urine volume during the early postoperative period was found. There was no significant difference in serum creatinine in the early postoperative period between patients receiving diclofenac, ketorolac, indomethacin, ketoprofen or etodolac. No cases of postoperative renal failure requiring dialysis were described. The trials were not heterogeneous for the primary outcome. AUTHORS' CONCLUSIONS: NSAIDs caused a clinically unimportant transient reduction in renal function in the early postoperative period in patients with normal preoperative renal function. NSAIDs should not be withheld from adults with normal preoperative renal function because of concerns about postoperative renal impairment.

Growth hormone for children with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is an uncommon but important condition. Growth retardation, one of the complications of CKD, is of concern to families. Recombinant human growth hormone (rhGH) treatment has been used to help short children with CKD attain a height more in keeping with their age group. However, there are concerns that rhGH may have an adverse effect on the preservation of native kidney function, predispose to acute rejection in kidney transplant recipients, and cause benign intracranial hypertension and slipped capital femoral epiphysis. OBJECTIVES: To evaluate the benefits and harms of rhGH treatment in children with CKD. SEARCH STRATEGY: Randomised controlled trials (RCTs) were identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, article reference lists and through contact with local and international experts in the field. Date of most recent search: July 2005 SELECTION CRITERIA: RCTs were included if they were carried out in children aged 0-18 years, diagnosed with CKD, who were pre-dialysis, on dialysis or post-transplant; if they compared rhGH treatment with placebo/no treatment or two doses of rhGH treatments; and if they included height outcomes. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed studies for methodological quality and extracted data from eligible trials. Data was pooled using a random effects model with calculation of weighted mean difference (MD) for continuous outcomes and relative risk (RR) for categorical outcomes with 95% confidence intervals (CI). MAIN RESULTS: Fifteen RCTs (629 children) were identified. Treatment with rhGH (28 IU/m(2)/wk) resulted in a significant increase in height standard deviation score (SDS) at one year (MD 0.78 SDS, 95% CI 0.52 to 1.04), and a significant increase in height velocity at six months (MD 2.85 cm/6 mo, 95%CI 2.22 to 3.48) and one year (MD 3.80 cm/y, 95%CI 3.20 to 4.39). Compared to the 14 IU/m(2)/wk group, there was a 1.34 cm/y (0.55 to 2.13) increase in height velocity in the 28 IU/m(2)/wk group. The frequency of reported side effects of rhGH were similar to that of the control group. AUTHORS' CONCLUSIONS: One year of 28 IU/m(2)/wk rhGH in children with CKD resulted in a 3.80 cm/y increase in height velocity above that of untreated patients. Trials were too short to determine if continuing treatment resulted in an increase in final adult height.

Corticosteroid therapy for nephrotic syndrome in children.

BACKGROUND: In nephrotic syndrome protein leaks from the blood to the urine through the glomeruli resulting in hypoproteinaemia and generalised oedema. While the majority of children with nephrotic syndrome respond to corticosteroids, 70% experience a relapsing course. Corticosteroid usage has reduced the mortality rate to around 3%, however they have known serious adverse effects. OBJECTIVES: To determine the benefits and harms of corticosteroid regimens in preventing relapse in children with steroid sensitive nephrotic syndrome (SSNS). SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Renal Group Specialised Register, MEDLINE and EMBASE without language restriction, reference lists of articles, abstracts from conference proceedings and contact with known investigators. Date of most recent search: October 2004 SELECTION CRITERIA: Randomised controlled trials performed in children (three months to 18 years) in their initial or subsequent episode of SSNS, comparing different durations, total doses or other dose strategies using any corticosteroid agent, with outcome data at six months or more. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Statistical analyses were performed using a random effects model and results expressed as relative risk (RR) with 95% confidence intervals (CI).Meta-regression was used to explore potential between-study differences due to baseline risk of relapse, study quality and interventions. MAIN RESULTS: Nineteen trials were identified. Six trials comparing two months of prednisone with three months or more in the first episode showed longer duration significantly reduced the risk of relapse at 12 to 24 months (RR 0.70; 95% CI 0.58 to 0.84). There was an inverse linear relationship between treatment duration and risk of relapse (RR = 1.26 - 0.112 duration; P = 0.03). There was a significant reduction in the number of frequent relapsers and the mean relapse rate/patient/year. Deflazacort was significantly more effective in maintaining remission than prednisone in children who frequently relapsed (RR 0.44; 95% CI 0.25 to 0.78). There were no increases in adverse events. AUTHORS' CONCLUSIONS: Children in their first episode of SSNS should be treated for at least three months with an increase in benefit being demonstrated for up to seven months of treatment For a baseline risk for relapse following the first episode of 60% with two months of prednisone, daily prednisone for four weeks followed by alternate-day therapy for six months would reduce the number of children relapsing by 33%. Deflazacort deserves further study for frequent relapsers.

Corticosteroid therapy for nephrotic syndrome in children.

BACKGROUND: In nephrotic syndrome protein leaks from the blood to the urine through the glomeruli resulting in hypoproteinaemia and generalised oedema. Children with untreated nephrotic syndrome frequently die from infections. The majority of children with nephrotic syndrome respond to corticosteroids. However about 70% of children experience a relapsing course with recurrent episodes of oedema and proteinuria. Corticosteroid usage has reduced the mortality rate in childhood nephrotic syndrome to around 3%, with infection remaining the most important cause of death. However corticosteroids have known adverse effects such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis and adrenal suppression. The original treatment schedules for childhood nephrotic syndrome were developed in an ad hoc manner. The optimal doses and durations of corticosteroid therapy that are most beneficial and least harmful have not been clarified. OBJECTIVES: The aim of this review was to determine the benefits and harms of different corticosteroid regimens in preventing relapse in children with steroid sensitive nephrotic syndrome (SSNS). SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (Cochrane Library, Issue 2, 2002), Cochrane Renal Group Specialised Register (July 2002), MEDLINE (1966 - July 2002) and EMBASE (1980 - July 2002) without language restriction, reference lists of articles, abstracts from conference proceedings and contact with known investigators in the area. SELECTION CRITERIA: Randomised controlled trials were included if they were carried out in children (aged three months to 18 years) in their initial or subsequent episode of SSNS, if they compared different durations, total doses or other dose strategies using prednisone or other corticosteroid agent and if they had outcome data at six months or more. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed all eligible studies for inclusion, assessed study quality and extracted data. The principle outcome measure was the number of children with and without relapse after six and 12-24 months. Secondary outcomes sought included the number of children who developed frequently relapsing nephrotic syndrome and adverse events. A random effects model was used to estimate summary effect measures (relative risk (RR), risk difference (RD)) after testing for heterogeneity. Meta-regression was used to explore potential between-study differences due to the baseline risk of relapse, study quality and types of interventions used. MAIN RESULTS: Nineteen trials have been included in this review. A meta-analysis of six trials, which compared two months of prednisone with three months or more in the first episode, showed that the longer duration significantly reduced the risk of relapse at 12 - 24 months (RR 0.70; 95% CI 0.58 to 0.84) without an increase in adverse events. There was an inverse linear relationship between the duration of treatment and risk of relapse (RR = 1.26 - 0.112 duration; r(2) = 0.56; p = 0.03). The number of children who became frequent relapsers and the mean relapse rate/patient/year were also significantly reduced without increase in serious adverse events. In children with frequently relapsing nephrotic syndrome, deflazacort was significantly more effective in maintaining remission than prednisone (RR 0.44; 95% CI 0.25 to 0.78). REVIEWERS' CONCLUSIONS: Children in their first episode of SSNS should be treated for at least three months with an increase in benefit being demonstrated for up to seven months of treatment. In a population with a baseline risk for relapse following the first episode of 60% with two months of prednisone, daily prednisone for four weeks followed by alternate day therapy for six months would be expected to reduce the number of children experiencing a relapse by about 33%. In children who relapse frequently, deflazacort deserves further study.

Effects of nonsteroidal anti-inflammatory drugs on postoperative renal function in adults with normal renal function.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) can play a major role in the management of acute pain in the peri-operative period. However, there are conflicting views on whether NSAIDs are associated with adverse renal effects. OBJECTIVES: The primary objective of this review was to determine the effects of NSAIDs on postoperative renal function in adults with normal preoperative renal function. SEARCH STRATEGY: Electronic searches for relevant randomised and quasi-randomised controlled trials in Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE were performed. Attempts were also made to identify trials from citation lists of relevant trials, review articles and clinical practice guidelines. Handsearching of conference abstracts published in major anaesthetic journals was also performed. (Search date: 7 February 2003) SELECTION CRITERIA: The inclusion criteria were randomised or quasi-randomised comparisons of individual NSAIDs with either each other or placebo for treatment of postoperative pain, with relevant postoperative renal outcome measures, in adult surgical patients with normal renal function. DATA COLLECTION AND ANALYSIS: The data was extracted independently by two reviewers. The primary outcome measure was creatinine clearance within the first two days after surgery. Secondary outcome measures included serum creatinine, urine volume, urinary sodium level, urinary potassium level, fractional excretion of sodium, fractional excretion of potassium, need for dialysis and need for diuretic or dopamine treatment for renal insufficiency. Weighted mean differences for continuous outcomes and relative risk for dichotomous outcomes were estimated. MAIN RESULTS: Nineteen trials ( n = 1204) fulfilled the selection criteria for this review. NSAIDs reduced creatinine clearance by 16 ml/min (95%CI 5 to 28) and potassium output by 38 mmol/day (95%CI 19 to 56) on the first day after surgery compared to placebo. There was no significant difference in serum creatinine on the first day (0 umol/L, 95%CI -5 to 4) compared to placebo. No significant reduction in urine volume during the early postoperative period was found. There was no significant difference in serum creatinine in the early postoperative period between patients receiving diclofenace and ketorolac (or indomethacin). No cases of postoperative renal failure requiring dialysis were described. The trials were homogeneous for the primary outcome. REVIEWERS' CONCLUSIONS: NSAIDs caused a clinically unimportant transient reduction in renal function in the early postoperative period in patients with normal preoperative renal function. NSAIDs should not be withheld from adults with normal preoperative renal function because of concerns about postoperative renal impairment.

Renal impairment and anaemia in a population-based study of older people.

BACKGROUND: Established renal failure is a known cause of anaemia. However, the association between more modest levels of renal impairment and anaemia is unclear. AIMS: The aim of the present study was to investigate the association between mild renal impairment and anaemia in the general population. METHODS: A population-based, cross-sectional study was conducted in the general community in an urban area of the Blue Mountains, just west of Sydney, Australia. The study included 3222 people aged > or =49 years (mean age 65 years). Serum creatinine and haemoglobin were measured using standard laboratory techniques. Creatinine clearance was estimated from serum creatinine, body weight, sex and age. RESULTS: Two hundred and seventy subjects (8.4%) had serum creatinine levels > or =125 micromol/L and estimated -creatinine clearances were <0.84 mL/s (50 mL/min) in 894 subjects (27.7%) and <0.50 mL/s (30 mL/min) in 120 subjects (3.7%). There was a strong association between reduced renal function and anaemia. Compared to those with serum creatinine <125 micromol/L, the age-adjusted relative risk (RR) of anaemia in women (haemoglobin <12.0 g/dL) with serum creatinine > or =125 micromol/L was 5.5 (95% confidence interval (CI) 2.9-10.7) and the RR of anaemia in men (haemoglobin < 13.0 g/dL) was 3.1 (95% CI 1.6-6.0). Estimated -creatinine clearance <50 mL/min was associated with a three-fold increased risk of anaemia in women and a five-fold increased risk in men. CONCLUSIONS: The results of the present study suggest that even modestly impaired renal function is associated with anaemia in older men and women. The possibility of renal impairment should be considered in the diagnosis and management of anaemia in people aged>50 years.

Corticosteroid therapy for nephrotic syndrome in children.

BACKGROUND: In nephrotic syndrome protein leaks from the blood to the urine through the glomeruli resulting in hypoproteinaemia and generalised oedema. Children with untreated nephrotic syndrome frequently die from infections. The majority of children with nephrotic syndrome respond to corticosteroids. However about 70% of children experience a relapsing course with recurrent episodes of oedema and proteinuria. Corticosteroid usage has reduced the mortality rate in childhood nephrotic syndrome to around 3%, with infection remaining the most important cause of death. However corticosteroids have known adverse effects such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis and adrenal suppression. The original treatment schedules for childhood nephrotic syndrome were developed in an ad hoc manner. The optimal doses and durations of corticosteroid therapy that are most beneficial and least harmful have not been clarified. OBJECTIVES: The aim of this review was to determine the benefits and harms of different corticosteroid regimens in preventing relapse in children with steroid sensitive nephrotic syndrome (SSNS). SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (Cochrane Library, Issue 2, 2002), Cochrane Renal Group Specialised Register (July 2002), MEDLINE (1966 - July 2002) and EMBASE (1980 - July 2002) without language restriction, reference lists of articles, abstracts from proceedings and contact with known investigators in the area. SELECTION CRITERIA: Randomised controlled trials were included if they were carried out in children (aged three months to 18 years) in their initial or subsequent episode of SSNS, if they compared different durations, total doses or other dose strategies using prednisone or other corticosteroid agent and if they had outcome data at six months or more. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed all eligible studies for inclusion, assessed study quality and extracted data. The principle outcome measure was the number of children with and without relapse after six and 12-24 months. Secondary outcomes sought included the number of children who developed frequently relapsing nephrotic syndrome and adverse events. A random effects model was used to estimate summary effect measures (relative risk (RR), risk difference (RD)) after testing for heterogeneity. Meta-regression was used to explore potential between-study differences due to the baseline risk of relapse, study quality and types of interventions used. MAIN RESULTS: Five additional trials were included in the review for a total of 17 trials. A meta-analysis of six trials, which compared two months of prednisone with three months or more in the first episode, showed that the longer duration significantly reduced the risk of relapse at 12 - 24 months (RR 0.70; 95% CI 0.58 to 0.84) without an increase in adverse events. There was an inverse linear relationship between the duration of treatment and risk of relapse (RR = 1.26 - 0.112 duration; r(2) = 0.56; p = 0.03). The number of children who became frequent relapsers and the mean relapse rate/patient/year were also significantly reduced without increase in serious adverse events. In children with frequently relapsing nephrotic syndrome, deflazacort was significantly more effective in maintaining remission than prednisone (RR 0.44; 95% CI 0.25 to 0.78). REVIEWER'S CONCLUSIONS: Children in their first episode of SSNS should be treated for at least three months with an increase in benefit being demonstrated for up to seven months of treatment. In a population with a baseline risk for relapse following the first episode of 60% with two months of prednisone, daily prednisone for four weeks followed by alternate day therapy for six months would be expected to reduce the number of children experiencing a relapse by about 33%. In children who relapse frequently, deflazacort deserves further study.

Expression of T cell receptor variable region families by bone marrow gammadelta T cells in patients with IgA nephropathy.

IgA nephropathy (IgAN) is characterized by mesangial deposition of polymeric IgA (pIgA). Abnormalities of the IgA system include reduced mucosal and increased bone marrow (BM) pIgA production. Gammadelta T cells are regulators of mucosal IgA production and oral tolerance. We have described previously a deficiency of gammadelta T cells expressing Vgamma3 and Vdelta3 from the duodenal mucosa in IgAN. Since pIgA production is displaced to the BM, we have now studied BM gammadelta T cells in IgAN. Peripheral blood and BM aspirates were obtained from 14 patients with IgAN and 15 controls. Expression of TCR gamma and delta V region families was analysed by semiquantitative RT-PCR, and CDR3 spectratyping of Vgamma1-4 and Vdelta3 genes was performed. We found no difference between IgAN and controls in the V region usage of blood gammadelta T cells. However, in the BM of patients with IgAN, there was significantly reduced expression of the V region families Vgamma3 and Vdelta3, with the decrease in Vdelta3 being particularly striking. CDR3 spectratyping showed no abnormalities in blood or BM samples. Vgamma3 and Vdelta3 are underexpressed in the duodenum and the BM in IgAN. The combination of imbalanced mucosal and systemic pIgA production with deficient expression of gammadelta T cells using Vgamma3 and Vdelta3 in both sites may imply a role for these gammadelta T cells in the normal regulation of IgA immune responses, and in the complex immunopathogenesis of IgAN.

Growth hormone for children with chronic renal failure.

OBJECTIVES: To evaluate the benefits and harms of recombinant human growth hormone (hGH) treatment in children with chronic renal failure (CRF). SEARCH STRATEGY: Published and unpublished randomised controlled trials (RCTs) were identified from the Cochrane Controlled Trials Register, Medline, Embase, article reference lists and through contact with local and international experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) were included if they were carried out in children aged 0-18 years, diagnosed with CRF who are pre-dialysis, on dialysis or post-transplant; if they compared hGH treatment with placebo/no treatment or two doses of hGH treatments; and if they included height outcomes. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed studies for methodological quality and extracted data from eligible trials. The primary outcome measure was difference in mean change in height standard deviation score (SDS). Secondary outcome measures included change in height SDS from treatment onset to completion, change in height SDS during puberty, change in height velocity, final height, quality of life and adverse effects. To estimate summary treatment effects, data was pooled using a random effects model with calculation of weighted mean difference (WMD) for continuous outcomes and relative risk for categorical outcomes. MAIN RESULTS: Ten RCTs involving 481 children were identified. Treatment with hGH (28 IU/m(2)/wk) resulted in a significant increase in height standard deviation score (SDS) at one year (four trials, WMD0.77, 95% confidence limits (CI) 0.51 to 1.04), and a significant increase in height velocity at six months (two trials, WMD 5.7 cm/yr, 95%CI 4.4 to 7.0) and one year (two trials, WMD 4.1 cm/yr, 95%CI 2.6 to 5.6), but there was no further increase in height indices during the second year of administration. Compared to the 14 IU/m(2)/wk group, there was a 1.4 cm/yr (0.6 to 2.2) increase in height velocity in the 28 IU/m(2)/wk group. The frequency of reported side effects of hGH were similar to that of the control group. REVIEWER'S CONCLUSIONS: On average, one year of 28 IU/m(2)/wk hGH in children with CRF results in a 4 cm/yr increase in height velocity above that of untreated controls, however, it is not certain if this will result in an increase in final adult height. Benefits of longer courses or higher doses of treatment warrants further study.

Glomerular T cells in Heymann nephritis.

Active Heymann nephritis (HN) is a rat model of human membranous nephropathy. The appearance of T cells within the glomeruli of HN rats suggests a role for these cells in the pathogenesis of the disease. The aims of this study were to investigate T cells infiltrating the glomerulus in HN in Lewis rats by polymerase chain reaction (PCR) of their Vbeta chains, CDR3 spectratyping and sequencing. HN was induced in Lewis rats by immunization with renal tubular antigen (Fx1A) in CFA. Kidneys were collected between 4 and 10 weeks. The glomeruli were separated, homogenized and RNA extracted. RT-PCR, CDR3 spectratyping and sequencing were used to further characterize the infiltrating T cells. Multiple Vbeta families showed restriction of their CDR3 spectratypes in each animal. Several TCR Vbeta families had identical-sized restricted spectratypes across several different animals. Four Vbeta families were sequenced. In three of those four families, the dominant clones showed identical sized CDR3 regions and a striking over-expression of Jbeta2.6. Further analysis of the CDR3 regions of the Jbeta2.6 clones showed a significant restriction of the amino acids at four of the six CDR3 positions. Glomerular T cells bearing similar CDR3 sequences, using Jbeta2.6 and expressing at least two, and possibly more, Vbeta genes are involved in the pathogenesis of HN.

Growth hormone treatment in children with chronic renal failure: a meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the benefits and side effects of recombinant human growth hormone (hGH) treatment in children with chronic renal failure. METHODS: Two reviewers independently assessed relevant randomized controlled trials for methodologic quality, extracted data, and estimated summary treatment effects by use of a random effects model. RESULTS: Ten randomized controlled trials involving 481 children were identified. Treatment with hGH (28 IU/m(2)/wk) resulted in a significant increase in height standard deviation score at 1 year (4 trials, weighted mean difference [WMD] = 0.77, 95% CI = 0.51 to 1.04), and a significant increase in height velocity at 6 months (2 trials, WMD = 5.7 cm/y, 95% CI 4.4 to 7.0) and 1 year (2 trials, WMD = 4.1 cm/y, 95% CI 2.6 to 5.6), but there was no further increase in height indexes during the second year of administration. Compared with the 14 IU/m(2)/wk group, there was an increase of 1.4 cm/y (0.6 to 2.2) in height velocity in the group treated with 28 IU/m(2)/wk. The frequency of reported side effects of hGH were similar to that of the control group. CONCLUSION: On average, 1 year of treatment with 28 IU/m(2)/wk hGH in children with chronic renal failure results in an increase of 4 cm/y in height velocity above that of untreated control subjects, but there was no demonstrable benefit for longer courses or higher doses of treatment.

Restricted gammadelta T-cell receptor repertoire in IgA nephropathy renal biopsies.

BACKGROUND: We have previously reported that gammadelta T cells are involved in the progression of IgA nephropathy (IgAN) to renal failure. Our current study examined the diversity of the CDR3 region of the gammadelta T-cell receptor (TCR), and characterized the junctional sequences of gammadelta chain TCR transcripts from T cells infiltrating renal biopsies from patients with IgAN and in peripheral blood T cells (PBLs) from the same patients. METHOD: RNA extracted from renal biopsies and PBLs of IgAN patients (N = 15) was transcribed and then amplified with primers specific for the four Vgamma and six Vdelta families. Controls were renal biopsies from thin basement membrane disease (N = 6) and a sample from a kidney with suppurative pyelonephritis. CDR3 length spectratyping and sequencing of TCR gammadelta-chain were used to analyze the diversity of CDR3 region of these receptors. RESULTS: CDR3 spectratyping of gammadelta TCR junctional diversity demonstrated that TCR gammadelta chains (Vgamma1-3 and Vdelta1-3) expressed by T cells from PBLs of IgAN patients and the infected kidney showed highly diverse junctional lengths that were broadly distributed. In contrast, the junctional lengths of Vgamma1 (Vgamma2, 3, 4, 5, and 8 genes) and Vdelta1 transcripts in the T cells infiltrating kidneys with IgAN were much more restricted than those of PBLs. Renal biopsies from thin basement membrane disease demonstrated no significant signal for any Vgamma or Vdelta family. Sequence analysis of Vgamma1 and Vdelta1 transcripts from those patients with restricted CDR3 spectratyping profiles confirmed oligoclonal expansion of gammadelta T cells infiltrating the kidneys in those IgAN patients and also revealed recurrent junctional amino acid motifs in the TCR Vdelta1 chain in the kidney with IgAN. CONCLUSION: The data show that gammadelta T cells infiltrating the kidneys of IgAN patients use a restricted subset of gammadelta T cells, indicating clonal expansion of individual gammadelta T cells in the kidneys with IgAN. The feature of recurrent junctional amino acid motifs in Vdelta1 T cells may indicate antigen-driven selection.

Infiltration of canonical Vgamma4/Vdelta1 gammadelta T cells in an adriamycin-induced progressive renal failure model.

We have previously reported an infiltration of renal interstitial gammadelta T cells in Adriamycin-induced progressive glomerulosclerosis in the rat kidney. The TCR repertoire and sequences used by these gammadelta T cells have now been studied. Two injections of Adriamycin 14 days apart caused segmental glomerulosclerosis, massive interstitial infiltration of mononuclear cells, and end-stage renal failure. Flow cytometry of lymphocyte subpopulations with Abs to CD3, the gammadelta TCR, and the alphabeta TCR showed that gammadelta T cells as a proportion of CD3(+) cells were increased in Adriamycin-treated kidneys (8.5 +/- 5.4%), but not in lymph nodes (1.3 +/- 0.4%). A semiquantitative score of glomerular damage (r = 0.65; p < 0.01) and creatinine (r = 0.62; p < 0.01) correlated significantly with the presence of gammadelta T cells. TCR Vgamma repertoire analysis by RT-PCR and Southern blotting showed that Vgamma2 was the dominant subfamily in lymph nodes, whereas Vgamma4 became the predominant subfamily in advanced stages of the rat Adriamycin-treated kidney. Sequencing of the Vgamma4-Jgamma junctional region showed an invariant sequence. The amino acid sequence of the junctional region of the Vgamma4 TCR was the same as the reported mouse canonical Vgamma4 TCR sequence. Analysis of the kidney Vdelta repertoire showed dominant expression of Vdelta1, and sequencing again revealed the selective expression of a canonical Vdelta1 gene. Semiquantitative RT-PCR for cytokine gene expression showed that gammadelta T cells from the kidneys expressed TGF-beta, but not IL-4, IL-10, or IFN-gamma. These results suggest that the predominant gammadelta T cells in the Adriamycin kidney use an invariant Vgamma4/Vdelta1 receptor.

T cell receptor BV gene usage in interstitial cellular infiltrates in active Heymann nephritis.

BACKGROUND: Infiltration of the kidney by mononuclear cells is a prominent feature of active Heymann nephritis (HN). These cells could be present as a part of generalized inflammatory response, or could be proliferating in response to specific antigens. To examine these questions, we have analysed the T cell receptor (TCR) BV repertoire of T cells infiltrating the renal interstitium at regular time intervals throughout the course of the disease. METHODS: HN was induced in Lewis rats by immunization with renal tubular antigen (Fx1A) in complete Freund's adjuvant (CFA). Kidneys were collected 8 and 12 weeks after immunization. Renal tissue was homogenized and RNA extracted. RT-PCR and sequencing were used to characterize expression of TCR BV genes. RESULTS: Preferential expression of TCR BV2 and BV16 gene families was seen at 8 weeks. By 12 weeks the diversity of the TCR BV gene repertoire had increased and was highly heterogeneous. Sequence analysis of BV2, and BV16 RT-PCR products from 8 week HN kidneys revealed conserved usage of CDR3 regions, and an over-representation of arginine residues in the CDR3 regions at a frequency of between 60 and 100% of clones sequenced in most of BV2 and BV16 subfamilies. CONCLUSION: The preferential usage of CDR3 region sequences in TCR BV2 and BV 16 families indicates clonal expansion of individual T cells in HN kidneys at 8 weeks. The conserved usage of arginine residues in the CDR3 regions may indicate recognition of select antigenic epitopes. By 12 weeks, the diverse TCR BV repertoire in the kidney may be due to epitope spreading or may represent a non-specific inflammatory response in the late phase of the disease.

Corticosteroid therapy for nephrotic syndrome in children.

BACKGROUND: In nephrotic syndrome protein leaks from the blood to the urine through the glomeruli resulting in hypoproteinaemia and generalised oedema. Children with untreated nephrotic syndrome frequently die from infections. The majority of children with nephrotic syndrome respond to corticosteroids. However about 70% of children experience a relapsing course with recurrent episodes of oedema and proteinuria. Corticosteroid usage has reduced the mortality rate in childhood nephrotic syndrome to around 3%, with infection remaining the most important cause of death. However corticosteroids have known adverse effects such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis and adrenal suppression. The original treatment schedules for childhood nephrotic syndrome were developed in an ad hoc manner. The optimal doses and durations of corticosteroid therapy that are most beneficial and least harmful have not been clarified. The aim of this systematic review was to assess the benefits and harms of corticosteroid therapy in treating children with nephrotic syndrome. OBJECTIVES: To determine the benefits and harms of different corticosteroid regimens in preventing relapse in children with steroid responsive nephrotic syndrome (SRNS). SEARCH STRATEGY: Published and unpublished randomised controlled trials were identified from the Cochrane Controlled Trials Register, Medline, Embase, reference lists of articles, abstracts from proceedings and contact with known investigators in the area. SELECTION CRITERIA: Randomised trials were included if they were carried out in children (aged three months to 18 years) in their initial or subsequent episode of SRNS, if they compared different durations, total doses or other dose strategies using prednisone or other corticosteroid agent and if they had outcome data at six months or more. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed all eligible studies for inclusion, assessed study quality and extracted data. The principle outcome measure was the number of children with and without relapse after six and 12-24 months. Secondary outcomes sought included the number of children who developed frequently relapsing nephrotic syndrome and adverse events. A random effects model was used to estimate summary effect measures (relative risk RR, risk difference RD) after testing for heterogeneity. Meta-regression was used to explore potential between-study differences due to the baseline risk of relapse, study quality and types of interventions used. MAIN RESULTS: Twelve trials were identified. A meta-analysis of five trials, which compared two months of prednisone with three months or more in the first episode, showed that the longer duration significantly reduced the risk of relapse at 12 - 24 months (relative risk 0.73; 95% CI 0.60,0.89) without an increase in adverse events. There was an inverse linear relationship (RR = 1.382 (SE 0.215) - 0.133 duration (SE 0.048); r2 = 0.66; p = 0.05) between the duration of treatment and risk of relapse. The number of children who became frequent relapsers and the mean relapse rate/patient/year were also significantly reduced without increase in serious adverse events. In children with frequently relapsing nephrotic syndrome, deflazacort was significantly more effective in maintaining remission than prednisone (RR 0.44; 95% CI 0.25, 0.78). REVIEWER'S CONCLUSIONS: From this meta-analysis of randomised controlled trials it can be concluded that children in their first episode of nephrotic syndrome should be treated for at least three months with an increase in benefit being demonstrated for up to seven months of treatment. In a population with a baseline risk for relapse following the first episode of 60% with two months of prednisone, daily prednisone for four weeks followed by alternate day therapy for six months would be expected to reduce the number of children experiencing a relapse by about 40%. In children who relapse frequently, deflazacort deserves further study.

Effects of nonsteroidal anti-inflammatory drugs on post-operative renal function in normal adults.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) can play a major role in the management of acute pain in the peri-operative period. However, there there are conflicting views on whether NSAIDs are associated with adverse renal effects. OBJECTIVES: The primary objective of this review was to determine the effects of NSAIDs on post-operative renal function in adults with normal pre-operative renal function. SEARCH STRATEGY: Electronic searches for relevant randomised and quasi-randomised controlled trials in Cochrane Controlled Trials Register, MEDLINE and EMBASE were performed. Attempts were also made to identify trials from citation lists of relevant trials, review articles and clinical practice guidelines. Hand-searching of conference abstracts published in major anaesthetic journals was also performed. SELECTION CRITERIA: The inclusion criteria were randomised or quasi-randomised comparisons of individual NSAIDs with either each other or placebo for treatment of post-operative pain, with relevant post-operative renal outcome measures, in adult surgical patients with normal renal function. DATA COLLECTION AND ANALYSIS: Of the 14 trials that fulfilled the selection criteria for this review, eight trials were relevant with sufficient data for meta-analysis. The data was extracted independently by two reviewers. The primary outcome measure was creatinine clearance within the first two days after surgery. Secondary outcome measures included serum creatinine, urine volume, urinary sodium level, urinary potassium level, fractional excretion of sodium, fractional excretion of potassium, need for dialysis and need for diuretic or dopamine treatment for renal insufficiency. Weighted mean differences for continuous outcomes and relative risk for dichotomous outcomes were estimated. MAIN RESULTS: As a group, NSAIDs reduced creatinine clearance by 18ml/min (95%CI: 6 to 31) and potassium output by 38mmol/day (95%CI: 19 to 56) on the first day after surgery compared to placebo. Serum creatinine clearance increased on the second day after surgery by 15umol/L (95%CI: 2 to 28) compared to placebo. No significant reduction in urine volume during the early post-operative period was found. There was no significant difference in serum creatinine in the early post-operative period between patients receiving ketorolac and diclofenac in one trial. No cases of post-operative renal failure requiring dialysis were described. REVIEWER'S CONCLUSIONS: NSAIDs caused a clinically unimportant transient reduction in renal function in the early post-operative period in patients with normal pre-operative renal function. NSAIDs should not be withheld from adults with normal pre-operative renal function because of concerns about post-operative renal impairment.

A reproducible pediatric daytime urinary incontinence questionnaire.

PURPOSE: We developed and tested the reliability of a new, structured, parent administered questionnaire to determine the prevalence of and risk factors for daytime urinary incontinence in children. MATERIALS AND METHODS: A new questionnaire was developed and evaluated in a pilot study for ease of understanding and acceptability. It was then tested for reproducibility of responses in a randomly selected sample of new primary school entrants in Western Sydney 4 weeks after baseline data were collected. The questionnaire obtained data on demographics, prevalence of daytime incontinence, family history of incontinence, voiding symptoms and socioeconomic status. Categorical data agreement was assessed using the kappa statistic and continuous data agreement was analyzed using the Bland-Altman method. RESULTS: A total of 166 subjects 3.5 to 7 years old (mean and median ages 5.6 and 5.7, respectively) completed the repeat questionnaire with a 78.5% response rate. Mean agreement of the responses to the first and second questionnaires was 91% (range 83% to 100%, mean kappa = 0.70, range 0.34 to 1.00). For continuous data the 95% confidence limits were narrow (0.3 for birth weight data). CONCLUSIONS: We have developed a new daytime urinary incontinence questionnaire using parent reported data and demonstrated that it is reproducible. We consider it to be a useful instrument for ascertaining information on urinary incontinence and other voiding symptoms.

Daytime urinary incontinence in primary school children: a population-based survey.

OBJECTIVES: To determine the prevalence and severity of, and risk factors for, daytime urinary incontinence in children starting primary school. DESIGN AND SETTING: Population-based cross-sectional survey of new entrant primary school children in Sydney, Australia. METHODS: A random cluster sample of 2020 primary school children was surveyed by using a daytime incontinence questionnaire with known substantial repeatability (mean kappa = 0.70). RESULTS: The questionnaire was returned for 1419 (70%) children with a mean age of 5.9 years; 16.5% of children had experienced one or more episodes of wetting in the last 6 months (mild), 2.0% had wet twice or more per week (moderate), and 0.7% were wet every day (severe) (overall prevalence of 19.2%). On multivariate analysis, recent emotional stress (odds ratio 5.7), a history of daytime wetting along the paternal line (odds ratio 9.3), and a history of wetting among male siblings (odds ratio 5.3) were independent risk factors for moderate to severe daytime wetting. Expressed as population attributable risk, 59% and 28% of moderate-severe and mild daytime wetting, respectively, can be attributed to these 3 factors. Only 16% of families with affected children had sought medical help. CONCLUSIONS: Daytime urinary incontinence in the first year of primary school is more common than previously reported, and only a small proportion of affected children seek medical help. Emotional stress and family history are likely to be major causal factors.