Demethylation of the TSDR is a marker of squamous cell carcinoma in transplant recipients.

Malignancy is an important cause of death in transplant recipients. Cutaneous squamous cell carcinoma (cSCC) causes significant morbidity and mortality as 30% of transplant recipients will develop cSCC within 10 years of transplantation. Previously we have shown that high numbers of regulatory T cells (Tregs) are associated with the development of cSCC in kidney transplant recipients (KTRs). Demethylation analysis of the Treg-specific demethylated region (TSDR) provides a more accurate association with cSCC risk after transplantation. Age, gender and duration of immunosuppression matched KTRs with (n=32) and without (n=27) cSCC, were re-analyzed for putative clinical and immunological markers of cancer risk. The proportion of FOXP3+ CD4+ cells was higher in the population with a previous SCC. Major T cell subsets remained stable over time; although B cell, CD8 and CD4 subpopulations demonstrated age-related changes. TSDR methylation analysis allowed clarification of Treg numbers, enhancing the association of high Treg levels in KTRs with cSCC compared to the cSCC-free cohort. These data validate and expand on previous findings in long-term KTRs, and show that immune markers remain stable over time. TSDR demethylation analysis provides a more accurate biomarker of cancer posttransplantation.

Alemtuzumab and sirolimus in renal transplantation: six-year results of a single-arm prospective pilot study.

mTOR inhibitors avoid calcineurin nephrotoxicity, but sirolimus de novo is associated with unacceptable side effects and higher rejection rates. We have investigated a modified strategy: alemtuzumab induction with tacrolimus and mycophenolate maintenance, switching from tacrolimus to sirolimus at 6 months and stopping mycophenolate at 12 months. Here, we report the 6-year follow-up of 30 patients prospectively recruited to this single-arm pilot study and compare outcomes to a matched contemporaneous control group of 30 patients who received standard induction and calcineurin-inhibitor-based immunosuppression.Six-year patient and graft survival were 83% and 80%(alemtuzumab) versus 77% and 70% (control). Rejection rates in the first 6 months were similar in alemtuzumab (6.6%) and control groups (10%). A higher than expected incidence of rejection in the alemtuzumab group following cessation of mycophenolate at 1 year (17%) was mitigated in later patients by retaining low dose mycophenolate. Mean eGFR was higher in the alemtuzumab group at all time points but not significantly (p»0.16). Tacrolimus levels in the first 6 months were significantly higher in the contemporaneous control group (p<0.001). Alemtuzumab induction with initial treatment with tacrolimus enables conversion to sirolimus without the side effects and incidence of acute rejection seen in earlier protocols.

Single estimated glomerular filtration rate and albuminuria measurement substantially overestimates prevalence of chronic kidney disease.

BACKGROUND/AIMS: Guidelines require repeatedly diminished estimated glomerular filtration rate (eGFR) and/or albuminuria to diagnose chronic kidney disease (CKD), and advise screening only in select populations. Many estimates of CKD prevalence have used single measurements. This longitudinal study assessed eGFR and albuminuria reproducibility, and impact on estimate of CKD prevalence, in factory workers. METHODS: A total of 512 white workers in a Belarusian industrial factory were initially tested, identifying 206 with abnormal (eGFR <59 ml/min/1.73 m(2) or albuminuria) or near-abnormal (eGFR up to 1 SD above abnormal) renal function. At 3 months, 142 of the abnormal/near-abnormal cohort were re-tested. RESULTS: Analysis of repeat samples revealed no significant change in eGFR in this population, however 21% individually changed CKD stage. Initial proteinuria was reproducible in only 48% at 3 months. This had a major impact on estimated CKD prevalence: a point prevalence of 8.2% halved with repeat testing. The predictive value of initially abnormal eGFR or albuminuria for repeat abnormality at 3 months was 0.5. CONCLUSION: Non-targeted screening for CKD is inaccurate and can overestimate prevalence. This study emphasises the importance of confirming abnormal eGFR and proteinuria on at least one further sample 3 months apart before categorising the individual as having CKD. This has wide implications for screening in European general populations.

Poorer graft survival in ethnic minorities: results from a multi-centre UK study of kidney transplant outcomes.

BACKGROUND: The STEPP group was established to investigate factors that affect long-term transplant outcomes including quality of life and other patient-reported outcomes between different transplant centers and patients. METHODS: Data were collected for 2,650 patients whose first renal transplant took place between 1992 and 2003 in five UK centers. Univariable and multivariable survival analyses were performed using eleven candidate explanatory variables. RESULTS: Graft survival was worse in Black (B) patients (HR B v W 1.57 95% CI 1.10, 2.24), and in South Asian (A) patients (HR A v W 1.39 95% CI 1.03, 1.85) compared to Whites (W) after adjusting for other factors including HLA mismatch, and time on dialysis. Time spent on dialysis pre-transplantation was non-linearly associated with patient, but not death-censored graft survival. Losing a functioning graft was a strong predictor of patient death. One site had both the best graft and the worst patient survival. CONCLUSIONS: Differences in patient and graft survival between ethnic groups cannot be explained by currently recognized factors. These, and the complex balance between optimum patient and graft survival which differs between sites in this study require further investigation.

Skin cancer surveillance in renal transplant recipients: re-evaluation of U.K. practice and comparison with Australian experience.

BACKGROUND: Nonmelanoma skin cancer (NMSC) is the most common tumour following solid organ transplantation. In 2000 a survey of U.K. centres managing renal transplant recipients (RTRs) showed that only 21% offered skin cancer surveillance. OBJECTIVES: The survey was repeated in 2006 in the U.K. and Australia. The aims were to determine if U.K. practice had changed since 2000, to define skin cancer surveillance practice in Australian RTRs and to compare this with that in the U.K. METHODS: Questionnaires were sent to 84 U.K. and 45 Australian centres providing long-term RTR follow-up. RESULTS: Fifty-six (67%) U.K. centres caring for 82% (n = 16 349) of the RTR population replied. Sixty-six per cent provided annual skin cancer surveillance and 39% offered full skin examination (FSE) compared with 21% and 20% in 2000. Eighty-one per cent of surveillance was performed by nondermatologists (n = 30), nine (30%) of whom had received formal training for the role. Thirty-one (69%) Australian centres covering 86% (n = 5392) of the RTR population responded. Ninety-seven per cent provided skin cancer surveillance, and 61% offered FSE. Forty per cent (n = 12) of skin cancer surveillance was conducted by nondermatologists. Two nondermatologists had received formal training. CONCLUSIONS: Despite a substantial improvement in the provision of skin cancer surveillance for RTRs in the U.K. between 2000 and 2006, only 39% of units offer FSE. In contrast, virtually all Australian centres offer annual skin cancer surveillance, with more dermatology involvement. Lack of training for nondermatologists involved in skin cancer surveillance is evident in both countries. The availability of dermatologists and the variation in NMSC risk between the populations may explain the different practices observed.

Polymorphisms in glutathione S-transferases are associated with altered risk of nonmelanoma skin cancer in renal transplant recipients: a preliminary analysis.

Non-melanoma skin cancer (NMSC) represents a significant cause of morbidity and mortality among renal transplant recipients, with tumors behaving more aggressively than those in nontransplant patients. Not all immunosuppressed patients develop NMSC, however, and in those that do, the rate of accrual and numbers of lesions vary considerably. Though ultraviolet light is critical, it is unlikely that this alone explains the observed phenotypic diversity, suggesting the possible involvement of genetic factors. Furthermore, although twin studies in nontransplant patients with NMSC suggest a low genetic component, several genes associated with susceptibility and outcome in these patients have been identified. Thus, having previously shown that polymorphism in members of the glutathione S-transferase (GST) supergene family is associated with altered NMSC risk in nontransplant patients, we examined allelism in GSTM1, GSTP1, GSTM3, and GSTT1 in 183 renal transplant recipients. GSTM1 null was associated with increased squamous cell carcinoma (SCC) risk (p = 0.042, OR = 3.1). This remained significant after correction for age, gender, and ultraviolet light exposure (p = 0.012, OR = 8.4) and was particularly strong in patients with higher ultraviolet light exposure (e.g., sunbathing score > 3, p = 0.003, OR = 11.5) and in smokers (p = 0.021, OR = 4.8). Analysis of the interaction between GSTM1 null and sunbathing score showed that the two factors were synergistic and individuals with both risk parameters demonstrated a shorter time from transplantation to development of the first SCC (p = 0.012, hazard ratio = 7.1). GSTP1*Ile homozygotes developed larger numbers of SCC (p = 0.002, rate ratio = 7.6), particularly those with lower ultraviolet light exposure and cigarette consumption. GSTM3 and GSTT1 also demonstrated significant associations, though some genotype frequencies were low. These preliminary data suggest that genetic factors mediating protection against oxidative stress are important in NMSC development in immunosuppressed patients and may be useful in identifying high-risk individuals.

The role of genetic polymorphisms of angiotensin-converting enzyme in the progression of renal diseases.

The renin-angiotensin system is likely to be important in the progression of renal diseases because of its effect on tissue hemodynamics and glomerular cell function. Recent evidence from small studies has suggested a possible role for the genetic determinants of angiotensin converting enzyme activity in the rate of progression of renal failure. We studied the effect of the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme gene on the rate of renal function deterioration in 822 patients with a variety of renal diseases. We found that the slope of the reciprocal serum creatinine-versus-time plot was steeper in patients homozygous for the deletion allele (DD) compared with those homozygous for the insertion allele (II) (P = .015). When patients with similar renal function at presentation (creatinine < 200 mumol/L) were compared, II homozygotes had significantly improved renal survival (P = .039). Separate analyses of patients with glomerular diseases and tubulointerstitial diseases demonstrated an effect of this genotype in glomerular diseases only. These data provide further evidence of the possible role of the angiotensin-converting enzyme gene in the rate of progression of renal failure, although further studies are required to evaluate the role of this and other proposed candidate genes in renal diseases.

Renal artery stenosis managed by Palmaz stent insertion: technical and clinical outcome.

OBJECTIVE: To assess the technical and clinical outcome of Palmaz renal artery stent insertion in patients with renal artery stenosis. DESIGN: Twenty-nine patients with radiological evidence of renal artery stenosis and hypertension (16 patients, mean +/- SD diastolic blood pressure 100.5 +/- 8.16 mmHg) and/or renal impairment (17 patients, mean +/- SD serum creatinine 376 +/- 169 mu mol/l) were referred for radiological intervention. Of these, 22 had ostial atheromatous lesions, six had atheromatous non-ostial lesions and one patient had fibromuscular dysplasia. Palmaz stent insertion was performed where either previous or concomitant percutaneous transluminal renal angioplasty (PTRA) had been unsuccessful. Technical success was defined primarily as <30% residual stenosis. A prospective radiological and clinical follow-up was performed and the results compared with the outcome following PTRA alone in a similar group of patients from our centre. RESULTS: Immediate technical success was achieved in all 29 patients. Follow-up angiography in 24 patients after a mean of 7 months showed restenosis in four patients. The hypertension was not 'cured' in any patient; a blood pressure fall was observed in seven patients (44%) and no change in the remaining nine subjects (56%). Renal function improved in four patients (24%), two of whom had angiotensin converting enzyme inhibitor-exacerbated renal impairment. This compares with an immediate technical success of 81% for PTRA alone, with cure in 50% and improvement in 32% of patients with hypertension and improvement in renal function in 64.7% of patients with renal impairment. CONCLUSIONS: Palmaz renal artery stent insertion has a higher technical success rate than PTRA, but the clinical improvement is disappointing in our patient population.

A combinatorial approach to the identification of dipeptide aldehyde inhibitors of beta-amyloid production.

In an effort to rapidly identify potent inhibitors of Abeta production and to probe the amino acid sequence specificity of the protease(s) responsible for the production of this peptide, a large number of dipeptide aldehydes were combinatorially synthesized and manually evaluated for their inhibitory properties. The starting point for this study was the dipeptide aldehyde carbobenzoxyl-valinyl-phenylalanal previously shown to inhibit the production of Abeta in CHO cells stably transfected with the cDNA encoding betaAPP695. Pools of related dipeptide aldehydes were combinatorially synthesized, and the most active pool was deconvoluted, resulting in the identification of the most active inhibitor of this pool. Systematic optimization of this inhibitor resulted in a series of dipeptide aldehydes with enhanced potencies relative to carbobenzoxyl-valinyl-phenylalanal. The most active dipeptide aldehydes were those that possessed hydrophobic amino acids at both the P1 and P2 positions. The most potent compound identified in this study was 3, 5-dimethoxycinnamamide-isoleucinyl-leucinal with an IC(50) of 9.6 microM, approximately 10-fold more active than carbobenzoxyl-valinyl-phenylalanal. In immunoprecipitation experiments using antibodies directed toward either Abeta1-40 or Abeta1-42, 3,5-dimethoxycinnamamide-isoleucinyl-leucinal, like carbobenzoxyl-valinyl-phenylalanal, preferentially inhibited the shorter 1-40 form of Abeta, whereas the longer 1-42 form was not as strongly inhibited. These results suggest that dipeptide aldehydes related to carbobenzoxyl-valinyl-phenylalanal inhibit Abeta through similar mechanisms and demonstrate the utility of a combinatorial synthesis approach to rapidly identify potent inhibitors of Abeta production.

Clinical risk factors associated with nonmelanoma skin cancer in renal transplant recipients.

A single-center, cross-sectional, longitudinal study was conducted to determine the prevalence, annual incidence, and clinical risk factors for skin cancer in a white renal transplant population. One hundred eighty-two white patients (95% of population) with functioning allografts, a mean age at transplantation of 38.9 +/- 15. 6 (SD) years, and a mean follow-up of 8.5 +/- 6.3 years were interviewed and examined between May 1997 and June 1999. All case notes were carefully reviewed. Since transplantation, 16.5% of the patients had developed nonmelanoma skin cancer; 15.4%, actinic keratoses (AK); 53%, viral warts; and 1.6%, lentigo maligna melanoma (n = 3). Thirty-nine percent of the tumors were detected as a consequence of this study, and 20% of these occurred on covered body sites. The squamous cell (SCC)-basal cell carcinoma (BCC) ratio was 3.8:1. Eighty-two percent of the patients were examined a second time 12 months after the initial assessment. Using these data to identify new lesions, the annual incidence was calculated at 6.5%, increasing to 10.5% at more than 10 years posttransplantation. Duration of immunosuppression, older age at transplantation, presence of AK, male sex, and outdoor occupation were significantly associated with both SCC and BCC; SCC alone was associated with a history of having smoked tobacco. Early identification of those at greatest risk using a clinical risk profile may allow the development of more structured preventative and surveillance strategies than currently exist.

Acute effect of altered tryptophan levels and alcohol on aggression in normal human males.

Normal males received amino acid mixtures designed to raise or lower tryptophan availability, and thus to raise or lower brain serotonin synthesis. They also received alcoholic or non-alcoholic drinks. The subjects were tested in the Taylor Competitive Reaction Time Task in which they competed against a (non-existent) partner in a reaction time task. The magnitude of electric shocks that the subjects were willing to give to their bogus partner was used as a measure of aggression. Lowered tryptophan levels and ingestion of alcohol were associated with increased aggression. Our data support the idea that low serotonin levels may be involved in the etiology of aggression. They suggest that subjects with low brain serotonin levels may be particularly susceptible to alcohol-induced violence.

Rhabdomyolysis and acute renal failure resulting from alcohol and drug abuse.

Rhabdomyolysis is a common cause of acute renal failure (ARF) associated with drug misuse. Abuse of the gel formulation of temazepam has been a particular problem in the West of Scotland. We performed a retrospective review of dialysis-dependent ARF from rhabdomyolysis and drug misuse in the West of Scotland, 1986-1997. We identified 76 patients, of whom 87% were male. Seventeen cases occurred in the first 6 years, compared with 59 in the subsequent 6 years. Median age was 32. Thirty cases followed intravenous drug misuse, 46 followed oral drug misuse. The substances most frequently misused were alcohol (54%), heroin (24%) and parenteral temazepam (17%). The temazepam cases all followed the introduction of the gel formulation. Three out of 4 patients requiring limb amputation had injected temazepam. Of intravenous drug misusers tested, 72% were hepatitis-C-positive. Some 43% of patients had deprivation scores in the worst category. ARF due to rhabdomyolysis from substance misuse is increasing in our area. Alcohol is frequently responsible. The introduction of the gel formulation of temazepam has contributed to the increase. Those at risk in this study were young, male, had a high incidence of hepatitis C and lived in the most deprived areas.

Evaluation of a new assay for antibodies to LAV/HTLV III.

The sensitivity, specificity and reproducibility of an enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies to LAV/HTLV III produced by Genetic Systems was assessed with the identical panel of sera used in previous evaluations of anti-HTLV III ELISAs. The results from this study show that the Genetic Systems anti-LAV/HTLV III ELISA proved to be of equivalent sensitivity and to have higher specificity than assays currently used in Australia for screening purposes while maintaining high levels of intra- and inter-laboratory reproducibility.

Methotrexate removal during haemodialysis in a patient with advanced laryngeal carcinoma.

A 62-year-old patient on long-term haemodialysis who developed an inoperable T2N3Mo squamous-cell carcinoma of the larynx was treated with weekly low-dose methotrexate (MTX) after failing to respond to radiotherapy. The patient was initially given one dose of 10 mg MTX (6 mg/m2) as a 1-h infusion, then he received three further i.v. doses of 20 mg (12 mg/m2). Haemodialysis was performed 15-18 h after each dose and the patient received folinic acid (30 mg i.v.q 6 h) until the MTX concentration was < 0.1 mumol/l. The MTX concentration was measured regularly until it reached < 0.1 mumol/l, and additional samples were withdrawn pre- and post-dialysis. The MTX elimination rate constant and half-life were estimated with the patient on and off dialysis. The patient failed to respond to treatment but did not experience MTX-related toxicity. The elimination half-life ranged from 22 to 42 h when he was off dialysis but fell to a median of 5.5 h during dialysis. Low-dose MTX was given to a patient on regular haemodialysis without evidence of toxicity. The rate of MTX elimination was increased during haemodialysis, although high MTX concentrations persisted for several days and prolonged rescue with folinic acid was required.

Cognitive function, cardiovascular reactivity, and behavior in boys at high risk for alcoholism.

Boys (average age = 12.1 years) from families with an extensive history of paternal alcoholism differed from controls of similar age and IQ on measures of cognitive function, cardiovascular reactivity, and parent-rated conduct problems. High-risk boys performed most poorly on neuropsychological tests of frontal lobe function. According to tests of temporal organization and conditional-associate learning, control over working memory was the frontal subfunction primarily affected. A mental arithmetic task also elicited greater heart rate increases and peripheral vasoconstriction among high-risk boys than among controls. After controlling for group status, significant correlations remained between frontal lobe test scores and disruptive behavior and between cardiovascular hyperreactivity and anxiety levels. The possible contribution of these findings to alcohol abuse was discussed.

Cognitive and neuropsychological characteristics of physically aggressive boys.

Cognitive-neuropsychological tests were given to adolescent boys (N = 177) to investigate processes associated with physical aggression. Factor analysis yielded 4 factors representing verbal learning, incidental spatial learning, tactile-lateral ability, and executive functions. Physical aggression was assessed at ages 6, 10, 11, and 12, and 3 groups were created: stable aggressive, unstable aggressive, and nonaggressive. The authors found main effects for only the executive functions factor even when other factors were used as additional covariates in a step-down analysis; nonaggressive boys performed better than stable and unstable aggressive boys. The covariates family adversity and anxiety were both related only to the verbal learning factor. This study highlights the importance of deficits in executive function in the expression of physical aggression relative to other cognitive-neuropsychological functions.

The benefit of STent placement and blood pressure and lipid-lowering for the prevention of progression of renal dysfunction caused by Atherosclerotic ostial stenosis of the Renal artery. The STAR-study: rationale and study design.

BACKGROUND: Atherosclerotic renal artery stenosis (ARAS) is associated with progressive loss of renal function and is one of the most important causes of renal failure in the elderly. Current treatment includes restoration of the renal arterial lumen by endovascular stent placement. However, this treatment only affects damage caused by ARAS due to the stenosis and ensuing post-stenotic ischemia. ARAS patients have severe general vascular disease. Atherosclerosis and hypertension can also damage the kidney parenchyma causing renal failure. Medical treatment focuses on the latter. Lipid-lowering drugs (statins) could reduce renal failure progression and could reduce the overall high cardiovascular risk. The additional effect on preserving renal function of stent placement as compared to medical therapy alone is unknown. Therefore, the STAR-study aims to compare the effects of renal artery stent placement together with medication vs. medication alone on renal function in ARAS patients. METHOD: Patients with an ARAS of > or = 50% and renal failure (creatinine (Cr) clearance < 80 mL/min/1.73 m2) are randomly assigned to stent placement with medication or to medication alone. Medication consists of statins, anti-hypertensive drugs and antiplatelet therapy. Patients are followed for 2 yrs with extended follow-up to 5 yrs. The primary outcome of this study is a reduction in Cr clearance > 20% compared to baseline. This trial will include 140 patients.

Use of the Tesio catheter for hemodialysis in patients with end-stage renal failure: a 2-year prospective study.

BACKGROUND: The Tesio catheter system has been proposed to be a reliable source of vascular access for the dialysis patient with low rates of infection and other complications. Whether such catheters provide reliable short- and long-term access remains undetermined. METHODS: This study prospectively examined all Tesio lines inserted over a 2-year period in patients with end-stage failure with careful recording of all catheter complications and reasons for catheter loss. RESULTS: 100 catheters were inserted in 82 patients giving a total experience of 13,749 catheter days; 74 catheters were inserted into the jugular veins, the remainder into the femoral veins; 82 insertions were covered with antibiotics. At the end of the study, 29 catheters remained in situ. Of the remaining 71 catheters, 27 catheters were removed because of fashioning of definitive access. Nine catheters were lost due to infection and 10 were lost due to non-function; 19 patients died with a functioning catheter. Episodes ofnon-function were the major complications, although catheter patency was restored in 90% of cases utilizing urokinase and warfarin. Overall 80% of femoral and 16% of jugular catheters required anticoagulation. CONCLUSIONS: Tesio catheters inserted into the jugular or femoral veins can provide excellent access whilst awaiting definitive dialysis access. They are well-tolerated with a low complication rate compared to standard temporary central venous catheters. Non-function remains a significant problem, especially in femoral catheters, which should be anticoagulated following insertion. Because of our results we suggest that these catheters be used as part of the co-ordinated approach to the management of vascular access in end-stage renal failure patients without definitive access.

Renal metastases from a squamous cell carcinoma of the larynx.

Laryngeal squamous cell carcinoma (SCC) tends to exhibit local spread with a low incidence of distal metastases. The majority of distal metastases are to the lungs and renal involvement is extremely rare. We present a case of laryngeal SCC with metastatic spread to the left kidney presenting as a large, mainly cystic mass. The radiological differentiation of renal metastases from primary renal tumours is discussed.

Colour Doppler ultrasound in renal artery stenosis: intrarenal waveform analysis.

Renal artery stenosis (RAS) is the commonest secondary cause of hypertension and may result in renal ischaemia with resultant renal failure. Recent studies hve suggested that colour Doppler ultrasound, with spectral analysis of the intrarenal waveforms, can identify those patients with a significant RAS. A prospective study was performed in which colour Doppler ultrasound was compared with angiography in 73 patients (143 kidneys) presenting for renal angiography. Colour Doppler ultrasound was unsuccessful in 16% of kidneys due to a combination of technical failures and small kidney size. Accessory renal vessels were present in 14% of kidneys on angiography but none was detected by ultrasound. Of the 120 kidneys that had both examinations, no significant difference in intrarenal pulsatility or resistive index was noted between the angiographically stenosed and normal arteries. There were significant differences for intrarenal peak and end diastolic velocities, and acceleration time and index. Of these measurements, acceleration time was the best indicator of RAS. The probability of detecting a high grade RAS in an individual patient did not reach 90% until the acceleration time was prolonged to more than 0.12 s. Intrarenal colour Doppler ultrasound is not a general screening test for RAS and it should be reserved for selected patient groups where the incidence of disease is high. Patients with prolonged acceleration times of more than 0.12 s have a high likelihood of at least 70% RAS and should proceed directly to angiography.