Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis.

OBJECTIVES: To assess the safety of intra-articular (IA) autologous tolerogenic dendritic cells (tolDC) in patients with inflammatory arthritis and an inflamed knee; to assess the feasibility and acceptability of the approach and to assess potential effects on local and systemic disease activities. METHODS: An unblinded, randomised, controlled, dose escalation Phase I trial. TolDC were differentiated from CD14+ monocytes and loaded with autologous synovial fluid as a source of autoantigens. Cohorts of three participants received 1×106, 3×106 or 10×106 tolDC arthroscopically following saline irrigation of an inflamed (target) knee. Control participants received saline irrigation only. Primary outcome was flare of disease in the target knee within 5 days of treatment. Feasibility was assessed by successful tolDC manufacture and acceptability via patient questionnaire. Potential effects on disease activity were assessed by arthroscopic synovitis score, disease activity score (DAS)28 and Health Assessment Questionnaire (HAQ). Immunomodulatory effects were sought in peripheral blood. RESULTS: There were no target knee flares within 5 days of treatment. At day 14, arthroscopic synovitis was present in all participants except for one who received 10×106 tolDC; a further participant in this cohort declined day 14 arthroscopy because symptoms had remitted; both remained stable throughout 91 days of observation. There were no trends in DAS28 or HAQ score or consistent immunomodulatory effects in peripheral blood. 9 of 10 manufactured products met quality control release criteria; acceptability of the protocol by participants was high. CONCLUSION: IA tolDC therapy appears safe, feasible and acceptable. Knee symptoms stabilised in two patients who received 10×106 tolDC but no systemic clinical or immunomodulatory effects were detectable. TRIAL REGISTRATION NUMBER: NCT01352858.

Land contamination and urinary abnormalities: cause for concern?

AIMS: To determine the prevalence of proteinuira and enzymuria among a cohort of subjects exposed to hexachlorobutadiene (HCBD) in their homes and to determine whether there was a change in observed effects when exposure ceased. METHODS: Residents underwent a health check, which included a panel of urinary markers of both glomerular and tubular origin, within two months of cessation of long term exposure to HCBD and again at least 10 months after exposure ceased. Analysis of the results was performed to determine if there was any early evidence of renal effects, and to ascertain whether changes in these parameters occurred after exposure to HCBD ceased. RESULTS: Tubular proteinuria and enzymuria were increased in the initial health check and significantly decreased after the residents had left their homes for about 10 months. As the early renal tubular markers improved when exposure ceased it is anticipated that the long term nephrotoxic risk will be minimal, but the carcinogenic risk remains unknown. CONCLUSIONS: Results show there was a renal effect which improved when subjects left their homes. This suggests there was a local environmental factor responsible for the observations. This is consistent with the predicted toxicological effects of HCBD from animal studies.

Changes in the corrected QT interval and corrected QT dispersion during haemodialysis.

The link between increased QT dispersion and cardiac death in subjects with diabetes and arterial disease is well recognised. Corrected QT dispersion was studied in subjects with end stage renal failure on haemodialysis. Thirty one stable, chronic subjects on haemodialysis had 12-lead electrocardiograms (ECGs) taken before and after a single haemodialysis session. The QT interval was measured manually in each and the corrected QT and corrected QT dispersion calculated. Serum concentrations of potassium, calcium, and magnesium were measured at the same time as ECG acquisition. Corrected QT dispersion increased from a mean (SEM) 90.6 (5.8) to 117.7 (10.2) ms (p=0.002). Serum potassium and magnesium decreased from 5.0 (0.14) to 3.5 (0.09) mmol/l and 0.95 (0.04) to 0.89 (0.09) mmol/l respectively, while serum calcium increased from 2.56 (0.04) to 2.77 (0.04) mmol/l. Intradialytic weight fell by a mean of 2.1 kg. There was no significant correlation between the change in QTc dispersion and the changes in measured serum anions or the subjects' weight during dialysis. Corrected QT dispersion was higher in subjects on haemodialysis than previously suggested normal values, and was significantly increased by haemodialysis. This reflects increased inhomogeneous ventricular repolarisation, which may lead to an increased risk of arrhythmias and sudden death. Studies looking at QT dispersion in subjects on dialysis should standardise the timing of ECG recordings taken with respect to dialysis.

Acute myocardial infarction in young adults: causes and management.

The case report in this review illustrates an acute myocardial infarction in a young adult probably due to arterial thrombosis that can be attributed to a hypercoagulable state resulting from the nephrotic syndrome. Although rare, acute myocardial infarction should be considered in young adults presenting with chest pain. A detailed clinical history may help to identify the aetiology, and guide subsequent management, but diagnostic coronary angiography is essential. Careful risk factor modification and treatment of the underlying cause should reduce the incidence of recurrent cardiac events.

Cox-2 inhibitors and other nonsteroidal anti-inflammatory drugs in the treatment of pain in the elderly.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed therapies for acute and chronic pain in the elderly. NSAIDs are effective in treating many disorders, but their use often is limited by toxicities, especially gastrointestinal and renal toxicity. COX-2 inhibitors are a major therapeutic advance, providing the analgesic and anti-inflammatory activity of NSAIDs, with a significant improvement in gastrointestinal safety. These new agents may be ideal therapies for older patients at risk for NSAID-related gastrointestinal toxicity.

Peritoneal dialysis: new developments and new problems.

AIMS: To ascertain the incidence of hyponatraemia, and the impact of an icodextrin-based dialysis solution regime on hyponatraemia, in diabetic and non-diabetic patients using peritoneal dialysis (PD). METHODS: Following severe hyponatraemia, resulting in neurological sequelae, in two diabetic patients who were on icodextrin-based PD for established renal failure, we reviewed the results of all our PD patients. Data was gathered retrospectively, from our database and case notes, on plasma sodium, haematocrit, dry weight estimation, plasma albumin and residual renal function. Patients using icodextrin-based solutions were compared with a random selection of patients using dextrose-based peritoneal solutions. We also compared diabetic patients on and off icodextrin with their non-diabetic counterparts using the same dialysis regime. The data were analysed using the paired Student's t-test. RESULTS: Plasma sodium was significantly lower in all patients using icodextrin-based solutions compared with those patients on dextrose-based PD. Plasma sodium was also found to fall in all patients following the initiation of an icodextrin-based PD regime. The fall in plasma sodium was statistically significant in diabetic and non-diabetic patients, but only fell below the laboratory reference range in the diabetic patients. CONCLUSIONS: Icodextrin-based PD is a risk factor for hyponatraemia and may produce clinically relevant symptoms if, as in our two cases, the hyponatraemia is compounded by other factors.

Maternal repression of the human GRB10 gene in the developing central nervous system; evaluation of the role for GRB10 in Silver-Russell syndrome.

The GRB10 gene encodes a growth suppressor and maps to human chromosome 7p11.2-p13. Maternal duplication (matdup) of this region has recently been associated with Silver-Russell syndrome (SRS), which is characterised by pre- and postnatal growth restriction, craniofacial dysmorphism and lateral asymmetry. Maternal uniparental disomy for chromosome 7 (mUPD7) occurs in approximately 7% of SRS patients. Exposure of a recessive allele due to isodisomy has been ruled out in five mUPD7 cases, suggesting genomic imprinting as the basis for disease. Assuming SRS patients with matdup of 7p11.2-p13 and mUPD7 share a common aetiology, this would implicate a maternally expressed gene from this interval, which is involved in growth inhibition. Murine Grb10 was identified as a maternally expressed gene by subtractive hybridisation using normal and androgenetic mouse embryos. Grb10 maps to the homologous region of proximal mouse chromosome 11, for which mUPD incurs reduced birthweight. A role for GRB10 in SRS was evaluated by determining its imprinting status in multiple human foetal tissues using expressed polymorphisms, and by screening the coding region for mutations in 18 classic non-mUPD7 SRS patients. Maternal repression of GRB10 was observed specifically in the developing central nervous system including brain and spinal cord, with biallelic expression in peripheral tissues. This is in contrast to mouse Grb10, and represents the first example of opposite imprinting in human and mouse homologues. While a role for GRB10 in mUPD7 SRS cases can not be ruled out on the basis of imprinting status, no mutations were identified in the patients screened.

Membranous nephropathy, hydrocarbon exposure and genetic variants of hydrocarbon detoxification.

Modulation of biotransformation by genetic traits may be important in determining environmentally-induced nephrotoxicity. We conducted a case-control study to investigate the role of occupational hydrocarbon exposure, along with polymorphisms of the genes coding for N-acetyltransferase 2 (NAT2) and glutathione S-transferase mu (GSTmu), in the development of idiopathic membranous glomerulonephritis (IMGN). Patients (n=36) with biopsy-proven IMGN were matched with healthy controls for age, gender, and geographical area. Lifetime hydrocarbon exposure was assessed by a validated questionnaire. The polymorphisms of the NAT2 and GSTmu genes (GSTM1) were defined by use of a polymerase chain reaction on white-cell DNA from peripheral blood. Exposure to hydrocarbons was significantly greater in patients with IMGN than in controls (mean+/-SEM hydrocarbon exposure score 11 003+/-2955.7 vs. 4352+/-1418, p<0.02). NAT2 acetylator status was identical in patients and controls with 23 (63.9%) fast and 13 (36.1%) slow acetylators in each group. GSTmu was present in 15 (41.7%) patients and 16 (44.4%) controls. While occupational exposure to hydrocarbons remains a likely factor in its pathogenesis, further work is required to identify the genetic polymorphisms that modulate the risk of IMGN.

Substance abuse and the kidney.

Substance abuse has been increasing steadily in the UK and some other countries. Recent evidence suggests more than 40% of young people have tried illicit drugs at some time. There are numerous medical consequences to recreational drug use, and a physician should always consider substance abuse in any unexplained illness. The renal complications of drug abuse are also becoming more frequent, and may encompass a spectrum of glomerular, interstitial and vascular diseases. Although some substances are directly nephrotoxic, a number of other mechanisms are also involved. These effects are often chronic and irreversible, but occasionally acute with possible recovery. The rapid growth of illicit drug use is clearly a major public health problem. We review the commonly used substances of abuse and their associations with renal disease.

Pregnancy does not adversely affect renal transplant function.

Women with functioning transplanted kidneys often become fertile again. Indeed, renal function, endocrine status and libido rapidly improve after renal transplantation, and 1:50 women of childbearing age become pregnant. However, there is concern regarding the haemodynamic changes of pregnancy, which could lead to a decline in graft function (temporary or permanent). We examined obstetric data and renal parameters in 29 patients and 33 pregnancies. Mean serum creatinine and creatinine clearance remained stable throughout pregnancy and 1 year postpartum. However, there was a significant increase in proteinuria from a mean of 0.45 g/24 h around the time of conception to 1.11 g/24 h at delivery (p<0.05). The proteinuria resolved to baseline levels at 3 months postpartum. We highlight certain parameters to be considered before conception to allow a good obstetric outcome and prolong stable renal function: serum creatinine <150 micromol/l, proteinuria <1 g/day, absence of histological evidence of chronic allograft rejection, controlled blood pressure (140/90) and stability of maintenance immunosuppression.

Biomarkers in occupational volatile organic chemical exposure.

Evidence exists that in certain groups of workers exposed to volatile organic chemicals, there is subclinical renal damage and dysfunction. Also, there is activation of biological mechanisms that are suggested links between volatile organic chemical exposure and renal disease. Notably, the workers studied are employed in factories where exposures are considered controlled, with on-site professional health and safety management. Recent studies continue to indicate an increased risk of renal disease in those exposed to volatile organic chemicals.

CD2-mediated activation of the Tec-family tyrosine kinase ITK is controlled by proline-rich stretch-4 of the CD2 cytoplasmic tail.

Ligation of the CD2 co-stimulatory receptor on human T lymphocytes induces tyrosine phosphorylation and activation of the Tec-family tyrosine kinase, ITK. To examine whether any of several proline-rich (PR) stretches of the CD2 cytoplasmic tail are necessary for ITK activation we introduced wild-type and mutated versions of rat CD2, each missing at least one PR stretch of the tail, into human Jurkat T leukemia cells. The influence of cytoplasmic tail mutations was then studied following stimulation of transfectants with the rat CD2 mAb pair, OX54/OX55. As predicted, wild-type rat CD2 was able to activate ITK in Jurkat cells. In addition, a truncation mutant, lacking the most membrane-distal PR stretch, PR6, was able to activate ITK. By contrast, all other studied truncation mutants, each of which is missing at least PR4-PR6, were unable to induce ITK activation. Of deletion mutants, deletion of the membrane-proximal PR stretches, PR1-PR3, did not impair rat CD2-mediated ITK activation. However, additional deletion of PR4 from a tail missing PR1 and PR2, deletion of PR2 and PR4, and deletion of PR4 alone from rat CD2 abrogated an ability to activate ITK. Thus, these results identify PR4 as an element of the CD2 tail that is required for activation of ITK. Furthermore, we show that, unlike wild-type rat CD2, PR4-deleted rat CD2 is unable to induce IL-2 secretion from Jurkat cells. This is consistent with the view that PR4-mediated activation of ITK is important for downstream signaling events induced by CD2 co-stimulation.

Occupational hydrocarbon exposure and nephrotoxicity: a cohort study and literature review.

Hydrocarbon exposure has been shown to play an important role in the development of renal dysfunction in several occupational settings. In this study, renal screening was performed in a group of paint sprayers with exposure to hydrocarbon-based paints, recruited from a car manufacturing plant where personal protective equipment was widely used. The hydrocarbon exposure scores and various markers of renal injury were compared between these subjects and a group of paint sprayers from a previous study who did not use personal protective equipment regularly. Cumulative hydrocarbon exposure scores were calculated from a validated questionnaire. Serum creatinine, urinary total protein, albumin, transferrin, retinol-binding protein, and N-acetylglucosaminidase were evaluated, Both groups experienced heavy hydrocarbon exposure but sprayers who regularly used personal protective equipment had significantly reduced exposure scores due to improved skin and respiratory protection. A significant number of sprayers from both groups had elevated levels of serum creatinine. Interestingly, urinary N-acetylglucosaminidase activity, a marker of proximal tubular damage, was abnormal in a significant proportion of sprayers in the unprotected group but normal in those with improved protection. Our results are in keeping with the hypothesis that hydrocarbon exposure through paint spraying may result in active proximal tubular damage which may be reduced by improvement of protection at the worksite. However, renal impairment independent of tubular injury may result from chronic paint exposure, even with improved protection.

Chronic bronchiectasis and anti-myeloperoxidase antibody related rapidly progressive necrotizing glomerulonephritis.

We reported two cases of chronic bronchiectasis and rapidly progressive necrotizing glomerulonephritis/severe renal failure which were also positive for anti-myeloperoxidase antibody, and followed their treatment and outcome. Immunosuppressive therapy was complicated by superimposed chest infection in both cases. Nonetheless, cautious use of immunosuppressive and antibiotic therapy reversed dialysis-dependent renal failure in one of the two cases.

A case of hepatitis B in a haemodialysis unit.

A patient probably acquired hepatitis B virus (HBV) from a transfused infected unit of fresh frozen plasma. She had been on regular haemodialysis for four months before her infection was discovered. One hundred and seventy-six patients and 304 staff contacts were screened and there were no secondary cases. At donation the infected blood donor was hepatitis B surface antigen (HBsAg) negative but subsequently proved to be anti-hepatitis B core (HBc)-positive and positive for HBV DNA. Consideration should be given to screening blood donations for anti-HBc in addition to HBsAg. Vigilance needs to be maintained on dialysis units against sporadic cases of hepatitis B. All staff should be immunized and be able to demonstrate protective levels of anti-HBs.