Randall J. Faull

Tubular expression of intercellular adhesion molecule-1 during renal allograft rejection.

Molecules responsible for adhesion between cells are known to play an important role in the immune response. The expression of one of these molecules, intercellular adhesion molecule-1 (ICAM-1), was examined on normal and allografted kidneys using a specific monoclonal antibody and an indirect immunoperoxidase technique. The expression of this molecule was compared to that of HLA class II antigens. On normal kidneys and most allograft biopsies taken immediately before implantation, ICAM-1 was expressed only on vascular endothelial cells (VEC) and parietal epithelium of Bowmans capsule. In the 11 kidneys where biopsies were available before and after transplantation, the appearance of rejection was associated with de novo expression of ICAM-1 on renal tubular epithelial cells that closely paralleled that of HLA class II antigens. In addition, an increase in endothelial cell expression of these molecules was also seen in rejection. In 23 random allograft biopsies, most of those with rejection showed tubular expression of both HLA class II antigens and ICAM-1. However, the presence of these molecules on tubules in several biopsies that did not show rejection limits the clinical usefulness of monitoring these antigens in posttransplant biopsies. The upregulation of these molecules is presumed to be secondary to the release of cytokines by cells infiltrating the allograft, although other mechanisms may be operating that explain the expression of these molecules in nonrejecting grafts.

Laparoscopic placement of peritoneal dialysis catheters: 7 years experience

Background:  Since 1994 we have placed all peritoneal dialysis (Tenckhoff) catheters at our hospital laparoscopically using a technique that incorporates suture fixation into the pelvis. The purpose of this study was to determine the long‐term outcome of this approach.

Endothelial cell activation in vasculitis of peripheral nerve and skeletal muscle.

To clarify the role of endothelial cells in the pathogenesis of vasculitis affecting peripheral nerve and skeletal muscle, the endothelial expression of adhesion molecules and major histocompatibility antigens (MHC) in different vasculitic syndromes were studied, and related to the presence of anti-endothelial cell antibodies (AECA). Increased expression of the intercellular adhesion molecule ICAM-1 in vasculitic lesions in nerve and muscle was shown, and this was associated with increased expression of MHC class I and II antigens. AECA were detected in low titre in only a minority of patients. The findings suggest that endothelial cells have a critical role in mediating the tissue injury in vasculitis affecting nerve and muscle and that the process is triggered by cellular and not antibody-mediated mechanism in the majority of patients.

A novel activating anti-β1 integrin monoclonal antibody binds to the cysteine-rich repeats in the β1 chain

The functional status of an integrin depends on the conformation of its extracellular domain, which is controlled by the cell expressing that receptor. The transmission of regulatory signals from within the cell is considered to be via propagated conformational changes from the receptors cytoplasmic tails to the extracellular ligand binding “pocket.” The end result is increased accessibility of the ligand binding pocket in the high affinity (“active”) form of integrins. We report a novel monoclonal antibody (QE.2E5) that binds within the cysteine-rich repeats in the integrin β1 chain and induces high affinity binding of fibronectin to the integrin α5β1. The QE.2E5 epitope is located approximately 200 residues both from the predicted binding site for fibronectin and from the epitopes recognized by other activating anti-β1 monoclonal antibodies. It is also expressed on β1 integrins from a number of nonhuman species. Although they have the same functional effects, the binding of QE.2E5 and another activating antibody (8A2) to the receptor have contrasting effects on the expression of an activation-dependent epitope in the β1 chain. We propose that the cysteine-rich repeats contain a regulatory region that is distinct from those previously described in the integrin β1 chain.

Using GI-specific patient outcome measures in renal transplant patients: Validation of the GSRS and GIQLI

Introduction: Gastrointestinal (GI) side-effects occur frequently as a result of immunosuppressant regimens used in renal transplant patients. Little effort has been made to quantify the impact of these side-effects on patients’ health-related quality of life and symptom severity. Objective: To assess the psychometric characteristics of two GI-specific outcome instruments (the Gastrointestinal Rating Scale (GSRS) and the Gastrointestinal Quality of Life Index (GIQLI)) for use in post-renal transplant patients. Methods: Cross-sectional study conducted at 5 clinical centers in 4 countries. Patients were required to be on mycophenolate mofetil and a calcineurin inhibitor. Patients completed the GSRS, GIQLI and two generic instruments (the Psychological General Well-Being Index and the EQ-5D) at one timepoint. Reliability, construct and known groups validity were assessed. Results: In general the GSRS and the GIQLI demonstrated Cronbach’s alphas higher than 0.70. The GIQLI was moderately to highly correlated with the PGWB and EQ-5D. Correlations among the GSRS and generic instruments were slightly lower. The GSRS and GIQLI both distinguished between patients with and without GI complaints (all p<0.05). Conclusions: The GSRS and the GIQLI are appropriate for use in a post-renal transplant population. Scores on both instruments demonstrated significant differences between renal transplant patients with GI complications and without GI complications.

Endogenous plasma carnitine pool composition and response to erythropoietin treatment in chronic haemodialysis patients

BACKGROUND Anaemia is a common complication associated with haemodialysis and is usually managed by treatment with recombinant human erythropoietin (rHuEPO). However, many patients remain hyporesponsive to rHuEPO treatment despite adequate iron therapy. The effect of L-carnitine administration on rHuEPO dose and/or haematocrit in haemodialysis patients has been previously reported with equivocal results. This study examined the relationship between endogenous carnitine pool composition and rHuEPO requirements in long-term haemodialysis patients. METHODS Pre-dialysis blood samples were collected from 87 patients and analysed for plasma L-carnitine and individual acylcarnitine levels by LCMS/MS. As an indication of rHuEPO responsiveness, erythropoietin resistance index (ERI) was calculated as rHuEPO dose/kg/week normalized for haemoglobin levels. RESULTS A significant negative correlation between L-carnitine levels and ERI was found (P = 0.0421). All patients categorized as high ERI (>0.02 microg/kg/week/gHb) exhibited subnormal L-carnitine levels (<30 microM); conversely, patients with normal L-carnitine levels (>30 microM) displayed low ERI values (<0.02 microg/kg/week/gHb). More importantly, the ratio of non-acetyl acylcarnitines/total carnitine was significantly positively correlated with ERI (P = 0.0062). CONCLUSIONS These data illustrate the relationship between carnitine levels and response to rHuEPO treatment in haemodialysis patients, in particular, the importance of the proportion of long-chain acylcarnitines within the plasma carnitine pool. This proportion may be more indicative of the response to L-carnitine supplementation than absolute L-carnitine levels alone.

Management of Bone Disease, Calcium, Phosphate and Parathyroid Hormone

(Suggestions are based on Level III and IV evidence) • Vitamin D therapy should be avoided when serum phosphate and/or calcium levels are significantly elevated, in order to reduce the risk of further elevation of calcium ¥ phosphate product and excess vascular and extravascular calcification. • Patients on vitamin D therapy must have regular monitoring of serum calcium, phosphate and PTH levels. • Oral calcitriol is effective for prevention or treatment of hyperparathyroidism in most patients on haemodialysis (HD) or peritoneal dialysis (PD). • Oral calcitriol can be effectively used either daily or less frequently as pulsed therapy, although there is insufficient evidence to say that the latter is superior to the former, either in terms of lowering PTH or reducing adverse effects. • Intravenous calcitriol may be more effective at lowering PTH levels and be less likely to cause hypercalcaemia, but the lack of well-designed studies of sufficient size prevent a more definitive statement. • Consideration may be given to using intravenous calcitriol when high PTH levels are resistant to oral calcitriol, or if patient compliance with self-administered oral calcitriol is in doubt. • Vitamin D analogues are effective at lowering PTH, but human studies proving their effectiveness with fewer side-effects (hypercalcaemia and/or hyperphosphataemia) are either lacking or are not definitive. On the basis of current evidence, there is little reason to recommend their use over either conventional oral calcitriol or intravenous calcitriol. • Use of alternatives to oral calcitriol (intravenous or the vitamin D analogues) needs to be balanced against their significantly higher costs.

Transmission of toxoplasmosis in two renal allograft recipients receiving an organ from the same donor

Abstract: Toxoplasma gondii is a ubiquitous protozoan parasite. After acute infection it continues to exist as cysts in the muscles and brain. Recipients of organ allografts are susceptible to the disease as a result of reactivation of quiescent infection either by transmission from the organ donor or by consumption of undercooked meat. We describe 2 cases of fatal toxoplasmosis in renal allograft recipients who received their organs from the same cadaveric donor. Both recipients died 5 weeks after renal transplantation, within days of each other. Multiorgan involvement with toxoplasmosis was demonstrated at autopsy. No evidence of the parasite was found in the transplanted kidney, either at the time of insertion or at autopsy. Neither recipient had serologic evidence of previous exposure to T. gondii. The donor had positive IgG but indeterminate IgM antibodies suggesting acute infection at the time of death; there was no clinical suspicion that the donor died from acute toxoplasmosis. We conclude that toxoplasmosis was transmitted by the donor kidneys. In an attempt to minimize the possibility of future transmission, donors are now tested for anti‐toxoplasma IgM antibodies and recipients are treated with trimethoprim/sulfamethoxazole for the first 6 months after renal transplantation.

Impact of haemodialysis on individual endogenous plasma acylcarnitine concentrations in end-stage renal disease

Background: Patients with end-stage renal disease (ESRD) undergoing long-term haemodialysis exhibit low L-carnitine and elevated acylcarnitine concentrations. This study evaluated endogenous concentrations of an array of acylcarnitines (carbon chain length up to 18) in healthy individuals and ESRD patients receiving haemodialysis, and examined the impact of a single haemodialysis session on acylcarnitine concentrations. Methods: Blood samples were collected from 60 healthy subjects and 50 ESRD patients undergoing haemodialysis (pre- and post-dialysis samples). Plasma samples were analysed for individual acylcarnitine concentrations by electrospray MS/MS. Results: Of the 31 acylcarnitines, 29 were significantly (P<0.05) elevated in ESRD patients compared with healthy controls; in particular, C5 and C8:1 concentrations were substantially elevated. For acylcarnitines with a carbon chain length less than eight, plasma acylcarnitine concentrations decreased significantly over the course of a single dialysis session; however, post-dialysis concentrations invariably remained significantly higher than those in healthy subjects. Dialytic removal of acylcarnitines diminished once the acyl chain length exceeded eight carbons. Conclusions: The accumulation of acylcarnitines during long-term haemodialysis suggests that removal by haemodialysis is less efficient than removal from the body by the healthy kidney. Removal is significantly correlated to acyl chain length, most likely due to the increased molecular weight and lipophilicity that accompanies increased chain length.

Clozapine-induced acute interstitial nephritis

Drug hypersensitivity reactions commonly cause acute interstitial nephritis (AIN). Clozapine, a new antipsychotic, can cause fatal bone-marrow toxicity. We report clozapine-induced AIN as another serious adverse drug reaction.