Julian R. Waller

Randomized clinical trial of the effect of microemulsion cyclosporin and tacrolimus on renal allograft fibrosis.

The aim of this study was to compare the effect of Neoral® cyclosporin‐ and tacrolimus‐based therapy on the development of renal allograft fibrosis (chronic allograft nephropathy; CAN) in a prospective randomized trial.

Living kidney donation: a comparison of laparoscopic and conventional open operations.

Laparoscopic donor nephrectomy has the potential to lessen the burden placed on live kidney donors. This study describes the first British comparison of donor morbidity and recovery following conventional open donor nephrectomy (ODN) and laparoscopic donor nephrectomy (LDN). An initial series of LDN (n=20) was compared to a historical control group of ODN (n=34). Laparoscopic operations were performed via a transperitoneal approach, the kidney being removed through a 6–12 cm Pfannensteil incision. Open operations were performed using a retroperitoneal flank approach with resection of the 12th rib. Postoperatively, donors were managed with a patient controlled analgesia system. LDN was associated with shorter mean (SD) inpatient stay (6 (2) v 4 (1) days; p=0.0001) and lower parenteral narcotic requirements (morphine 179 (108) v 67 (54) mg; p=0.0001). Laparoscopic donors started driving their cars sooner (2 (1.5) v 6 (4) weeks; p=0.0001) and returned to work more quickly (5 (3) v 12 (6) weeks; p=0.0001) than open nephrectomy donors. There were no differences in recipient serum creatinine levels at three months post-transplant but two recipients of transplant kidneys retrieved laparoscopically (10%) developed ureteric obstruction, whereas this complication did not occur after ODN (p=0.13). LDN is associated with less postoperative pain and a substantial improvement in donor recovery times. It is not yet clear whether or not the outcome of the recipient kidney transplants are the same after ODN and LDN and much more experience is required before the place of this new technique can be defined.

The surgical management of peritoneal dialysis catheters.

Peritoneal dialysis is a safe and effective form of renal-replacement therapy. Its use is increasing as the gap widens between the number of patients waiting for renal transplants and the number of available organs. This article reviews the surgical considerations and complications of peritoneal dialysis that may present to general surgeons.

Fibrosis-associated gene expression in renal transplant glomeruli after acute renal allograft rejection.

Acute allograft rejection is thought to be a risk factor for chronic allograft nephropathy, the cardinal features of which are vasculopathy, interstitial fibrosis and glomerulosclerosis. Fibrosis‐associated genes might act as ad interim surrogate markers for chronic allograft nephropathy. The aim of this study was to determine mRNA expression of fibrosis‐associated genes in glomeruli plucked from protocol renal transplant biopsies, in patients with or without a history of acute rejection.

PROGRAF PRODUCES A MOLECULAR ENVIRONMENT FAVOURING ANTIFIBROSIS, AN EFFECT REVERSED BY THE ADDITION OF RAPAMUNE

Rapamune, an inhibitor of the mammalian target of rapamycin, exhibits antiproliferative actions and is increasingly used as adjuvant therapy with calcineurin inhibitors. This study investigated the effect of Rapamune on functional and molecular markers in a rat model of calcineurin inhibitor-induced graft dysfunction. Prograf (6 mg), with or without addition of Rapamune (1 mg), was administered to salt-depleted male rats (n = 6/group). Urinary protein excretion and serum creatinine were measured. Rats were culled at 28 days, and messenger RNA expression of TGF-beta, MMP-2, MMP-9, TIMP-1, and collagen III was evaluated with reverse transcriptase polymerase chain reaction. Serum creatinine increased with Prograf (P = .01), but not Rapamune (P = .69) treatment, compared to controls at 28 days. The combination of Rapamune and Prograf produced a rise in serum creatinine at 7 (P = .007) and 14 (P = .01) days, but this was not observed at later time points. Urinary protein excretion was unaltered by any drug or combination. While confirming a synergistic effect of Rapamune and calcineurin inhibitors on renal function, these results suggest that sole therapy with Prograf produces inhibition of fibrotic gene expression. Rapamune alone has no deleterious effect on gene expression but addition of Rapamune cancels out the beneficial effects of Prograf.

MYCOPHENOLATE MOFETIL INHIBITS INTIMAL HYPERPLASIA AND ATTENUATES THE EXPRESSION OF GENES FAVOURING SMOOTH MUSCLE CELL PROLIFERATION AND MIGRATION

AIM Intimal hyperplasia remains the leading cause of late graft failure following heart transplantation. The immunosuppressive drug mycophenolate mofetil has been shown to inhibit the development of intimal hyperplasia. This study aimed to assess the efficacy of a combination of mycophenolate mofetil, calcineurin inhibition, and sirolimus on the development of intimal hyperplasia. METHODS Male Sprague-Dawley rats received mycophenolate mofetil (30 mg/kg per day) and either tacrolimus (0.1 mg/kg per day), cyclosporine (5 mg/kg per day), or sirolimus (0.05 mg/kg per day) and were compared to an untreated control group. All animals underwent left common carotid artery balloon angioplasty. Morphometric analysis was performed on representative transverse sections, and intima medial ratios calculated at 2 weeks. Profibrotic gene expression was assessed with competitive RT-PCR at 2 weeks for metalloproteinase-2, metalloproteinase-9, TIMP-1, collagen III, and TGF-beta. Sections were stained with sirius red, and extracellular matrix deposition was quantified. RESULTS Mycophenolate mofetil in combination with rapamycin was associated with the greatest reduction in intimal thickening (intima medial ratio 0.79; range 0.45-0.86), compared to its combination with either cyclosporine (1.41; range 1.06-1.68, P < .02) or tacrolimus (0.93; range 0.81-1.37, P < .05) and controls (1.47; range 1.02-2.04, P < .005). Mycophenolate mofetil and rapamycin significantly inhibited all profibrotic genes studied compared to controls (P < .01) but there were no differences between tacrolimus and cyclosporine. Mycophenolate mofetil and sirolimus significantly attenuated extracellular matrix deposition compared to tacrolimus and cyclosporin (P < .023). CONCLUSION The benefits of mycophenolate mofetil in combination with sirolimus are preferential over those with cyclosporine or tacrolimus. Randomised trials are warranted to assess if mycophenolate mofetil should be an alternative agent to calcineurin-inhibitors when used in combination with sirolimus.