Randomized clinical trial of laparoscopic versus open donor nephrectomy.

BACKGROUND: This randomized controlled trial was designed to determine the safety and efficacy of laparoscopic donor nephrectomy (LDN) in comparison with short-incision open donor nephrectomy (ODN). METHODS: Eighty-four live kidney donors were randomized in a 2 : 1 ratio to LDN (56 patients) or short-incision ODN without rib resection (28). Primary endpoints were pain relief and duration of inpatient stay. RESULTS: There was no donor death or allograft thrombosis in either group. The first warm ischaemic time median (range) 4 (2-7) versus 2 (1-5) min; P = 0.001) and the duration of operation (160 (110-250) versus 150 (90-200); P = 0.004) were longer for LDN. LDN led to a reduction in parenteral morphine requirement 59 (6-136) versus 90 (35-312) mg; P = 0.001) and hospital stay (4 (2-6) versus 6 (2-9) days; P = 0.001), and earlier return to employment (42 (14-84) versus 66.5 (14-112) days; P = 0.004). Postoperative respiratory function was improved after LDN. There were more postoperative complications per donor in the ODN group (0.6(0.7) versus 0.3(0.5); P = 0.033). At a median follow-up of 74 months, there were no differences in renal function or allograft survival between the groups. CONCLUSION: LDN removes some of the disincentives to live donation without compromising the outcome of the recipient transplant.

Tunnelled catheters for the haemodialysis patient.

Haemodialysis depends upon the establishment of a durable means of vascular access. Although the creation of a successful arterio-venous Fistulae (AVF) is the ideal, this is not always possible or practical. Tunnelled catheters play an important role as an interim/bridge technique for emergency access or while an AVF matures, but may be associated with significant morbidity. The aim of this review is to highlight recent evidence based developments in tunnelled catheters, including methods of placement, complications and possible management strategies.

Preservation solutions for solid organ transplantation.

Solid organ transplantation was one of the greatest medical advances of the 20th century. Current preservation technology falls short of maintaining organs ex vivo in perpetuity. This review examines the biochemical basis of organ degradation in response to ischaemia, preservation solution composition and potential future organ preservation technology.

Pre-incision infiltration of local anesthetic reduces postoperative pain with no effects on bruising and wound cosmesis after thyroid surgery.

Optimizing postoperative pain control is an important aspect in perioperative patient care. The aim of this study was to investigate the efficacy of preincision local anesthetic infiltration in postoperative pain management for thyroid surgery and its relationship to bruising and wound cosmesis. In a randomized single-blinded study, 39 consecutive patients listed for thyroid surgery were assigned into two groups. Group I (n = 19) received subcuticular preincision infiltration with 10 ml of bupivacaine (0.5%) and Group II (n = 20) received no infiltration. Postoperatively, the pain experienced was evaluated by two methods: verbal response scores and linear analogue scores (0-100 mm) at different time intervals following surgery. Bruising and cosmetic effects resulting from surgery were assessed using a linear analogue score at discharge. The two groups were well matched for confounding variables. Pain scores were significantly different at 6 hours post operatively (p = 0.0341) with mean scores Group I = 33 and Group II = 50, but this difference disappeared at 24 hours. No patients (0%) received IV morphine in Group I compared to 5 patients (25%) in Group II. There was no significant difference in the mean bruising scores (p = 0.8864) and mean cosmetic scores (p = 0.3339) at discharge. Preincision infiltration with bupivacaine provides easy and better analgesic control postoperatively in patients following thyroid surgery with no effects on bruising or wound cosmesis.

Evaluation of daclizumab to reduce delayed graft function in non-heart-beating renal transplantation: a prospective, randomized trial.

Daclizumab (DZB), an interleukin-2 receptor blocker, has been shown to reduce the rate of acute rejection, while non-heart-beating kidney recipients have high rates of delayed graft function that may be prolonged by high levels of calcineurin inhibitors. This study assessed whether DZB could safely replace calcineurin inhibitors in the immediate postoperative period and promote recovery from ischemic acute tubular necrosis. Patients were randomized into one of two groups: DZB induction and daily mycophenolate mofetil (MMF; 2 g) with steroids (20 mg prednisone) or standard triple therapy with tacrolimus, MMF, and prednisone. Patients in the DZB arm were converted to the control arm when either the serum creatinine dropped to <350 micromol/L or there was biopsy evidence of acute rejection. Over 2 years, Leicester and Newcastle non-heart-beating donor (NHBD) centers recruited 51 patients. There was one patient death in the DZB arm, during the study period, after a nonfunctioning graft was removed. A total of two (8%) grafts in the DZB arm and three (11.5%) grafts in the control arm failed to function. The overall rate of immediate function improved from around 5% (pre-2001) to 28%. There were no significant differences in the incidence of acute rejection or graft function (GFR) at 3 months. Machine-perfused kidneys in DZB-treated recipients had the highest rates of immediate function (53%, P = .015). We found that a calcineurin-sparing regime is safe and may be beneficial for recipients of machine-perfused grafts damaged by warm ischemia.

Prograf produces a molecular environment favoring 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.

The novel antifibrotic agent pirfenidone attenuates the profibrotic environment generated by calcineurin inhibitors in the rat salt-depletion model.

Calcineurin inhibitors (CNIs) promote fibrosis in renal allografts by altering the dynamics of extracellular matrix (ECM) turnover. Graft structure is changed and functional disturbance may follow. This study examined the effects of an antifibrotic agent, pirfenidone, on functional, structural, and molecular markers of fibrosis in a rat model. Cyclosporine or tacrolimus were administered to salt-depleted rats, with or without varying doses of pirfenidone. Both CNIs increased serum creatinine, and pirfenidone attenuated this functional disturbance. No changes in urinary protein excretion or graft histology were observed, suggesting structural and functional alterations can be dissociated. Messenger RNA expression of pro- and antifibrotic genes affecting ECM was estimated with semiquantitative RT-PCR. Cyclosporine-induced increases in collagen III mRNA expression were attenuated by pirfenidone (500 mg/kg/d), and increases in TIMP-1 expression were reversed by all doses of pirfenidone. Matrix metalloproteinase-2 expression was decreased by cyclosporine; all doses of pirfenidone significantly reversed this effect. Tacrolimus alone decreased TGF-beta and TIMP-1 expression, suggesting some antifibrotic action; addition of pirfenidone had no further effect. The mechanism of action of pirfenidone is reversal of some CNI-induced changes in fibrotic gene expression. It also attenuates creatinine rise in salt-depleted rats in this model of CNI-induced nephrotoxicity.

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.

Cyclosporine and rapamycin act in a synergistic and dose-dependent manner in a model of immunosuppressant-induced kidney damage.

The combination of cyclosporine (CSA) and rapamycin (RAPA) is a potent and commonly used approach to immunosuppression following solid-organ transplantation. By applying varying doses of CSA and RAPA to the rat salt-depleted model, we aimed to find a dose combination that favored antiproliferation/antifibrosis rather than toxicity. Male Sprague-Dawley rats (350 to 500 g) were salt-depleted for 7 days prior to commencing CSA and RAPA treatment. Serum creatinine and urinary protein/creatinine ratios were measured. Fibrosis was estimated with Sirius red staining of extracellular collagen. mRNA expression of TGF-beta, MMP-2, MMP-9, TIMP-1, and collagen III was assessed with reverse transcriptase PCR. A rise in serum creatinine at 7 and 28 days was observed for CSA 15 mg/kg/d (P = .002) but not CSA 7.5 mg (P = .06) or RAPA 1 mg (P = .69) compared to controls. Twenty-four-hour urinary protein excretion was unchanged compared to controls for all drug doses and combinations. Of the dose combinations, CSA 7.5 mg/d + RAPA 0.5 mg/d produced the lowest serum creatinine for all time points, and inhibited profibrotic TIMP-1 (P = .017), while increasing antifibrotic MMP-2 (P = .009) mRNA expression, compared to CSA treatment alone. Expression of TGF-beta and collagen III was unaltered between groups. CSA treatment produced molecular and biochemical changes indicating renal damage. Addition of RAPA can attenuate this damage, but only with a dose reduction of both agents. The most favorable results were for the dose combination CSA 7.5 mg/kg/d plus RAPA 0.5 mg/kg/d.

Alterations in the practice of open and laparoscopic live donor nephrectomy at renal transplant centers in the UK and Ireland.

Live kidney donor (LKD) activity has increased over recent years. In response, the British Transplantation Society (BTS) has issued guidelines for best practice. This study involved two questionnaires sent to all renal transplant centers in the UK and Ireland to examine practice for the years 2000 and 2002. Findings were compared to BTS guidelines. There was a 100% response rate from 28 centers for both years. Twenty-seven centers performed LKD in the year 2000, falling to 24 in 2002. Consultants reported 356 procedures in 2000, representing 19% of all kidney transplants, and 403 in 2002, representing 23% of all kidney transplants. Three centers offered laparoscopic donor nephrectomy in 2000, and five did so in 2002. The majority of centers organize donor and recipient operations synchronously, and most have a consultant anaesthetist present for the donor procedure. There were variations in the use of thromboprophylaxis, and in donor follow-up. There is widespread practice of live kidney donation in the UK and Ireland, but BTS guidelines are not closely adhered to. Laparoscopic donor nephrectomy is offered at a small number of centers, but many have plans to introduce it.

Laparoscopic donor nephrectomy yields kidneys with structure and function equivalent to those retrieved by open surgery.

The technical challenges of laparosopcic transperitoneal donor nephrectomy (LapDN) have raised concerns over the quality of the procured allografts. This study reports the anatomical and functional outcomes of kidneys retrieved from 60 live donors entered into a randomized controlled trial of open versus laparoscopic procurement. Open and laparoscopic donors were well matched for age (P = .18) and body mass index (P = .49). Operating time (P = .0001) and first warm ischaemic time (P < .001) were longer for the laparoscopic donors but total warm time was not different (P = .52). Left renal vein length (P = .14) and left renal artery length (P = .38) were similar. No differences in right vessel length were observed. Rates of acute rejection did not differ, and recipient renal function was similar in the two groups. This study demonstrates that LapDN yields kidneys that are structurally and functionally equivalent to those acquired by the open operation. This data may go some way towards allaying concerns over the effect of laparoscopic procurement on live donor kidneys.

A consecutive series of 70 laparoscopic donor nephrectomies demonstrates the safety of this new operation.

Laparoscopic donor nephrectomy (LDN) has the potential to overcome some of the disincentives to living kidney donation. This study presents the results of a consecutive series of 70 LDN from a single center with an emphasis on postoperative complication rates and donor recovery times. There was no selection bias based on donor body mass index or because of difficult vascular anatomy. All donors received postoperative analgesia using a patient-controlled system and returned to activities and employment at their discretion. There was no donor mortality and no episode of thromboembolic disease. One operation was converted from open to LDN because of renal artery bleeding. Postoperative complications encompassed chest infection (6%), unilateral pulmonary edema (3%), ileus (3%), wound infection (3%), paraesthesia of L1 (4%), testicular pain (3%), persistent wound pain (1.4%), and reoperation for division of adhesions (3%). In conclusion, LDN is a safe procedure with low postoperative morbidity. There were some unexpected complications, but recovery time was short.

Randomized clinical trial of daclizumab induction and delayed introduction of tacrolimus for recipients of non-heart-beating kidney transplants.

BACKGROUND: Kidneys from non-heart-beating donors (NHBDs) have high rates of delayed graft function (DGF). Use of calcineurin inhibitors is associated with a reduction in renal blood flow, which may delay graft recovery from ischaemic acute tubular necrosis. METHODS: To assess whether daclizumab (DZB) could safely replace tacrolimus in the immediate postoperative period, patients were randomized to receive DZB induction and daily mycophenolate mofetil with steroids (DZB group) or standard tacrolimus-based triple therapy (control group). Tacrolimus was given to patients in the DZB group when the serum creatinine level dropped below 350 micromol/l. RESULTS: Fifty-one patients were recruited at two centres over a 2-year interval between 2000 and 2003. The overall rate of immediate function was 28 per cent (13 of 46 grafts), with the highest rate in recipients of machine-perfused kidneys treated with DZB (eight of 15 patients). CONCLUSION: Induction with DZB and delayed introduction of tacrolimus reduced the incidence of DGF in recipients of machine-perfused NHBD kidneys.

Comparison of renal allograft fibrosis after transplantation from heart-beating and non-heart-beating donors.

BACKGROUND: Renal transplants from non-heart-beating donors (NHBDs) yield acceptable function and allograft survival rates in the medium term. However, the long-term results are less certain and there is a paucity of information relating to the development of chronic allograft nephropathy. The aim of this study was to compare allograft fibrosis in kidneys transplanted from NHBDs and conventional heart-beating donors (HBDs). METHODS: A series of 37 NHBD and 75 HBD renal transplants were studied. Protocol renal transplant biopsies were performed at 6 and 12 months after transplantation. Biopsy sections were stained with Sirius red to demonstrate interstitial extracellular matrix. Renal allograft fibrosis was quantified using a computerized image analysis system. RESULTS: The mean first warm ischaemia time for kidneys from NHBDs was 24 min. A significant delay in graft function occurred in eight of 75 recipients in the HBD group and 31 of 37 in the NHBD group (P < 0.001). There were no significant differences in the level of allograft fibrosis between the two groups at any time point. CONCLUSION: Despite high rates of delayed graft function secondary to a prolonged warm ischaemia time, NHBD kidneys do not appear to be more susceptible to the development of renal allograft fibrosis. This study supports the growing body of evidence that kidneys from NHBDs are an acceptable alternative to those from HBDs.

A comparison of traditional open, minimal-incision donor nephrectomy and laparoscopic donor nephrectomy.

Laparoscopic donor nephrectomy (LDN) and minimal-incision donor nephrectomy (MILD) are less invasive procedures than the traditional open donor nephrectomy approach (ODN). This study compares donor and recipient outcome following those three different procedures. Sixty consecutive donor nephrectomies were studied (n = 20 in each group). Intra-operative variables, analgesic requirements, donor recovery, donor/recipient complications and allograft function were recorded prospectively. Operating and first warm ischaemia times were longer for LDN than for ODN and MILD (232+/-35 vs 121+/-24 vs 147+/-27 min, P < 0.001; 4+/-1 vs 2+/-2 vs 2+/-1 min, P < 0.01). Postoperative morphine requirements were significantly higher after ODN than after MILD and LDN (182+/-113 vs 86+/-48 vs 71+/-45 mg; P < 0.0001). There was no episode of delayed graft function in this study. Donors returned to work quicker after LDN than after ODN and MILD (6+/-2 vs 11+/-5 vs 10+/-7; P = 0.055). Donor and recipient complication rates and recipient allograft function were comparable. We concluded that MILD and LDN reduce postoperative pain and allow a faster recovery without compromising recipient outcome.

Prospective randomised trial of the use of Daclizumab in renal transplantation using kidneys from non heart beating donors.

OBJECTIVES: Transplantation using non-heart beating donors (NHBD) is one way of reducing the global kidney shortage. Unfortunately the large warm ischaemic insult sustained by the graft leads to a high rate of delayed graft function (DGF). We have investigated the use of a regimen utilising an II-2r blocker (DZB) in place of Tacrolimus for the initial post-operative immunosupression with the aim of reducing the incidence of DGF. METHODS: Prospective randomised controlled trial based in two NHBD UK centres (Leicester and Newcastle). 51 patients were enrolled over two years and randomised into two treatment arms: 1. DZB/MMF/Steroids (Tacrolimus started when creatinine dropped below 350 micromol/l) 2. Tacro/MMF/Steroids. RESULTS: There was one death, during the study period, in a patient who had had a non-functioning graft removed. The overall incidence of immediate function (IF) was higher than expected (28%), no significant difference was found in the incidence of immediate graft function between the two groups (35% group 1 and 22% group 2). Sub-group analysis however has shown a significant advantage for the delayed introduction of Tacrolimus for machine perfused grafts (IF: 53% vs 13%, chi2 p=0.015). There was no difference in the rate of rejection. CONCLUSIONS: The delayed introduction of Tacrolimus reduces the incidence of DGF in machine-perfused NHBD kidney transplantation.

An audit over 2 years' practice of open and laparoscopic live-donor nephrectomy at renal transplant centres in the UK and Ireland.

OBJECTIVE: To collate information on the practice of live-donor nephrectomy and compare this with the published British Transplantation Society (BTS) guidelines for best practice, using two questionnaires sent to all renal transplant centres in the UK and Ireland to cover practice for the years 2000 and 2002. METHODS: A postal questionnaire was sent to all surgical kidney transplant consultants in the UK and Ireland, including questions on the practice of live-donor nephrectomy in the year 2000 (the questionnaire was sent in 2001) and 2002 (questionnaire sent in 2003). RESULTS: All 28 centres responded fully for both years; 27 centres used live kidney donation in 2000, decreasing to 24 in 2002. Consultants reported 356 operations in 2000, representing 19% of all kidney transplants, and 403 in 2002, representing 23% of all kidney transplants. Three centres offered laparoscopic donor nephrectomy in 2000, and five did so in 2002. Most centres organize donor and recipient operations synchronously, and most have a consultant anaesthetist present for the donor procedure. There were variations in the use of analgesia and thromboprophylaxis, and in donor follow-up. CONCLUSIONS: There is widespread application of live-donor nephrectomy in the UK but BTS guidelines are not closely followed. Minimal access donor nephrectomy is offered at a few centres but many have plans to introduce this into their practice.

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

BACKGROUND: 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. METHODS: A consecutive series of 52 patients (31 male, 21 female) was assessed. Donor categories were cadaveric, living related or asystolic. Transplant recipients received either cyclosporin- or tacrolimus-based immunosuppression. Patients routinely underwent percutaneous needle-core renal transplant biopsy at 1 week, and 3 and 6 months. Acute rejection episodes were confirmed histologically and treated with intravenous methylprednisolone, or antithymocyte globulin if steroid resistant. Individual glomeruli were plucked and total mRNA was extracted. Fibrosis-associated genes were amplified by reverse transcriptase-polymerase chain reaction (PCR) and quantified by enzyme-linked immunosorbent assay. RESULTS: The expression of both collagen type III (mean 0.42 versus 0.31 arbitrary units of PCR products corrected for a housekeeping gene) and collagen IV (mean 0.46 versus 0.42 arbitrary units) at 6 months did not differ between recipients who experienced acute rejection episodes and those who were free from rejection. There was also no significant difference between groups in terms of mRNA expression of collagen IValpha2, matrix metalloproteinase 2, tissue inhibitor of matrix metalloproteinases 1 and 2, transforming growth factor beta or tenascin. CONCLUSION: These results suggest that acute rejection episodes do not increase the expression of fibrosis-associated genes in glomeruli from renal transplant biopsies.