Results of renal transplantation using kidneys harvested from living donors at the University of Heidelberg

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1 Nephrol Dial Transplant (2004) 19 [Suppl 4]: iv48 iv54 doi: /ndt/gfh1042 Results of renal transplantation using kidneys harvested from living donors at the University of Heidelberg Arianeb Mehrabi*, Manfred Wiesel*, Martin Zeier, Arash Kashfi, Peter Schemmer, Thomas Kraus, Markus W. Bu chler and Jan Schmidt Division of Kidney and Pancreas Transplantation and Department of General, Visceral and Transplant Surgery, University of Heidelberg, Germany Abstract Background. Although a majority of patients undergoing renal transplantation currently receive a cadaver kidney, living donors continue to be an important source of transplanted kidneys. Recipients of living donor kidneys demonstrate improved graft survival. To expand the pool of suitable organ donors an organ procurement programme of living donors has been developed over the past 35 years. We have reviewed our living donor nephrectomy experience over this period to analyse the donor and recipient peri- and postoperative morbidity and mortality rate. Methods. We reviewed the operative complications and the long-term outcome of 219 living donated kidney transplantations before and after introduction of cyclosporine A. Donor and graft complications as well as recipient complications and survival rate were investigated. Additionally, the findings of 16 laparoscopically operated living donors were compared to a group of 20 patients who underwent a conventional surgery. Results. The overall recipient 3 and 5 year survival rates in the cyclosporine A era were 95 and 94%, respectively. Prior to the introduction of cyclosporine A, the overall recipient survival rates at 3 and 5 years were 84 and 84%, respectively. The overall graft survival rates were 92 and 85% for the cyclosporine A era compared to 68 and 60% before introduction of cyclosporine A, at 3 and 5 years, respectively. The patient and graft survival rate in the cyclosporine group were significantly higher than in the precyclosporine group (log-rank: P ¼ and P ¼ , respectively). Donor complications included pain at the incision site (35%), mild hypertension *A.M. and M.W. have contributed equally to this work. Correspondence and offprint requests to: Priv.-Doz. Dr med. Jan Schmidt, Department of General, Visceral and Transplant Surgery, University of Heidelberg, INF 110, Heidelberg, Germany. jan_schmidt@med.uni-heidelberg.de (27%), proteinuria (19%), urinary tract infections (11%), pneumothorax (5%), blood transfusion (3.5%) and wound infection (3%), with no mortalities. Our results showed a longer duration of operation, and longer warm ischaemia and cold ischaemia times in laparoscopically operated living donors than those that were seen in the conventional approach. There was no statistically significant difference in complications between both techniques. However, the hospitalization days and usage of analgesic medication in laparoscopy donors were lower than in the conventional approach. Conclusions. Similar to previous studies the results of the present analysis confirm an increase in patient and graft survival rates in the cyclosporine era compared to before its usage. Living donor nephrectomy, done through a conventional or laparoscopic approach, remains a valuable source of kidneys for transplantation with low complication rates. Keywords: cyclosporine; kidney transplantation; laparoscopy; living donors; surgical approach; survival rate Introduction Although transplantation offers the best option for rehabilitation, many patients with end-stage renal disease (ESRD) do not have an opportunity for this type of treatment, mainly because of organ shortage. Cadaveric organ donations have reached a plateau which is far below the demand. Consequently, the number of ESRD patients on the transplant waiting lists is progressively increasing [1]. In an attempt to address the shortage of conventional brain-dead kidney donors, a living donation or non-heartbeating organ retrieval programme has been established by many kidney transplant centres [2 4]. To expand the pool of Nephrol Dial Transplant Vol. 19 Suppl 4 ß ERA EDTA 2004; all rights reserved

2 Living donor kidney transplantation at Heidelberg University in 35 years suitable organ donors, the University of Heidelberg has developed an organ procurement programme of living donation over the past 35 years. In many reports, it has already been shown that the living-related and unrelated kidney transplantations had better results than cadaveric transplantations [5 9]. Living kidney donors provided an alternative supply of organs, which increased our donor pool by 10% with an increasing tendency (currently 25%). Cyclosporine A is a potent immunosuppressive agent that has been used extensively in clinical renal transplantation. Treatment with cyclosporine after kidney transplantation has substantially improved graft survival [10 13]. However, there is a risk of nephrotoxicity and potential for graft loss from its chronic use. Although many reports do suggest that long-term cyclosporine does not lead to significant graft dysfunction, most of the benefits from cyclosporine therapy appear to result from a decrease in the number of acute rejection episodes during the first few months after transplantation [14]. The aim of this study was to present and compare the long-term results on survival and function of kidney transplantations harvested from living (related or unrelated) donors before and after cyclosporine introduction in a single centre. In addition, in a subgroup of donors the results of kidney harvesting were compared according to the surgical approach chosen (laparoscopic vs open). Subjects and methods The transplant histories of our living kidney donors as well as our recipients were analysed for patient and graft survival rates, and for technical and non-technical complications. Kidney transplantation at the University of Heidelberg From 1967 to 2003, 1561 adult and 354 paediatric kidney transplants were performed at the University of Heidelberg (Table 1 and Figure 1). For these recipients, 219 kidneys were procured from living and 1696 kidneys from brain-dead donors. Brain-dead donors were evaluated by the Deutsche Stiftung Organtransplantation (DSO) and distributed by the centre of Eurotransplant in Leiden. All of the cadaveric donors fulfilled the brain death criteria and consent from relatives had been obtained before procurement according to Eurotransplant rules. All families, according to the German law, were approached to know if the brain-dead relative was opposed to procurement. Donor population Figure 2 shows the living donor renal transplantations performed over the past decades. Of these 219 living donated kidney transplantations, 91.7% of patients received grafts from related and 8.3% from unrelated donors (male 30% and female 70%). In our living donation programme, in addition to the conventional approach, the kidney procurement was done in 16 cases by using a minimally invasive approach. Our donor population, which underwent a laparoscopic approach, is shown in Table 2. The mean age of living donors was 43.9 and the median was 43 years. Seventy-eight percent of the donors were in the 30- to 59-year-old range, with years as the most prevalent decade for living donation (32%). For living donation, donors (between 18 and 73 years old) were carefully evaluated for medical and psychological characteristics. Every effort was made to evaluate as many prospective donors as possible from the families, with the aim of identifying the most suitable donor. Donor distribution by related and unrelated individuals is shown in Figure 3. Exclusion criteria for organ donation were the presence of Table 1. Overview of all kidney transplants from 1967 to 2003 at the University of Heidelberg Adults Children (<18 years) iv49 Total Cadaveric donor Living donor Total Fig. 1. Overall kidney transplantations at the University of Heidelberg from 1967 to 2003.

3 iv50 A. Mehrabi et al. Fig. 2. Living donated kidney transplantations at the University of Heidelberg from 1967 to Table 2. Living donors basic data in the laparoscopic and conventional group Laparoscopic kidney procurement (n ¼ 16) Conventional kidney procurement (n ¼ 20) Mean age 41 (23 61) 43 (21 74) (years, range) Gender (m:f) 37.5:62.5% 25:75% Organ side 68.75/31.25% 60/40% (left/right) Access route 68.75/31.25% 95/5% (retrop./transp.) Multiple vessels 6.25% 30% median of 25 years. In our living donor recipients the causes of the primary renal failure are listed as follows: chronic glomerulonephritis 30%, kidney malformation 13%, chronic pyelonephritis 7%, nephronophtisis 7%, reflux nephropathy 7%, IgA nephropathy 5%, polycystic kidney 3%, diabetic nephropathy 2% and others (Alport syndrome, Prune-Belly syndrome, Goodpasture syndrome, Wegener s disease, systemic lupus erythematosus, oxalosis and amyloidosis) 26%. Most recipients were on dialysis prior to kidney transplantation with a mean of 24 months and a median of 12.5 months (haemodialysis 80%, continuous ambulatory peritoneal dialysis 20%). In recent years preemptive transplantation to avoid imminent haemodialysis was done in selected cases. m, male; f, female; retrop., retroperitoneal; transp, transperitoneal. Fig. 3. Donor distribution by family relationship in living donation for kidney transplantation. cancer, major cardiac or cerebrovascular disease not amenable to operation, liver disease or alcoholism, severe pulmonary disease, and a positive T-cell crossmatch. The reasons for donor refusal included anatomical reasons, obesity, mild hypertension, urinary tract infection, kidney stones, metabolic disease, peptic ulcer disease and prediabetic or diabetic stage. Recipient population The mean age of our recipients (male 59.8% and female 40.2%) were 27.4 years (between 2 and 72 years) with a Surgical technique The surgical methods for living donor organ harvesting, as well as the implantation of the procured grafts in our recipients were performed by a previously published technique [15]. For living donation, donor nephrectomies were performed using an open (flank or anterior) or a laparoscopic (hand-assisted or traditional) approach. Standard transplantation was performed using a Lich-Gregoire ureteroneocystostomy with a Double J insertion. In 2003, the use of Double J catheters was stopped. Immunosuppression and antibiotic prophylaxis Prior to the cyclosporine era, the initial immunosuppression was based on corticosteroids and azathioprine. Since 1983 cyclosporine has been integrated in the standard immunosuppression protocol. Between 1983 and 1995 we used a triple therapy consisting of cyclosporine (5 mg/kg), corticoids and azathioprine. Tacrolimus was introduced in 1994 and mycophenolate mofetil in Today our standard immunosuppression protocol consists of corticosteroids, cyclosporine and mycophenolate mofetil. Antibiotic prophylaxis consisted of ceftriaxone (1 2 g i.v. intraoperatively as a single shot and 1 2 g i.v. per day for 3 postoperative days), trimethoprim-sulphamethoxazole (160/800 orally per day

4 Living donor kidney transplantation at Heidelberg University in 35 years for 6 months postoperatively) to prevent urinary tract infections, and amphotericin B (4 10 mg orally) to prevent Pneumocystis carinii pneumopathy. Patients were routinely followed up each month during the first year and every 6 months thereafter. iv51 Statistics Statistical analysis of our results was performed with Kaplan Meier survival curves and compared by the logrank test. The t-test was used to test for difference between the open and laparoscopic donor operation. P<0.05 was considered as being significant. Results Patient and graft survival rates 80.5% of patients received kidney transplants from living donors in the cyclosporine A era (after 1983), while 19.5% patients were operated before introduction of cyclosporine A. The overall patient 3 and 5 year survival rates in the cyclosporine A era were 95 and 94%, respectively. Before using cyclosporine A, the overall patient survival rates at 3 and 5 years were 84 and 84%, respectively. The patient survival rate in our cyclosporine group was significantly higher than the pre-cyclosporine group (log-rank P ¼ ; Figure 4). In the above-mentioned transplantations, the overall graft survival rates were 92 and 85% for the cyclosporine A era compared to 68 and 60% prior to the introduction of cyclosporine A, at 3 and 5 years, respectively. The statistical comparison showed a significant difference in the graft survival after introduction of cyclosporine (log-rank P ¼ ; Figure 5). Perioperative donor data Perioperative findings in a subgroup of living donors are shown in Table 3 according to the laparoscopic or conventional surgical approach. Mean operation time, mean warm ischaemia times and cold ischaemia times were longer in the laparoscopic approach. The length of prepared renal artery and vein was longer in the Fig. 4. Estimated patient survival rate at the University of Heidelberg after living donor kidney transplantation before and after application of cyclosporine A (Cys A). Log-rank: P ¼ Fig. 5. Estimated graft survival rate at the University of Heidelberg after living donor kidney transplantation before and after application of cyclosporine A (Cys A). Log-rank: P ¼ Table 3. Perioperative findings of living donors in the laparoscopic and conventional group (mean and range) Operation time (min) Warm ischaemia time (min) Cold ischaemia time (min) Length of artery (cm) Length of vein (cm) Hospitalization (days) Laparoscopic kidney procurement (n ¼ 16) Conventional kidney procurement (n ¼ 20) 220 ( ) 124 (78 152) 4.3 (2 20) 1.4 (0.45 6) 165 (76 290) 118 (39 135) 3.13 ( ) 3.52 ( ) 3.63 ( ) 4.35 ( ) 6.1 (4 10) 10.2 (5 14) conventional approach. Mean hospitalization stay in our laparoscopic group was significantly shorter than in the conventional group (6.1 vs 10.2 days). Analgesic usage in the laparoscopy group was lower compared to our conventional group (Piritramid ml/patient: 44.6±47.4 vs 100.2±54.3), and additional analgesia was necessary in 18.75% of the laparoscopy group vs 45% of conventional patients. Postoperative donor complications The overall complication rate in our living donors was 14.4%. We did not encounter any mortality or renal failure. Of those 14.4%, subanalysis revealed scar pain in 35%, mild hypertension in 27%, proteinuria in 19%, urinary tract infection in 11%, pneumothorax in 5%, blood transfusion in 3.5% and wound infection in 3%. The findings of our subgroup of laparoscopically operated living donors (n ¼ 16) were compared to 20 conventionally operated donors. The surgical approach was converted in 12.5% (n ¼ 2) of laparoscopy operations to a conventional technique because of bleeding, and 6.3% (n ¼ 1) revisions were performed in the laparoscopic patients. 18.8% (n ¼ 3) of donors in our laparoscopy group needed blood transfusion,

5 ing for kidney transplantation has been seen. This has resulted in a critical shortage of donor organs that is the major limiting factor to expand the use of transplantation as the preferred therapeutic modality. The long waiting lists for cadaveric donors mandate finding of new resources to solve this shortage. Living donors, non-heartbeating donors and split kidney transplantation could potentially be the solution to overcome this problem. At this time, the split kidney transplantation is only in the experimental stages, but it has shown some promise for the future [20]. Despite a high rate of acute tubular necrosis, kidneys harvested from nonheartbeating donors had the same graft survival rates as those procured from heartbeating donors. Droupy et al. [21] have shown that the use of kidneys from non-heartbeating donors is not resulting in a higher rate of surgical complications compared to heartbeating donors. Many authors suggest that transplantation of selected kidneys procured from non-heartbeating donors should be promoted as a response to organ shortage [21 23], but living donor transplantation remains a valuable resource. The quality of life after living donor transplantation compares favourably to that seen in the general population [18,19]. In the present series, cadaveric transplantations accounted for 90% of all kidney transplantations, the remainder being from living donors. The recent increase in the use of living donors to more than 25% has been motivated, in part, by the long waiting times for cadaver organs, and is ethically justified by steadily improving outcomes for kidney transplant recipients. While living relatives are still the most common source of living donors, the number of transplants performed with living unrelated donors (e.g. spouse or friends) has dramatically increased during the past decade [19]. Allografts from living unrelated donors exhibit survival rates that exceed those from cadaver donors with equivalent degrees of human leukocyte antigen (HLA) matching, and approach those of zero-mismatched cadaveric donors [5 9,19,24 26]. As a result, an increasing number of transplantations involving grafts from living unrelated donors have been performed in recent years. The potential advantages of living vs cadaveric kidney donation include better short- and long-term results, more consistent early function and ease of management, avoidance of brain death stress, minimal incidence of delayed graft function, avoidance of long waiting for cadaveric transplants, capacity to time the transplantation for medical and personal convenience, performing transplantation at a time when the donor and recipient are both in optimal medical condition, sometimes less aggressive immunosuppressive regimen, relief of stress on national cadaveric donor supply, and emotional gain to the donor [24,27]. The living donors have minimal atherosclerosis and no hypertension or any other risk factors that many cadaver donors demonstrate. Minimized, or eliminated, are complications associated with donor haemodynamic instability (and the need for vasoactive pressors), technical injury to the kidney or its vasculature during organ procureiv52 compared to 5% (n ¼ 1) in the conventional group. The incidence of wound infection in laparoscopy and conventional groups was 6.3 (n ¼ 1) and 15% (n ¼ 3), respectively. 18.8% (n ¼ 3) of the patients in the laparoscopic approach had a decapsulation of the kidney due to preparation compared to only 5% (n ¼ 1) of the patients in the conventional group. Adrenal injury occurred in 6.25% (n ¼ 1) of the laparoscopy patients and intestinal injury occurred in 5% (n ¼ 1) using the conventional approach. The incidence of nerve injury in laparoscopy and conventionally operated patients was 12.5 (n ¼ 2) and 30% (n ¼ 6), respectively. These findings may represent in part the learning curve using the laparoscopic technique. Recipient follow-up and graft function With a follow-up period of 48 months in our subgroup recipients, 94 (n ¼ 15) and 85% (n ¼ 17) of laparoscopic and conventional approaches, respectively, had stable graft function. 18.8% (n ¼ 3) of laparoscopically and 10% (n ¼ 2) of conventionally harvested organs showed a reversible primary graft dysfunction after kidney transplantation. Graft rejection occurred in 16%. Revision surgery was performed in 6.3 (n ¼ 1) and 10% (n ¼ 2) of our recipients that received a laparoscopically and conventionally harvested kidney, respectively. Losses of the transplanted organ occurred in 10% (n ¼ 2) of our conventionally harvested group. Renal artery stenosis was observed in 6.3% (n ¼ 1) in our laparoscopically harvested group. Lymphocele was a problem in 25% (n ¼ 4) of the laparoscopically harvested group and 5% (n ¼ 1) of the conventionally harvested group. The mortality rates during the hospital stay in recipients with laparoscopically and conventionally harvested graft groups were 6.3 (n ¼ 1) and 5% (n ¼ 1), respectively. Serum creatinin concentration (mg/dl) during the follow-up period showed for both groups (laparoscopy vs conventional) a satisfactory decline (1st postoperative day: 8.0±1.7 vs 8.2±2.8; 7th postoperative day: 2.4±1.1 vs 2.2±7.4; 3rd postoperative month: 1.4±0.3 vs 1.5±0.4; 48th month: 1.3±0.3 vs 1.3±0.5). Discussion A. Mehrabi et al. For most patients with ESRD, kidney transplantation offers the greatest potential for restoring a healthy, productive life. Kidney transplantation provides a cost-effective option in comparison to dialysis after 4 years postoperatively [16]. Life satisfaction, physical and emotional well being, and the ability to return to work are all significantly better in transplant recipients than in dialysis patients. Transplantation may correct or improve some complications of uraemia that are typically not fully reversed by dialysis; these include anaemia, peripheral neuropathy, autonomic neuropathy and sexual dysfunction [17 19]. Due to standardization and availability of kidney transplantation a significant increase in patients wait-

6 Living donor kidney transplantation at Heidelberg University in 35 years ment, and renal injury caused by preservation. Warm ischaemia can essentially be eliminated and cold ischaemia is extremely short [27]. On the other hand, there are some potential disadvantages of living donation, such as psychological stress to the donor and family, inconvenience and risk of the evaluation process (i.e. intravenous contrast), operative mortality (1 in 2000 patients), major postoperative complications (2% of patients), minor postoperative complications (up to 50% of patients), long-term morbidity (possibly mild hypertension and proteinuria), risk for traumatic injury to the remaining kidney, risk for unrecognized chronic renal disease [24]. Similar to previous reports, our study showed that the patient and graft survival rates improved significantly after adding cyclosporine to the immunosuppressive regimen in 1983 [10 13]. Since 1988, the number of living kidney transplantations has increased in our department; the causative factors might include confirmation of the cyclosporine positive effect on graft survival, getting more experience, and better informing our patients about advantages of this type of donation [28]. Laparoscopic techniques for performing donor nephrectomies have shortened the period of postoperative rehabilitation for living kidney donors, and provide additional motivation for promoting living donor kidney transplantation [25]. Our results showed longer operation times and longer warm and cold ischaemia times in the laparoscopically operated living donors compared to those seen in the conventional approach. These findings may represent in part the learning curve using the laparoscopic technique. There are potential risks of bleeding, organ lesion and microperfusion disturbances both in the laparoscopic and open approach, which appear to be somewhat higher in the laparoscopic group. Moreover, the learning curve is a limiting factor that makes it difficult for some smaller transplantation centres to use this approach effectively. However, the hospitalization days in laparoscopy donors were significantly lower than in the conventional approach and the former group went back earlier to their job and active life. The surgical approach significantly affected the analgesic use so that the laparoscopy approach resulted in lower patient demand for analgesics. In our study, as well as in other studies, the organ quality has been equal in the laparoscopic and conventional approach [29]. It has to be mentioned that previous extensive abdominal surgery that involved retroperitoneal/perinephric tissue planes is a contraindication to laparoscopic donation [30]. Awareness by both donors and recipients that laparoscopic donor nephrectomy hastens donor recovery and leads to excellent recipient results has increased the chance that a live donor will be identified, especially in countries without the possibility of brain-dead donation [31]. This may result in higher rates of living donation transplantation. Careful dissemination of this technique will lead to the increased use of living donor transplantation for the treatment of ESRD [29]. In conclusion, the results of our study show an increase in patient and graft survival rates since the cyclosporine era. General progression in recipient selection, surgical routines, HLA typing techniques and patient care could also contribute to the increased success rates in the cyclosporine era. Living related and unrelated kidney transplantations have better results than cadaveric transplantations. Living donor nephrectomy remains a valuable source of kidneys for transplantation with a low complication rate. The laparoscopic approach provides an acceptable option in kidney transplantation surgery; its advantages have to be balanced against its possible disadvantages. Acknowledgements. We hereby acknowledge all present and previous members of the Heidelberg kidney transplantation team that have contributed to this series. Conflict of interest statement. None declared. References iv53 1. United States Renal Data System 1999 Annual Data Report. Am J Kidney Dis 1999; 34 [Suppl 1]: S51 S62 2. Nicholson ML, Metcalfe MS, White SA et al. A comparison of the results of renal transplantation from non-heartbeating conventional cadaveric and living donors. Kidney Int 2000, 58: Pacholczyk MJ, Lagiewska B, Szostek M et al. Transplantation of kidneys harvested from non-heart-beating donors: early and long-term results. Transplant Int 1996; 9: S81 4. Tanabe K, Oshima T, Tokumoto T et al. 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