Long-term risks for kidney donors.

Previous studies have suggested that living kidney donors maintain long-term renal function and experience no increase in cardiovascular or all-cause mortality. However, most analyses have included control groups less healthy than the living donor population and have had relatively short follow-up periods. Here we compared long-term renal function and cardiovascular and all-cause mortality in living kidney donors compared with a control group of individuals who would have been eligible for donation. All-cause mortality, cardiovascular mortality, and end-stage renal disease (ESRD) was identified in 1901 individuals who donated a kidney during 1963 through 2007 with a median follow-up of 15.1 years. A control group of 32,621 potentially eligible kidney donors was selected, with a median follow-up of 24.9 years. Hazard ratio for all-cause death was significantly increased to 1.30 (95% confidence interval 1.11-1.52) for donors compared with controls. There was a significant corresponding increase in cardiovascular death to 1.40 (1.03-1.91), while the risk of ESRD was greatly and significantly increased to 11.38 (4.37-29.6). The overall incidence of ESRD among donors was 302 cases per million and might have been influenced by hereditary factors. Immunological renal disease was the cause of ESRD in the donors. Thus, kidney donors are at increased long-term risk for ESRD, cardiovascular, and all-cause mortality compared with a control group of non-donors who would have been eligible for donation.

Minimally invasive renal auto-transplantation: the first report.

BACKGROUND: Regarding transplant surgery, the minimally invasive revolution was started in 1995 by laparoscopic living donor nephrectomy (L-LDN). In 2006, we made the first report on a minimally invasive technique for kidney transplantation; restricted to a 7-9 cm transverse incision targeted on the anastomotic area of the iliac vessels, and with the meticulously prepared kidney placed in a fitting, retroperitoneal pouch lateral to the skin incision. MATERIALS AND METHODS: By combining "hand-assisted laparoscopic nephrectomy" and "minimally invasive kidney transplantation" - using the same incision (7-8 cm) for hand-assistance, kidney harvesting, and transplantation - we have during 2009 conducted "minimally invasive renal auto-transplantation" in two patients. RESULTS: In both cases, the postoperative course was uneventful. When examined 3 mo postoperatively, both auto-transplants were shown to have excellent function by renal scintigraphy. CONCLUSIONS: Renal auto-transplantation, a traditionally major surgical procedure, can be made minimally invasive by a similar incision as that used for L-LDN. Taking into regard the highly traumatic conventional incisions, we expect the generally proven minimally invasive benefits to be considerable.

Minimally invasive living donor nephrectomy - introduction of hand-assistance.

Conventional open living donor nephrectomy (LDN) technique is perceived as a barrier for expanding living donor programmes. Thus, minimal invasive surgery techniques have been advocated to overcome this hurdle. The aim of this study was to evaluate our experience on minimally invasive LDN. During the last decade we have gradually expanded the use of minimally invasive LDN with various techniques; strictly laparoscopic versus hand-assisted, and laparoscopic versus retroperitoneoscopic. This study is based on 305 consecutive minimally invasive LDN's, from 1998 to 2009. By multiple regression analysis, minimally invasive hand-assisted technique was shown to be associated with a significantly lower risk of major complications and intraoperative incidents, as well as reduced warm ischemia and operative time. In our opinion, the introduction of hand-assisted technique is probably the most significant single factor for improved results, although accumulated experience and developments in equipment will contribute. Our experience indicates that learning curves are facilitated by the use of hand-assisted technique. Improvements in surgical outcomes following donor nephrectomy may enhance living donor programmes.

Laparoscopic adrenalectomy: Norwegian single-center experience of 242 procedures.

BACKGROUND: The last 15 years have been characterized by a rapid expansion of minimally invasive surgery as treatment for adrenal diseases. During these years, both indications and surgical techniques have shown improvements. This study analyzed an 11-year single-center experience with laparoscopic adrenalectomy. MATERIALS AND METHODS: Between January 1997 and April 2008, 242 laparoscopic adrenalectomies were performed in 220 patients at Rikshospitalet University Hospital. Of these, 192 patients were operated on for benign lesions, 23 for malignant lesions, and in 5 cases "en bloc" adrenalectomies were performed. Benign lesions included 136 hormonally active lesions (41 pheochromocytomas, 48 Conn adenomas, 25 Cushing adenomas, and 18 patients with Cushing's disease) and 56 with hormonally inactive lesions (among them, 47 nonfunctional adenomas). Malignant lesions included 16 adrenal metastases and 7 adrenocortical carcinomas. RESULTS: All adrenalectomies were completed laparoscopically. The median time of unilatateral adrenalectomy was 85 (range, 35-325) minutes. The median blood loss was 0 (range, 0-1100) mL. There were 6 intraoperative and 7 postoperative minor complications. The number of complications did not differ between the types of adrenal pathology. Only 19% of the patients required opioids postoperatively. Per- and postoperative parameters were homogeneous among patients with different adrenal lesions. The patients with adrenocortical carcinoma had a distinctive intraoperative course with an evidently longer operative time and higher blood loss. The median postoperative hospital stay was 2 (range, 1-15) days. Hospital stay was the only postoperative parameter where a difference was found between patients with different adrenal lesions. The patients with carcinoma, pheochromocytoma, and Cushing's disease had the longest median postoperative stay, respectively, 5 (range, 2-6), 3 (range, 1-15), and 3 (range, 2-6) days. CONCLUSIONS: Laparoscopic adrenalectomy is a safe, effective procedure providing improved fast and uncomplicated patient recovery independent of the type of adrenal lesion. Laparoscopic adrenalectomy can be easily introduced and may soon replace traditional open surgery in specialized centers.

Early changes in bone mass, biochemical bone markers and fibroblast growth factor 23 after renal transplantation.

BACKGROUND: Serum osteocalcin and C-terminal telopeptides of type-1 collagen (CTX-1) are known markers of bone turnover, whereas the role of fibroblast growth factor 23 (FGF-23) is yet unknown. We investigated early changes in bone mass and the association of these biochemical markers and FGF-23 with bone loss following renal transplantation (RTx). MATERIAL AND METHODS: In 44 first-kidney allograft patients, BMD was measured by dual-energy X-ray absorptiometry in the lumbar spine (LS), total femur (TF) and total body (TB) at baseline and 10 weeks post-transplant. Serum osteocalcin, CTX-1, intact FGF-23, intact parathormone (iPTH) and 25-hydroxyvitamin D (25-OHD) levels were measured. Associations were tested by correlation and multiple linear regression. RESULTS: We found a significant (p<0.05) decrease in bone mass in LS (2.6 %), TF (2.1 %) and TB (1.4 %). Osteocalcin (0.95 versus 1.56 nmol/L) and CTX-1 (1.05 versus 1.47 ng/mL) levels increased significantly, while serum FGF-23 and iPTH decreased. Serum osteocalcin and CTX-1 were significantly associated at both baseline and follow-up. Baseline osteocalcin and CTX-1 were independently associated with bone loss in TB and TF, respectively. Neither iPTH nor 25-OHD showed consistent association with bone loss. FGF-23 was not related to change in bone mass or to biochemical markers of bone turnover. CONCLUSION: Our results confirm an early decrease in bone mass with high bone resorption rate after RTx. Osteocalcin and CTX-1 are associated with bone loss in the early post-transplant period; thus, these markers may be a reasonable choice for routine assessment of bone turnover in this setting. The role of FGF-23 remains to be further elucidated.

Determinants of short-term changes in body composition following renal transplantation.

OBJECTIVE: Changes in body composition after renal transplantation (RTx) are of clinical significance, since increments in fat mass may contribute to glucose intolerance and cardiovascular morbidity. The aim of this study was to quantify the early changes in body composition after transplantation and identify predictors of these changes. MATERIAL AND METHODS: Total and regional body composition of 102 first kidney allograft recipients were measured at transplantation and after 10 weeks using dual-energy X-ray absorptiometry. The population comprised a high proportion of pre-emptive and well-nourished kidney recipients. Multiple linear regression was used to identify predictors of change. RESULTS: Mean fat mass was 27.1+/-8.7% of body weight at baseline. The fat mass percentage increased by 2.2% corresponding to a 1.3 kg increase in fat mass at 10 weeks (p< 0.001). Fat-free mass declined by 2.5 kg (p<0.001), with no significant loss of body weight (0.9 kg, p=0.11). Age, low-tertile fat mass, plasma C-reactive protein, time on dialysis and cumulative prednisolone dose were independent predictors (p<0.05) of the increase in fat mass. Cumulative prednisolone dose was the only significant predictor of decrease in fat-free mass. Essentially the same results were found for both genders. CONCLUSIONS: A significant increase in fat mass occurred rapidly after RTx along with a reduction in fat-free mass despite stable body weight. Early fat mass accumulation may predispose to comorbidity, but the long-term clinical significance of these early changes remains to be explored in prospective studies.

Determinants of bone mass in end-stage renal failure patients at the time of kidney transplantation.

BACKGROUND: Patients with chronic renal failure (CRF) are at high risk of renal osteodystrophy. Our study aimed to identify predictors of bone mass and cumulative fracture rate at the time of renal transplantation (RTx). This is important since the patients experience further substantial bone loss the first month post-transplant. MATERIAL AND METHODS: Altogether 133 renal transplant patients were examined for bone mineral density (BMD) using dual-energy X-ray absorptiometry shortly after RTx. RESULTS: The patients'Z-scores were significantly lower at the time of RTx compared to the reference population (p < 0.05), 32% were osteopenic and 11% had osteoporosis. Independent predictors of low bone mass were age (p < 0.001), female sex (p < 0.001), intact parathyroid hormone (iPTH) level (p < 0.001), former transplantation (p = 0.001) and time on hemodialysis (HD) (p = 0.005). Body mass index (BMI) (p < 0.001) and physical activity (p = 0.027) were associated with high BMD. Cumulative fracture rate (29%) was associated with physical inactivity (p = 0.003), BMI (p = 0.036) and osteopenia (p < 0.001) at the time of RTx. CONCLUSION: In a representative CRF population, BMD was reduced. Independent predictors of BMD were as for the general population, and uremia associated predictors were time on HD, previous transplantation and serum iPTH level. Fracture rate was high, and physical inactivity had the strongest association with fractures.

Declining intracellular T-lymphocyte concentration of cyclosporine a precedes acute rejection in kidney transplant recipients.

BACKGROUND: We investigated cyclosporine A (CsA) concentrations at the site of action, inside T-lymphocytes, to evaluate its applicability as a new supplementary therapeutic drug monitoring method after renal transplantation. METHOD: In this prospective single-center study, 20 kidney transplant recipients, mean age 54 (range 21-74) years, on CsA-based immunosuppression were included within 2 weeks posttransplant and followed for 3 months. Nine patients also had one full 12-hour pharmacokinetic profile performed. T-lymphocytes were isolated from 7 ml whole blood using Prepacyte and intracellular CsA concentrations were determined using a validated liquid chromatography double mass spectrometry method. RESULTS: Seven patients (35%) experienced acute rejections (all biopsy verified) during the first three months posttransplantation. Intracellular CsA concentrations tended to decline 1 week prior to acute rejection and the decrease was significant (-27.1+/-14.6%, P=0.014) three days before the rejection episodes were recognized clinically. In addition, the intracellular CsA area under the curve 0-12 measured during stable phase was 182% higher in the rejection-free patients (P=0.004). There was no difference between patients experiencing rejection and the rejection-free patients with respect to CsA C2-levels, dose (mg/kg), human leukocyte antigen mismatch, donor age, recipient age, or ABCB1 genotyping. CONCLUSION: Intracellular CsA T-lymphocyte concentrations declined significantly 3 days prior to a rejection episode and there was a general lower intracellular exposure of CsA in recipients experiencing rejection. Intracellular measurement of CsA therefore seems to have a potential to further improve individualization of therapeutic drug monitoring. Larger studies are needed to elucidate the role for intracellular T-lymphocyte measurements in ordinary clinical care, for both CsA and other immunosuppressive drugs.

Aberrant heparan sulfate profile in the human diabetic kidney offers new clues for therapeutic glycomimetics.

BACKGROUND: Diabetic nephropathy poses an increasing health problem in the Western world, and research to new leads for diagnosis and therapy therefore is warranted. In this respect, heparan sulfates (HSs) offer new possibilities because crude mixtures of these polysaccharides are capable of ameliorating proteinuria. The aim of this study is to immuno(histo)chemically profile HSs from microalbuminuric kidneys from patients with type 1 diabetes and identify specific structural HS alterations associated with early diabetic nephropathy. METHODS: Renal cryosections of control subjects and patients with type 1 diabetes were analyzed immunohistochemically by using a set of 10 unique phage display-derived anti-HS antibodies. HS structures defined by relevant antibodies were characterized chemically by means of enzyme-linked immunosorbent assay and probed for growth factor binding and presence in HS/heparin-containing drugs. RESULTS: In all patients, HS structure defined by the antibody LKIV69 consistently increased in basement membranes of proximal tubules. This structure contained N- and 2-O-sulfates and was involved in fibroblast growth factor 2 binding. It was present in HS/heparin-containing drugs shown to decrease albuminuria in patients with diabetes. The HS structure defined by the antibody HS4C3 increased in the renal mesangium of some patients, especially those who developed macroalbuminuria within 8 to 10 years. This structure contained N- and 6-O-sulfates. For 8 other antibodies, no major differences were observed. CONCLUSION: Specific structural alterations in HSs are associated with early diabetic nephropathy and may offer new leads for early diagnosis and the rational design of therapeutic glycomimetics.

Laparoscopic versus open living-donor nephrectomy: experiences from a prospective, randomized, single-center study focusing on donor safety.

BACKGROUND: Very few randomized studies on laparoscopic (L) versus open (O) living-donor nephrectomy (LDN) have been presented. The largest randomized series reported so far included 80 donors. In 2000, an Australian safety group concluded that the evidence base for L-LDN is inadequate to make recommendations regarding safety and efficacy. METHODS: With this background, at our single national center, 122 donors were randomized to left-sided L-LDN (n=63) or O-LDN (n=59), from February 2001 to May 2004. This article summarizes our experiences, in particular regarding complications and safety. RESULTS: There were significant differences in favor of O-LDN regarding operative time, warm ischemia time, and vessel lengths, whereas the analgesic requirements and pain data were significantly in favor of the laparoscopic procedure. In the L-LDN group, there were five major postoperative complications resulting in reoperations (8%), including two intestinal perforations. No major complications occurred in the O-LDN group. CONCLUSIONS: These results from our randomized study do suggest that conventional O-LDN is a very secure procedure, superior to L-LDN regarding donor safety. There has been an unacceptably high rate of reoperations in our L-LDN series but without mortality or significant sequelae. A careful look at some other L-LDN series also suggests increased morbidity/mortality. Our data do, however, support the view that a perfect, uncomplicated L-LDN appears to be the superior procedure, and the laparoscopic procedure is still evolving. Donor safety may be improved by avoiding obese donors, stapling of the renal artery (not clipping), and perhaps by hand assistance. Furthermore, we will consider the retroperitoneal approach.

Gender imbalance among donors in living kidney transplantation: the Norwegian experience.

BACKGROUND: In living donor (LD) kidney transplantation, a predominance of female-to-male donations has been observed. Gender demographics of living donors and outcomes of LD kidney transplantations in Norway were assessed, as this has not been explored previously. METHODS: Data from the Norwegian Renal Registry of first LD kidney transplantations (n = 1319) in the period 1985-2002 were used. RESULTS: The majority of all LD was female (57.8%; P<0.001), while 62.7% of the recipients were men (P<0.001). Females dominated as donors in the spousal group and the parental group (P<0.0001). However, no gender difference was observed in the parental group when the recipients were <30 years old (P = 0.65). In opposite-sex pairs, female-to-male donations were as expected based on the incidence of end-stage renal disease. Donor sex affected neither the incidence of acute rejections nor graft survival. Serum creatinine was higher in renal allografts from female donors to male recipients in the first 4 years after transplantation. Donor age also had significant impact on graft function measured as serum creatinine. CONCLUSIONS: Gender disparities in LD transplantation result from a higher proportion of female-to-female and a lower proportion of male-to-male donations than expected. Both donor age and donor sex influence graft function during the first years. Graft survival and acute rejection episodes appear not to be affected by donor sex in LD kidney transplantation.

C2 monitoring in maintenance renal transplant recipients: is it worthwhile?

Presently, there is little knowledge regarding cyclosporine (CsA) concentration at 2 hr post-dose (C2) monitoring in maintenance patients. This study evaluates the actual C2 range in stable renal transplant recipients (who underwent transplantation >12 months ago). In addition, we investigated whether underexposure or overexposure to CsA (assessed by C2) affects graft function (as measured by serum [S]-creatinine). All renal transplant recipients in Norway receiving CsA were asked to participate; 1447 fulfilled the criteria. Valid C2 and CsA trough concentration (C0) measurements were performed in 1032 renal transplant recipients (71%) monitored by C0. Target C0 level was 75 to 125 mumol/L. CsA levels were measured using a Cloned Enzyme Donor Immunoassay method, and all analyses were performed in the same laboratory (overall mean [+/-standard deviation] CsA C0=112+/-31 mug/L, CsA C2=697+/-211 mug/L [range 81-1580 mug/L], CsA dose [mg/day]=208+/-61, CsA dose [mg/kg/day]=2.8+/-1.1, and S-creatinine=141+/-58 mumol/L). A univariate analysis of variance showed that patients with C2 levels between 700 and 800 mug/L (n=203, S-creatinine=136+/-49 mumol/L) had significantly lower S-creatinine levels compared with patients with C2 levels greater than 950 mug/L (n=94, S-creatinine=152+/-56 mumol/L) (P<0.02). The same was true for patients with C2 levels less than 450 mug/L (n=95, S-creatinine 141+/-72 mumol/L) (P<0.05) when compared with patients with C2 levels greater than 950 mug/L. There was no significant difference in S-creatinine between patients in the low and intermediate C2 group; 666 patients had C0 levels in the therapeutic range (75-125 mumol/L). A linear regression showed a significant relation between S-creatinine and C2 for these patients (P=0.03). The corresponding relation between S-creatinine and C0 was nonsignificant (P=0.3). Monitoring of C2 in maintenance patients is a valuable tool to detect overexposure to CsA. Until results from prospective studies are available, we recommend C0 in the therapeutic range and reduction in CsA in overexposed patients, aiming at a C2 value between 700 and 800 mug/L.

Clinical outcomes during the first three months posttransplant in renal allograft recipients managed by C2 monitoring of cyclosporine microemulsion.

BACKGROUND: MO2ART (monitoring of 2-hr absorption in renal transplantation) is the first prospective, multicenter trial of cyclosporine (CsA) blood level 2 hr postdose (C2) monitoring in de novo kidney recipients receiving CsA microemulsion (ME) (Neoral; Novartis, Basel, Switzerland). Efficacy and safety results from the first 3 months are presented here. METHODS: MO2ART is a 12-month, open-label, randomized study involving 296 patients. In all patients, the dose of CsA-ME was adjusted to achieve protocol-defined C2 targets of 1.6 to 2.0 microg/mL for the first month, with subsequent tapering. Randomization into two target groups occurred at 3 months. All patients received steroids and mycophenolate mofetil (89%) or azathioprine. For patients with delayed graft function, the protocol permitted reduced C2 targets and prophylactic administration of antibodies. RESULTS: At 3 months, overall incidence of biopsy-proven acute rejection was 11.5%. Median serum creatinine was 132 micromol/L. Patient and graft survival were 96.6% and 91.2%, respectively. C2 levels greater than 1.6 microg/mL were achieved within 5 days by 60.6% of patients with immediate graft function and 19.5% of patients with delayed graft function. Prophylactic antibodies were used in 15% of the total population. Twenty-four patients (8.1%) experienced serious adverse events with a suspected relation to CsA, and 26 patients (8.8%) discontinued the study because of adverse events (n=15) or after a switch in immunosuppression after rejection episodes (n=11). CONCLUSIONS: Patient management by C2 monitoring resulted in a low incidence of biopsy-proven acute rejection in standard risk de novo kidney recipients, 85% of whom did not receive prophylactic antibodies. CsA-ME with C2 monitoring provides excellent short-term efficacy and safety among de novo renal transplant patients.

Effects of immediate switch from cyclosporine microemulsion to tacrolimus at first acute rejection in renal allograft recipients.

BACKGROUND: A number of institutions have reported favorable results in renal transplant patients after conversion from cyclosporine (CsA) to tacrolimus at the time of acute rejection, but no prospective, controlled study has been performed to date. Here, we report the first randomized study comparing patients whose therapy was changed at a first episode of acute rejection to tacrolimus with those who were maintained on CsA microemulsion (ME). METHODS: This 3-month, prospective, open, multicenter, parallel-group study was conducted at 15 centers in seven European countries. In total, 119 renal graft recipients experiencing a first biopsy-proven acute rejection episode while receiving CsA-ME were randomized (1:1) to start tacrolimus-based therapy (n=61) or to continue CsA-ME-based therapy (n=58). RESULTS: Baseline characteristics were comparable for both groups. The initial rejection episode responded to steroid treatment in 93.4% (tacrolimus) and 63.8% (CsA-ME) (P=0.001), respectively. In patients at risk, the incidence of recurrent rejection events within 3 months was significantly lower with tacrolimus therapy (5/57, 8.8%) compared with CsA-ME therapy (15/44, 34.1%) (P=0.002). Patient and graft survival were similar in both study groups 3 months after randomization. The most frequently reported adverse events were increased serum creatinine (29.5% vs. 22.4%), hypertension (24.6% vs. 22.4%), and urinary tract infection (18.0% vs. 20.7%) for tacrolimus versus CsA-ME. Tremor was more common in tacrolimus treated-patients (17.4% vs. 2.1%, P=0.011). CONCLUSIONS: Early conversion to tacrolimus therapy benefited the resolution of acute rejection episodes and significantly reduced the risk of recurrent rejection compared with continuation of CsA-ME.

Donor lymphocytes transferred with the graft to kidney recipients. Potential for establishing microchimerism.

After solid organ transplantation donor lymphocytes have been shown to survive and multiply in the organ recipient for a prolonged period. It is not clear whether this chimerism detected is the result of immunosuppression or the cause of allograft acceptance. The number of cells transferred, as well as the type of cells, and the degree of activation are likely to be of importance for the establishment of microchimerism. The cells that are flushed out of the vascular tree may be of particular importance since when an antigen primarily bypasses or secondarily avoids organised lymphoid collections, the immune system in the recipient may remain or become "indifferent" to its presence. In the present study we examined the amount of residual donor blood cells that we could flush out from the vascular tree of living donor kidneys and cadaveric donor kidneys immediately prior to transplantation, with special emphasis on T and B lymphocytes. Our study shows that perfusion of donor kidneys just prior to transplantation releases from 0.1 to 1.8x10(6) B-lymphocytes, with an average of 0.7x10(6) and from 0.5x10(6) to 2.6x10(6) T-lymphocytes, with an average of 1.8x10(6), for CD kidneys, and somewhat less for LD kidneys. These cells would otherwise have been flushed out into the organ recipient's circulation, where they might play a role in the establishment of microchimerism.

Improvement of post-transplant lymphocele treatment in the laparoscopic era.

Post-transplant lymphoceles are a common problem after renal transplantation, often inflicting the graft or adjacent iliac veins. Since 1991, there have been many reports on laparoscopic fenestration as the treatment of choice, but no larger series has been presented. At our department, 63 laparoscopic procedures were performed between 1993 and 2001 among 1502 renal graft recipients. The laparoscopic operation time, conversion rate, hospital stay, and complications have all decreased progessively. Duration of hospital stay and convalescence was markedly longer in patients treated with conventional open surgery (27 patients). Rejections, CMV disease, and post-transplant reoperations seem to have an increased incidence in the lymphocele population. According to our experience, laparoscopic fenestration is the superior treatment for symptomatic lymphoceles, allowing minimal trauma and fast recovery. Our series suggests that the rate of complications/graft injury decreases progressively with experience. Laparoscopic ultrasound seems useful in difficult cases. Prophylactic measures should be emphasised at the time of transplantation and reoperations.