Introduction of hand-assisted retroperitoneoscopic living donor nephrectomy at Karolinska University Hospital Huddinge.

Living donor kidney transplantation accounts for about 50% of the total number of renal transplantations at our center. From 1999 through 2005, 75 out of 220 living donor nephrectomies were performed with a laparoscopic technique (LLDN). In June 2005, we introduced the technique of hand-assisted retroperitoneoscopic nephrectomy (HARS) for living donors. Since the introduction until the end of 2005, 11 out of 18 living donor nephrectomies (LDN) were performed with HARS. Reduced operation time was observed for the HARS group (mean, 166 minutes) compared with the LLDN (mean, 244 minutes). Two grafts showed delayed function, one in the LLND group and one in the HARS group. No major perioperative or postoperative complications were observed in the HARS group, whereas one patient who underwent LLDN developed severe pancreatitis. So far in our hands HARS is a fast and safe procedure with results comparable with open LDN. Compared to LLDN, we experienced reduced operation time together with the advantage of retroperitoneal access.

Fifteen years' experience with pancreas transplantation with pancreaticoenterostomy.

We report on 92 pancreas transplantations with exocrine diversion by pancreaticoenterostomy. All recipients suffered from long-term type I (insulin-dependent) diabetes. In most transplantations, cadaveric segmental grafts were used (n = 89). In a few patients, segmental grafts from related donors were used (n = 3), and in a few other patients, whole-organ cadaveric grafts were used (n = 4). There were 9 retransplantations. Most pancreas transplantations were performed in uremic diabetic patients in combination with a kidney transplantation (n = 58). In a few patients the pancreas transplantation was performed after a kidney transplantation (n = 6). The remaining transplantations were in nonuremic diabetic patients who received only a pancreas (n = 25). Over the years, the results have improved considerably; in the 1986-1987 series the overall 1-yr patient survival (ps) and graft survival (gs) rates were 97 and 56%, respectively. The best results were achieved with the combined procedure (ps 100%, gs 77%); with pancreas only, the figures were inferior (ps 92%, gs 34%). Several factors explain the improved results. The incidence of graft thrombosis has been reduced by the use of anticoagulation, and posttransplantation pancreatitis has been reduced by avoiding ischemic injury to the graft. Cyclosporin has helped reduce the incidence of graft rejection, and monitoring of the exteriorized pancreatic juice has helped in the diagnosis of rejection.

Quality of life in diabetic patients after combined pancreas-kidney or kidney transplantation.

The quality of life was compared between 14 combined pancreas-kidney-transplant patients (group 1) and 16 diabetic kidney-transplant patients (group 2). Minimum follow-up was 2 yr with functioning grafts. Two-thirds of both groups' patients were working, but 90% in group 1 and 50% in group 2 had full-time occupations. Also 7% in group 1 and 43% in group 2 had to modify their activity posttransplantation. The amount of lost workdays was calculated during periods of 2 yr pre- and posttransplantation: the figure decreased by 44% in group 1 (from 278 to 155) and was unchanged in group 2 (from 211 to 213). The number of sickness pensions paid increased from 28% of the patients pretransplantation to 42% in October 1987 in group 1 and from 20 to 62% in group 2. Over the last 2 yr, an average of 12 days of hospitalization were necessitated in group 1 compared to 25 days in group 2. When physical activity was evaluated, both groups judged their present state of health as good or very good (group 1, 78%; group 2, 73%). In group 1, 80% claimed they had recovered the same or better quality of life as they had before renal failure, compared to 50% in group 2. The investigation showed that group 1 seemed to achieve a better quality of life than group 2; all combined pancreas-kidney-transplant patients returned to a normal diet and achieved a less restricted life-style.

Improvement of nerve conduction in diabetic neuropathy. A follow-up study 4 yr after combined pancreatic and renal transplantation.

Eighteen patients with long-standing insulin-dependent (type 1) diabetes mellitus and polyneuropathy were studied after combined pancreatic and renal transplantation. Repeated tests were performed on peripheral nerve function (electroneurography) and on autonomic function (R-R test) 6 mo and 1, 2, and 4 yr after the transplantation. Eighteen diabetic patients with only a kidney graft served as controls. After initial improvement of nerve conduction in both groups, probably caused by the elimination of uremia, further improvement was seen only in the euglycemic pancreas-graft recipients. Improvement of autonomic (parasympathetic) function was slight after 48 mo and was similar in both groups.

Pancreas-specific protein. New serum marker for graft rejection in pancreas-transplant recipients.

A radioimmunoassay for a novel human pancreatic protein (pancreas-specific protein, PASP) has been developed. We studied the possibility that serum PASP levels reflect pancreas-graft rejections in human pancreas-transplant recipients. Ten patients subjected to combined pancreas-kidney transplantation and 4 patients subjected to pancreas transplantation alone were studied. Twelve kidney recipients served as control subjects. On several occasions, PASP levels were elevated at kidney rejections in patients with combined pancreas-kidney grafts and then decreased after antirejection therapy, although no other indications for concomitant pancreas-graft rejection were at hand. In the recipients of pancreas grafts alone, PASP levels increased before or at the same time as graft rejections were indicated by current methods. In two cases of chronic graft rejection, PASP rose to high levels long before hyperglycemia occurred. In the control group of kidney-graft recipients, PASP levels were stable and were not affected by high serum creatinine levels, kidney-rejection episodes, or antirejection therapy. This study indicates that PASP may be a good serum marker for pancreas-graft rejection.

Effects of pancreas transplantation on metabolic and hormonal profiles in IDDM patients.

The diurnal patterns of relevant metabolites and hormones in five pancreas-kidney-transplanted patients (aged 36 +/- 2 yr, mean +/- SD) with insulin-dependent diabetes mellitus (IDDM) were compared with those in five kidney-transplanted nondiabetic patients (aged 28 +/- 2 yr). The groups were matched for body mass and current dose and type of immunosuppressive treatment. The serum creatinine levels did not differ between the two study groups, but the serum urea level in the nondiabetic patients was slightly but significantly higher than in the diabetic patients. In the pancreas-kidney-transplanted group the investigation was performed 8-47 mo posttransplantation; in the kidney-transplanted nondiabetic patients, 12-18 mo posttransplantation. The mean 24-h levels and rhythms of blood glucose, free fatty acid, 3-hydroxybutyrate, and alanine did not differ between the groups. The mean 24-h levels of blood lactate and glycerol were moderately but significantly higher in the pancreas-kidney-transplanted diabetic patients. At fasting, the level of serum immunoreactive insulin was more than twice as high in the pancreas-kidney-transplanted patients, whereas the plasma C-peptide levels did not differ significantly between the two groups. The meal-induced increases in serum insulin as well as in the plasma C-peptide levels were more marked in the pancreas-kidney-transplanted patients. The findings suggest that the hyperinsulinemia in these patients was due to both the systemic delivery of insulin and an increase in insulin resistance, the latter being particularly apparent in the postprandial phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Markers for pancreas-graft rejection in humans.

Rejection episodes were studied in 15 patients, in whom no kidney graft could serve as a marker for rejection, subjected to pancreas transplantation with pancreatoenterostomy and temporary exteriorization of the pancreatic juice (10 pancreas alone, 3 pancreas after kidney, and 2 combined pancreas and kidney in which the kidney was not functioning.) Twelve patients (80%) had a total of 18 rejection episodes. In the first 11 patients, 13 rejection episodes were diagnosed by a decline in amylase activity in the pancreatic juice, whereas in the next 4 patients, 5 rejection episodes were diagnosed by positive cytology in the pancreatic juice. Neopterin in pancreatic juice and immunoreactive anionic trypsin in serum showed promise as rejection markers, whereas serum neopterin, serum amylase, and serum immunoreactive cationic trypsin did not. Unspecific signs of rejections were an increase in white blood cell count, clinical symptoms such as fever, abdominal pain, and arthralgia. All acute rejection episodes were successfully reversed by antirejection treatment. However, late rejections diagnosed by impaired endocrine function were seen in 6 of the 15 (40%) patients, and the prognoses for these rejections were worse: 4 patients (27%) lost their grafts because of chronic rejections, and 2 patients still had impaired endocrine function.

Pregnancy after combined pancreas-kidney transplantation.

Four successful cases of pregnancy after combined pancreas-kidney transplantation at four different centers are summarized. The techniques used for the pancreas transplantations were duct obstruction in one patient and enteric exocrine diversion in two patients; in all three patients the insulin delivery was to the systemic circulation. In one patient exocrine diversion was to the stomach and the vascular anastomosis to the splenic vessels, thus accomplishing portal insulin delivery. Immunosuppression consisted of cyclosporin and prednisolone in two patients; cyclosporin alone in one patient; and cyclosporin, azathioprine, and prednisolone in one patient. In all a cesarean section was performed, due to deteriorating renal function in two patients, a fall in fetal growth in one patient, and fear of inducing pancreas-graft pancreatitis during normal delivery in one patient. In all four women, perfect metabolic control was retained throughout the pregnancy, and despite the proximity of the pancreas graft to the growing uterus in three of the women, the pancreas grafts did not suffer any damage during the pregnancy. However, in one patient the pancreas graft was lost in acute rejection after delivery. This pancreas had functioned normally for 3 yr before this occasion. Of the offspring, one was completely normal, one had a bilateral cataract, and two were small for date. The latter two subsequently showed normal growth development. At follow-up at 3, 5, 7, and 28 mo, all kidney grafts and three of the pancreas grafts remained functional. We conclude that after combined pancreas-kidney transplantation, successful conception and pregnancy can be obtained. Despite reduced islet mass (segmental grafts), normal metabolic control can be retained throughout the pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term metabolic control in recipients of segmental-pancreas grafts with pancreaticoenterostomy or duct obstruction.

Metabolic control in recipients of segmental-pancreas grafts with pancreaticoenterostomy (performed in Stockholm) or duct obstruction by polymer injection (performed in Oslo) were compared. The recipients were uremic diabetic patients and also received a kidney from the same donor. Because the patient population in the two Scandinavian countries is very similar and the immunosuppressive protocols used are almost identical, such a comparison seemed reasonable. The number of patients available for study at 1, 2, and 3 yr was 22, 10, and 4, respectively, with duct injection and 28, 10, and 3 with pancreaticoenterostomy. The mean age of the patients was somewhat higher in the Oslo series. There were no significant differences regarding immunosuppression or kidney-graft function as estimated by serum creatinine at 1, 2, and 3 yr. No significant differences were found in fasting blood glucose, glycosylated hemoglobin, and intravenous glucose tolerance between the two groups at 1, 2, and 3 yr.

Prevention of kidney graft diabetic nephropathy by pancreas transplantation in man.

Kidney graft biopsies were performed 2-3 yr after transplantation in eight type I (insulin-dependent) diabetic patients who had previously been subjected to kidney transplantation (six patients) or combined kidney and segmental pancreas transplantation (two patients). In five of the six patients that had undergone only kidney transplantation, light microscopic examination of the graft biopsy revealed changes compatible with diabetic nephropathy, and electron microscopic morphometry showed a thickening of the glomerular basement membrane (GBM). In the two patients who had been subjected to combined pancreas and kidney transplantation, the kidney graft biopsy showed no light microscopic changes suggestive of diabetic nephropathy, and electron microscopy showed no thickening of the GBM. Thus, it appears to be possible to prevent the recurrence of diabetic nephropathy in human kidney allografts by simultaneous pancreas transplantation.

Refractory acute renal allograft rejection successfully treated with photopheresis.

INTRODUCTION: Acute rejection episodes still occur in spite of modern immunosuppressive protocols. We present seven patients with biopsy-proven acute rejections after kidney transplantation refractory to repeated pulses of high-dose steroids and antithymocyte globulin (ATG) or OKT-3, but responsive to photopheresis therapy. METHODS: Photopheresis is a nontoxic immunomodulatory, apheresis-based treatment with no general immunosuppressive action. Rather, it suppresses specific pathogenic T-cell clones. During photopheresis mononuclear leukocytes are collected from the patient using centrifugation technique, treated with a photosensitizing agent, irradiated, and subsequently retransfused. RESULTS: All patients tolerated the treatment well, with no notable side effects. At the 12-month follow-up the median creatinine had decreased to 161 mumol/L compared to 282 mumol/L at the start of photopheresis and at the last follow-up 12 to 43 months after transplantation all patients still had functioning grafts. In five of the seven cases there had been a significant improvement in renal function, whereas in two of the patients the renal function remained stable but without a decrease in creatinine. CONCLUSIONS: It is our experience that the prognosis for renal allografts with acute rejection unresponsive to conventional antirejection treatment (ie, repeated pulses of methylprednisolone and ATG or OKT-3) is very poor. Therefore, we conclude that the photopheresis treatment contributed to the favorable outcome in this small group of patients. We are presently designing a prospective randomized study to further evaluate the effect of photopheresis after renal transplantation.

ABO-incompatible kidney transplantation and rituximab.

We have designed a protocol for ABO-incompatible kidney transplantations based on antigen-specific immunoadsorption rather than plasmapheresis to remove anti-A or anti-B antibodies and with a Prograf/Cellcept/prednisolone protocol using rituximab rather than splenectomy to prevent rebound antibodies. Twelve patients have successfully received transplants with this protocol. The ABO-antibodies were readily removed by the antigen-specific immunoadsorption and maintained at a low-level posttransplantation. There were no side effects. All patients have normal renal transplant function with a follow-up of 1 to 34 months.

Metabolic assessment after simultaneous pancreas-kidney transplantation.

UNLABELLED: Simultaneous pancreas-kidney (SPK) transplantation has become a standard therapy for patients with type 1 diabetes and end-stage renal disease. We analyzed metabolic data in this clinical setting under tacrolimus- versus cyclosporine microemulsion (ME)-based immunosuppressive therapy. PATIENTS AND METHODS: We analyzed 205 patients enrolled in the Euro-SPK001 study for fasting blood glucose, fasting C peptide, glycated hemoglobin (HbA(1c)), blood lipids (total cholesterol and triglycerides), and pancreatic enzymes at regular intervals during the study. We compared blood pressure values with target levels for diabetic patients published by the European Society for Hypertension. RESULTS: Throughout the study, HbA(1c) and fasting C peptide levels were within the normal range in the two groups. Fasting blood glucose was higher during the first 2 months posttransplant in the tacrolimus group than in the cyclosporine-ME group, but no differences were seen thereafter. From month 2 posttransplant, mean levels of total cholesterol were significantly lower among patients receiving tacrolimus than those in the cyclosporine-ME group. In addition, patients receiving cyclosporine-ME showed serologic features of mild pancreatitis with elevated blood amylase and lipase levels during the first 6 months posttransplant. The two regimens were comparable with respect to hypertension, but target levels were reached in only 50% of the patients. CONCLUSION: Except for lipid profiles, no major differences in metabolic effects or blood pressure control were observed among SPK transplant patients receiving immunosuppression based on tacrolimus versus cyclosporine-ME. In view of the potential risk of hypertension, antihypertensive strategies should be implemented for all patients.

Experimental pancreatic transplantation in diabetes.

Although transplantations of vascularized pancreas in diabetic patients show steadily improving results, the immediate operative risks and life-long immunosuppressive medication involved represent considerable disadvantages. Efforts are being made to develop simpler and safer methods of transplantation with isolated pancreatic islet grafts, e.g., isolated islets, fetal pancreas, or dispersed adult pancreas. Iso-, allo-, and xenografts of such preparations have been shown to reverse diabetes in animals. However, attempts to apply these techniques in clinical practice have remained largely unsuccessful, and major technical advances are needed before success is achieved. Attempts to use whole, segmented, or isolated islets from pancreatic grafts as a cure for diabetes in animals and in diabetic patients are reviewed. The importance to the graft's permanent function, of adequate preparation and storage of the graft, and of beta-cell growth and vascularization are reviewed. Various forms of immunomodulation by pretreatment of grafts in vitro have been employed in animal models of diabetes, but none of these have yet been employed with long-term success in humans. Recurrence of a specific autoimmune response toward the beta-cell in a spontaneously diabetic recipient is a potential mechanism for destruction of transplanted islet tissue.

Insulin secretion, insulin action and non-insulin-dependent glucose uptake in pancreas transplant recipients.

To assess individual factors responsible of overall glucose tolerance after successful pancreas transplantation, an i.v. glucose tolerance test, with frequent blood sampling and tolbutamide administration to elicit a second insulin response was used to estimate insulin sensitivity (SI) and glucose effectiveness (SG) with Bergman's minimal model. Insulin secretion was calculated from the combined insulin-C-peptide kinetics method. These parameters were quantified in identically immunosupressed transplants: ISPx, four segmental pancreas recipients with impaired glucose tolerance; TSPx, five segmental pancrease recipients with normal glucose tolerance; WPx, five whole pancreas recipients with normal glucose tolerance; and in two controls groups, Kx, eight nondiabetic kidney recipients, and Ns, eight normal subjects. All participants had normal fasting plasma glucose and normal glycosylated hemoglobin A1C levels. The glucose tolerance KG value was significantly reduced only in ISPx compared with Ns (P < 0.05). SI was reduced by 60% in ISPx, WPx, and Kx compared with normal subjects (P < 0.05), whereas SI was reduced by 30% in TSPx compared with normal controls (P = NS). The reduction in SG was the same in all pancreas transplanted groups, as compared to Kx and Ns (by 33% and 40%, respectively, P < 0.05). The first-phase insulin secretion (0-5 min) was markedly reduced in ISPx and TSPx compared with Ns (by 76% and 50%), to Kx (by 84% and 66%) and to WPx (by 73% and 45%), respectively (P < 0.05), but similar to Ns in WPx. The overall incremental insulin secretion was reduced in ISPx compared with Ns, WPx, and Kx (by 38%, 62%, and 73%, respectively, P < 0.05) and reduced in TSPx compared to WPx and Kx (by 47% and 67%, respectively, P < 0.05) Ns secreted 43% of the total amount of insulin during the first phase the corresponding value was only 13% in ISPx vs. 24% in TSPx, 24% in Kx, and 25% in WPx, respectively (P < 0.05). In conclusion, after pancreas transplantation, the overall glucose tolerance is determined by the net effect of reductions in insulin sensitivity and glucose effectiveness and in the adaptability of the beta-cells to ensure sufficient insulin secretion. beta-cell function was impaired in both the whole pancreas and segmental transplant recipients, and the failure to increase insulin secretion sufficiently leads to glucose intolerance.

Impaired glucose tolerance in cyclosporine-prednisolone-treated renal graft recipients.

In 33 renal transplant patients, an intravenous glucose tolerance test (IVGTT) was performed, and fasting plasma C-peptide concentrations analyzed. Nineteen of the patients were on treatment with cyclosporine-prednisolone (CsA-Po), and 14 were treated with azathioprine-prednisolone (Aza-Po). In the Aza-Po group, the K-values at IVGTT were normal in 13/14, but in the CsA-Po group they were only normal in 9/19 (P = 0.02). The fasting C-peptide levels were significantly higher in the CsA-Po group (P less than 0.001). within this group, there was no correlation between C-peptide level and serum-creatinine concentration, i.e. retention of C-peptide due to decreased renal function as judged by serum creatinine level was not suspected. Intrinsic prednisolone clearance was determined in the CsA-Po patients and was found to be lower than that previously described in Aza-Po patients. However, between those CsA-Po-treated patients with a pathologic K-value at IVGTT and those with a normal K-value there was no difference in prednisolone clearance, fasting C-peptide levels, CsA dose, or serum-creatinine concentrations. The pathophysiology of the cyclosporine-induced glucose intolerance is uncertain, and increased insulin resistance is possible.

Development of renal cell carcinoma in living donor kidney grafts.

BACKGROUND: Although development of malignancies after transplantation is well recognized, de novo development of cancer in renal transplants is a rare phenomenon. We describe two cases of de novo development of renal cell carcinoma in two living donor grafts. MATERIALS AND RESULTS: The recipients were 45 and 4 years, respectively, at transplantation and their fathers were donors. Because of failure to grow, they were both treated with human growth hormone. Over the years a number of cysts developed in the grafts and after 8 and 7 years the echogenecity of some of the cysts changed. Biopsy confirmed the diagnosis renal cell carcinoma 9 and 11 years after transplantation. The grafts were removed and the immunosuppressive therapy discontinued. The two fathers are well with normal function of the native kidney and no signs of cyst formation or cancer. CONCLUSION: Two cases of de novo development of cancer in living donor kidney transplants are described. Because a stimulatory effect of growth hormone on tumor genesis has been described, this treatment may have been of importance in the tumor development. The findings emphasize the importance of annual ultrasonographic surveillance of renal grafts, especially in the pediatric population.

Influence of donor and recipient ages and sex on graft function after pediatric renal transplantation.

BACKGROUND: Adult donor grafts adapt to the smaller size of the child recipient by reducing their absolute glomerular filtration rate (GFR) (ml/min). The question arises whether these grafts can increase the absolute GFR when the child recipient grows or whether a child donor graft can better increase its function. The aim of this study was to evaluate the influence of donor and recipient ages and sex on renal function. METHODS: Eighty-five children and adolescents, aged 0.4-20.5 years at transplantation, were monitored annually, by GFR and effective renal plasma flow (ERPF), determined by clearances of inulin and para-aminohippuric acid. The patients received 90 grafts from donors aged 3-67 years. Follow-up time was around 5 years. RESULTS: Absolute GFR and ERPF (ml/min) of grafts from donors <20 years of age (all cadaveric donor grafts) increased during follow-up, resulting in a constant relative GFR and ERPF (ml/min/1.73 m2), whereas absolute GFR and ERPF of grafts from donors >20 years of age remained constant during follow-up, resulting in a significant decrease in relative values. Relative GFR and ERPF fell during follow-up in young recipients (<12 years of age), but remained constant in older recipients (>12 years). Donor and recipient sex did not influence renal function. CONCLUSIONS: Child donor grafts seem better able to increase their function with the growth of the child recipient than adult grafts. However, the limited access to pediatric grafts and the fact that pediatric cadaveric grafts might involve technical problems in connection with grafting restrict their use.

Late graft pancreatitis.

Among 40 type I diabetic patients who received a segmental pancreatic allograft with enteric exocrine diversion and had normal endocrine graft function for more than one year, 12 patients have had occasional episodes of "graft pain" associated with short-term hyperamylasemia. The symptoms usually resolved after 1-4 days. To determine possible precipitating factors, 80 such episodes were analyzed by interviewing all the patients and reviewing their files. To study the impact on endocrine graft function, the results of the serial intravenous glucose tolerance tests were plotted versus time. Episodes of late graft pancreatitis occurred at any given time between 6 and 51 months after transplantation. The frequency of bouts ranged between 1 and 31 per patient. The symptoms and clinical course were clearly different from late rejection episodes. Except for one severe case which resulted in graft loss, endocrine graft function did not deteriorate. Four conditions were found to correlate with the attacks: mental stress, alcohol and food intake, infections, and direct mechanical pressure to the pancreatic graft. We conclude that late graft pancreatitis can be distinguished from late rejection episodes and that the pancreatic graft may be more prone to acute pancreatitis than the native pancreas. The endocrine capacity of the pancreatic graft is usually not affected even by repeated attacks.