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.

Pharmacodynamics of rituximab in kidney allotransplantation.

The anti-CD20 antibody rituximab has recently gained interest as a B-cell depleting agent in renal transplantation. However, little is known about the pharmacodynamics of rituximab in renal transplant recipients. We have therefore studied the effect of single-dose rituximab in combination with conventional triple immunosuppressive therapy on the B-cell population in peripheral blood as well as in tissues. A total of 49 renal transplant recipients received single-dose rituximab, as induction therapy (n = 36) or as anti-rejection therapy (n = 13). We counted B cells in peripheral blood and performed immunohistochemical staining on lymph nodes and kidney transplant tissue samples to assess the prevalence of B cells. In all but 6 patients (88%) complete depletion of B cells in peripheral blood was achieved. In adults, 15 months after treatment the CD19+ and CD20+ cell counts were still below 5 cells/muL in the majority of patients (78%). The immunohistochemical staining showed a complete elimination of B cells in kidney tissue and a reduction of B cells in lymph nodes. In conclusion, single-dose rituximab in kidney transplant recipients evokes a long-term elimination of B cells in peripheral blood as well as within the kidney transplant. The effect seems to extend beyond the expected 3-12 months observed in lymphoma patients.

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.

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.

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.

No evidence of accelerated loss of kidney function in living kidney donors: results from a cross-sectional follow-up.

BACKGROUND: There is a lack of kidneys available for kidney transplantation, and living donors are increasingly used. It is important to examine the possible long-term adverse affect on the renal function and blood pressure of the donors. METHODS: We have made a comprehensive follow-up of all living kidney donors at our center from 1964 to 1995. Of 402 donors still alive, we were able to get information about serum creatinine, urinary proteins, and blood cells in urine using reagent strips, and blood pressure from 87%. The glomerular filtration rate (GFR) was estimated using a formula and was measured with Iohexol clearance in 43 of the donors. Individual data on GFR and the prevalence of hypertension were compared with the age- and gender-expected values. RESULTS: The mean age of the examined donors was 61 years (SD:13) at follow-up, and the time since donation was 12 years (SD:8). The average estimated GFR was 72% (SD:18) of the age-predicted value. The ratio of the estimated to the predicted GFR showed no correlation to the time since donation, indicating that there is no accelerated loss of renal function after donation. GFR below 30 ml/min was found in five donors. No donor died in uremia or had dialysis treatment before death. However, three donors developed renal disease, and one was in dialysis treatment. In two of these cases, hereditary factors were possibly involved. Hypertension was present in 38% of the donors but the age-adjusted prevalence of hypertension among donors was not higher than in the general population. Significant proteinuria (> or =1.0 g/L) was found in 3% and slight proteinuria (<1.0 g/L) in 9% of the donors. Proteinuria was associated with hypertension and a lower GFR. CONCLUSIONS: On average, the remaining renal function of kidney donors did not deteriorate more rapidly than what may be expected from ageing. However one-third of the female and half of the male donors developed hypertension and, approximately, 10% displayed proteinuria. Nevertheless, our study supports the continued use of living kidney donors if strict criteria are used for acceptance.

Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients.

BACKGROUND: Supplementation of immunosuppressive therapy with mycophenolate mofetil (MMF) has been found to reduce the rate of acute rejection in renal transplantation. We report a dose-finding study for MMF when administered in combination with low-dose tacrolimus and corticosteroid prophylaxis in cadaveric renal transplant recipients. METHODS: Two hundred thirty-two patients at 16 centers were enrolled in this randomized, parallel-group study. The three treatment groups were tacrolimus and corticosteroids (MMF-0 group, n=82); tacrolimus, corticosteroids, and 1 g of MMF daily (MMF-1 g group, n=79); and tacrolimus, corticosteroids, and 2 g of MMF daily (MMF-2 g group, n=71). Study duration was 6 months, and patients were followed up for patient and graft survival for 12 months. RESULTS: At 6 months posttransplantation, daily doses of 1 g and 2 g of MMF were associated with significantly lower rates of acute rejection compared with tacrolimus alone. The Kaplan-Meier rates were 48.5%, 24.9%, and 22.9%, respectively, for the three treatment groups when acute rejection was determined by clinical criteria (P=0.007). At month 12, patient survival rates were 100%, 97.5%, and 97.2% and graft survival rates were 90.2%, 92.4%, and 93.0% for the MMF-0 group, MMF-1 g group, and the MMF-2 g group, respectively. Gastrointestinal adverse events and leukopenia were higher in the MMF groups, especially in the MMF-2 g group (P<0.05). CONCLUSIONS: Low-dose tacrolimus combined with a MMF dose of 1 g daily and corticosteroids provided an optimized efficacy and safety profile. A higher dose of MMF (2 g) was associated with greater toxicity without a significant improvement in efficacy.

The use of pretransplant erythropoietin to normalize hemoglobin levels has no deleterious effects on renal transplantation outcome.

BACKGROUND: The aim of this study was to establish the outcome of renal transplantation in patients given pretransplant erythropoietin (EPO) treatment targeted at reaching a normal hemoglobin concentration (Hb), compared to those given EPO-treatment aimed at maintaining subnormal Hb. METHODS: A total of 416 patients from Scandinavian countries and with renal anaemia were enrolled to examine the effects of increasing Hb from a subnormal level (90-120 g/liter) to a normal level (135-160 g/liter) by EPO treatment. Half of the patients were randomized to have their Hb increased, with the other half randomized to maintain a subnormal Hb. Thirty-two patients from the normal Hb group and 24 patients from the subnormal group received a renal graft during the study period. The outcomes of these transplantations were examined prospectively for 6 months. RESULTS: Preoperative Hb levels were 143+/-17 and 121+/-14 g/liter in the two groups, respectively (P<0.0001). The Hb remained higher in the normal Hb group during the first 2 weeks after transplantation. The percentage of patients requiring postoperative blood transfusions in the normal Hb group was 16%, compared with 50% in the subnormal group (P<0.01). No statistically significant difference in the proportion of functioning grafts or in the serum creatinine levels could be detected. No correlation between EPO treatment and creatinine levels after transplantation was found. The frequency of adverse events was similar in the two groups. CONCLUSIONS: EPO treatment aimed at reaching a normal Hb in renal transplant recipients reduces the postoperative requirement for blood transfusions and has no deleterious effects on kidney graft function.

Combined pancreas and kidney transplantation improves survival in patients with end-stage diabetic nephropathy.

The purpose of this study was to find out whether prolonged normoglycemia, as achieved by a successful pancreas transplantation, can improve survival in patients with insulin-dependent diabetes mellitus. A retrospective analysis of actual 10-yr patient survival rates was done for all renal graft recipients who were given transplants more than 10 yr ago but within the cyclosporin era (i.e. 1981-1988). The actual 10-yr patient survival rate in non-diabetic renal graft recipients was 72%, In recipients of pancreas and kidney grafts and with prolonged function of the pancreas graft, the survival rate was 60%, whereas in patients subjected to simultaneous pancreas and kidney transplantation, but where the pancreatic grafts failed within 2 yr, the survival rate was 33%. In diabetic recipients of kidney transplants alone, the survival rate was 37%. The patient survival rate was substantially higher in non-diabetic patients and patients with functioning pancreas grafts compared with diabetic patients with kidney transplants alone or with failed pancreas grafts. We speculate that the decrease in mortality was due to the beneficial effect of long-term normoglycemia on diabetic late complications.

Daclizumab prevents acute rejection and improves patient survival post transplantation: 1 year pooled analysis.

Daclizumab is a genetically engineered human IgG1 monoclonal antibody specific for the alpha chain of the IL-2 receptor. A pooled analysis of two randomized, double-blind studies was performed on the efficacy and safety of daclizumab in renal transplantation, given in addition to standard immunosuppression. Patients receiving their first cadaveric renal allograft were randomized to receive 5 doses of daclizumab (n = 267) or placebo (n = 268), starting pre-operatively. Acute rejection at 1 year occurred less frequently with daclizumab (n = 74, 27.7 %) than with placebo (n = 116, 43.3%) (P = 0.0001). Fewer patients treated with daclizumab required anti-lymphocyte therapy for acute rejection (7.9 % vs. 15.3 %; P = 0.005). Mean cumulative doses of corticosteroids were lower with daclizumab (4133 mg) than with placebo (4562 mg). One year graft survival was 91.4 % with daclizumab, compared with 86.6 % on placebo (P = 0.065), with patient survival of 98.5 % and 95.1 % for daclizumab and placebo respectively (P = 0.022). Daclizumab was well tolerated. No increase in infectious episodes or lymphoproliferative disorders was observed with daclizumab. The incidence of cytomegalovirus infections was similar with daclizumab and placebo (15 % vs. 17.5 %). Therapy with daclizumab significantly reduces acute rejection in renal transplantation and improves patient survival without any increase in morbidity.

Polyomaviruria in renal transplant patients is not correlated to the cold ischemia period or to rejection episodes.

Polyomaviruria was observed in one-third of all renal transplant patients, irrespective of whether their renal grafts came from a living or cadaver donor, and was not correlated to graft rejection episodes. This suggests that the renal graft ischemia period is not the major cause of polyomavirus reactivation and that reactivation of polyomavirus is not a dominant cause of graft rejection.

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.

Area under the serum creatinine time-curve is a strong predictor of chronic renal allograft rejection.

BACKGROUND: A number of risk factors for chronic renal allograft rejection have been identified; in particular the number and severity of acute rejections, hypertension, hyperlipidemia, and insufficient immunosuppression. METHODS: In a retrospective case control study, all histologically confirmed cases of chronic rejection (n=45) that occurred between 1985 and 1993 among patients transplanted at Huddinge Hospital were compared with twice as many controls. Determinants such as donor age and sex, HLA-mismatch, cold ischemia time, recipient age and sex, body mass index, cause of renal disease, time undergoing dialysis, condition of blood vessels at surgery, time of onset, number of acute rejection episodes during the first 3 months, area under the serum creatinine versus time curve (AUC(Creatinine)), blood pressure, blood lipids, and cyclosporine concentrations at various times after the transplantation were also compared. Additional data were obtained from a questionnaire, concerning 79% of the cases and controls. RESULTS: Cases and controls were similar with regard to most determinants, that is, blood pressure, blood lipids, and average cyclosporine concentrations. The main outstanding risk factor for chronic rejection was the time-averaged creatinine (AUC(Creatinine)) value between day 22 and 3 months after transplantation. The adjusted odds ratio for chronic rejection increased stepwise from 1.1 to 9.2, when AUC(Creatinine) increased from < 150 to >300 micromol/l. The number of acute rejection episodes and number of HLA-mismatches also had a significant effect on the risk of chronic rejection. CONCLUSIONS: To reduce the risk of developing chronic rejection after renal transplantation acute rejection episodes during the first 3 months should be avoided as much as possible.