Graft Neutrophil Sequestration and Concomitant Tissue Plasminogen Activator Release During Reperfusion in Clinical Kidney Transplantation.

BACKGROUND: Inflammation, coagulation, and fibrinolysis are tightly linked together. Reperfusion after transient ischemia activates both neutrophils, coagulation, and fibrinolysis. Experimental data suggest that tissue plasminogen activator (tPA) regulates renal neutrophil influx in kidney ischemia and reperfusion injury. METHODS: In 30 patients undergoing kidney transplantation, we measured renal neutrophil sequestration and tPA release from blood samples drawn from the supplying artery and renal vein early after reperfusion. tPA antigen levels were measured using a commercial enzyme-linked immunosorbent assay kit. For each parameter, transrenal difference (Δ) was calculated by subtracting the value of the arterial sample (ingoing blood) from the value of the venous sample (outgoing blood). RESULTS: Positive transrenal gradients of tPA antigen occurred at 1 minute [Δ = 14 (3-46) ng/mL, P < .01] and 5 minutes [Δ = 5 (-3 to 27) ng/mL, P < .01] after reperfusion. At 5 minutes after reperfusion, a negative transrenal gradient of neutrophils was observed [Δ = -0.17 (-1.45 to 0.24) x 10E9 cells/L, P < .001]. At 1 minute after reperfusion, neutrophil sequestration into the kidney (ie, negative transrenal neutrophil count) correlated significantly with tPA release from the kidney (ie, positive transrenal tPA concentration), (R = -0.513 and P = .006). CONCLUSIONS: The findings suggest a proinflammatory role for tPA in ischemia and reperfusion injury in human kidney transplantation.

Matrix Metalloproteinase-9 and Graft Preservation Injury in Clinical Renal Transplantation.

BACKGROUND: Deleterious effects of matrix metalloproteinase-9 (MMP-9) have been established in experimental renal ischemia-reperfusion models but not in clinical renal transplantation thus far. METHODS: We studied MMP-9 and its physiological inhibitor tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) in 45 consecutive patients of a larger trial in renal transplantation: perioperative anti-thymocyte globulin (group A, n = 15), perioperative basiliximab (group B, n = 16), and conventional triple therapy (group C, n = 14). In addition to systemic blood samples, local blood samples were obtained simultaneously at 1 and 5 minutes after reperfusion from iliac artery and graft vein for calculation of transrenal changes. Because anti-thymocyte globulin activates inflammation, group A was analyzed separately. Groups B and C were pooled (group BC). RESULTS: Anti-thymocyte globulin infusion caused a robust rise of MMP-9 in the systemic circulation in group A. No significant transrenal difference of MMP-9 or TIMP-1 occurred in either group during graft reperfusion. In group BC, strong transrenal release of MMP-9 at 1 minute after reperfusion correlated with cold ischemia time (R = 0.66, P = .0001) and was associated with delayed graft function (P = .052). CONCLUSIONS: Renal production of MMP-9 on graft reperfusion is associated with cold ischemia time and emergence of delayed graft function. MMP inhibition may offer a means to reduce reperfusion injury in renal transplantation.

Surgical complications following 1670 consecutive adult renal transplantations: A single center study.

BACKGROUND AND AIMS: The aim of the study was to clarify the frequency and the sequel of surgical complications occurring within 1 year after renal transplantation. PATIENTS AND METHODS: Surgical complications after 1670 consecutive adult kidney transplantations performed between 2000 and 2009 were retrospectively analyzed. In 2%, a living-related allograft was used, and 10% were retransplantations. An intravesical technique without stenting was used for the ureteric implantation. RESULTS: There were 282 surgical complications occurring in 259 (15.5%) transplantations. Ureteral obstruction occurred in 53 (3.1%), lymphoceles in 39 (1.5%), postoperative hemorrhage in 36 (2.1%), and renal vein thrombosis in 22 (1.3%) patients, respectively. Out of the 17 lung emboli, 4 were fatal. Male recipients had twice as much ureteral stenosis as female (2.4 vs 1.2%, p < 0.05), and the opposite was true of urinary leakage (1.8% vs 4.0%, p < 0.025). Five-year patient and graft survival was impaired in patients with complications compared with patients without complications. Five-year patient survival was 92% versus 88% and graft survival 87% versus 74%. CONCLUSION: Surgical complications impair patient and graft survival after kidney transplantation.

Current characteristics and outcome of cytomegalovirus infections after kidney transplantation.

INTRODUCTION: The clinical course of cytomegalovirus (CMV) infections in the current era is poorly described. We characterized the symptoms and outcome of all CMV infections in a large cohort of kidney transplant recipients. Among 1129 kidney transplant recipients transplanted between 2004 and 2011 in Charité Universitätsmedizin Berlin and Helsinki University Hospital, 297 patients with CMV infection were characterized. RESULTS: CMV disease occurred in 217/1129 patients (19.2%), and CMV infection in 297/1129 (26.3%). Gastrointestinal symptoms were recorded in 58% and fever in 47% patients with primary CMV disease, compared to 46% and 27% patients with symptomatic CMV reactivation, whereas leukopenia or thrombocytopenia were seen in only 17-28% patients, and malaise in 9-10%. Tissue-invasive CMV gastroenteritis was confirmed in 11% and CMV pneumonia in only 1% of patients with CMV disease. Only 1 patient died because of CMV infection (mortality 0.3%). Virus-related factors or the use of secondary prophylaxis did not predict the risk of recurrence, which occurred in 33% patients. CONCLUSION: In conclusion, CMV disease remains a common problem after kidney transplantation. Gastrointestinal symptoms were common, especially in patients with primary CMV infection, whereas bone marrow suppression, hepatopathy, or malaise were seen less frequently.

Scandiatransplant report 2009.

Scandiatransplant is the Nordic organ exchange organization that has existed for 41 years by a close collaboration between transplant centers. It has been valuable to ensure the optimal usage of available organs for transplantation. Analyzing the database for the past 15 years (1995-2009) revealed that the fraction of organ donors in the age category 60 to 90 years has increased considerably. The number of retrieved organs from deceased donors increased for kidney, liver, and lungs but only slightly for hearts. In the last time period, the mean number of organs retrieved per deceased donor counting only those having a recipient increased to 3.7 for younger donors and to 2.6 from the older group. In 2009, the STAMP (Scandiatransplant acceptable mismatch program) was launched to help highly immunized kidney patients. In 2009, kidney transplantations exhibited for Norway, 60 per million people (pmp); more than 40 pmp for Sweden and for Denmark; approximately 35 pmp for Finland; and more than 20 pmp for the living donor kidney transplantations in Iceland. The best year ever within Scandiatransplant with respect to total number of organ transplantations from deceased and living donors was 2009.

Primary CMV infections are common in kidney transplant recipients after 6 months valganciclovir prophylaxis.

Prolonging cytomegalovirus (CMV) prophylaxis in CMV seronegative recipients of a kidney from CMV seropositive donor (D+/R-) may reduce the incidence of late infections. We analyzed late-onset primary CMV infections after 6 months valganciclovir prophylaxis. Data from all CMV D+/R- kidney transplant recipients between January 2004 and December 2008 at our center were analyzed. Patients with a functioning graft at 6 months after transplantation who received 6 months of valganciclovir prophylaxis 900 mg once daily were included (N = 127). CMV was diagnosed with quantitative PCR. Prophylaxis was completed in 119 patients. Prophylaxis was stopped at 3-5 months due to leukopenia or gastrointestinal side effects in eight patients. Late-onset primary CMV infection developed in 47/127 (37%) patients median 244 days after transplantation (range 150-655) and median 67 days after the cessation of prophylaxis (range 1-475). Four infections were asymptomatic. In others, symptoms included fever (N = 28), gastrointestinal symptoms (nausea, vomiting, diarrhea) (N = 24), respiratory tract symptoms (N = 12), and hepatopathy (N = 6). Median peak viral load was 13500 copies/mL (range 400-2,831,000). Recurrent CMV infection developed in 9/47 (19%) patients. No significant risk factors for CMV infection were identified. Symptomatic primary CMV infections were commonly detected also after prolonged valganciclovir prophylaxis.

Positron emission tomography in clinical islet transplantation.

The fate of islets in clinical transplantation is unclear. To elude on this positron emission tomography combined with computed tomography (PET/CT) was performed for 60 min during islet transplantation in five patients receiving six transplants. A fraction of the islets (23%) were labeled with 18F-fluorodeoxyglucose ([(18)F]FDG) and carefully mixed with unlabeled islets just prior to intraportal transplantation. The peak radioactivity concentration in the liver was found at 19 min after start of islet infusion and corresponded to only 75% of what was expected, indicating that islets are lost during the transplantation procedure. No accumulation of radioactivity was found in the lungs. A nonphysiological peak of C-peptide was found in plasma during and immediately after transplantation in all subjects. Distribution in the liver was heterogeneous with wide variations in location and concentration. Islets found in areas with concentrations of >400 IEQ/cc liver tissue varied between 1% and 32% of the graft in different subjects. No side effects attributed to the PET/CT procedure were found. Clinical outcome in all patients was comparable to that previously observed indicating that the [(18)F]FDG labeling procedure did not harm the islets. The technique has potential to be used to assess approaches to enhance islet survival and engraftment in clinical transplantation.

Aspects of present and future data presentation in Scandiatransplant.

Scandiatransplant is the Nordic organ exchange organization having existed for almost 40 years. With close collaboration between transplant centers in the Nordic countries, it has been valuable to ensure the optimal usage of available organs. The heart is the most often exchanged organ within the collaboration. It has been decided to create a priority for hyperimmunized kidney patients for compulsory exchange of organs from deceased donors. The age of the deceased organ donors has changed from younger to older donors. The evaluation of deceased kidney transplantations and deceased liver transplantations from 1995 to 2007 is shown for 4 countries. Iceland by itself is performing living donor kidney transplantations with great intensity. Scandiatransplant will make efforts to present more data than just transplantation to yield a more complete picture of organ transplantation.

Heme oxygenase 1 gene polymorphisms and outcome of renal transplantation.

Heme oxygenase isoenzyme HO-1 has been linked to several cytoprotective functions with a potentially beneficial role in transplantation. In the present study, the effect of genetic variation in HO-1 on renal allograft outcome was investigated. Six hundred and eighty patients subject to renal transplantation in a single transplant unit and their cadaveric kidney donors were included in this study. Four single-nucleotide polymorphisms and one microsatellite marker in the HO-1 gene region were analysed. Some statistically nominally significant associations were observed in preliminary analyses between polymorphisms studied and clinical outcomes, but after correction for multiple comparisons none remained significant. Our data suggest that the HO-1 gene polymorphisms studied have no significant role on outcome of kidney transplantation in the Finnish population.

Complications of gallstone disease in kidney transplantation patients.

BACKGROUND: We studied the complications of gallstone disease in kidney transplantation patients and evaluated whether the screening and treatment of gallstones before acceptance to the kidney waiting list is relevant. METHODS: Complications of gallstone disease were evaluated in 1608 kidney transplantation patients on cyclosporine and long-term steroid treatment with median age 45.5 years, transplanted between 1990 and 2000. To evaluate the prevalence of cholecystolithiasis after kidney transplantation an abdominal ultrasound examination was cross-sectionally performed to a subgroup of 304 patients and the results were correlated to their serum lipid values, changes in BMI and use of statins. RESULTS: Pre-transplant cholecystectomy due to cholecystolithiasis (prerequisite for acceptance to kidney waiting list) had been performed on 71 (4%) of the patients. Thirty (15%) patients with diagnosed post-transplant gallstones and four without gallstones developed biliary complications. There were 25 cases of cholecystitis of which three resulted in gallbladder perforations. Seventeen patients (50%) with biliary complications required urgent surgery and one (3%) patient died of post-operative complications. In the subgroup of ultrasound examination patients (median 7 years post-transplant follow-up) 81% of the patients had no gallstones and 9% of the patients had gallstones had developed after transplantation. Patients with pre-transplant gallstones were older (P < 0.01) and patients with post-transplant gallstones gained the most weight during the follow-up. No differences in lipid values were found. CONCLUSION: In transplantation patients, the complications of gallstone disease may be severe. Screening and treatment of pre- and post-transplantation gallstone disease are recommended.

Tacrolimus combined with two different dosages of sirolimus in kidney transplantation: results of a multicenter study.

Tacrolimus combined with mycophenolate mofetil (MMF) is an effective regimen in kidney transplantation. This study compared the efficacy of combining tacrolimus and two different dosages of sirolimus with an established tacrolimus-MMF regimen. Each day in addition to tacrolimus, 325 patients received 2 mg sirolimus (TAC-SRL2 mg), 325 patients received 0.5 mg sirolimus (TAC-SRL0.5 mg) and 327 patients 1 g MMF (TAC-MMF). The initial tacrolimus dose was 0.2 mg/kg/day. Sirolimus patients received loading doses of 6 or 1.5 mg, and daily doses of 2 or 0.5 mg thereafter. Steroid administration was identical for all groups. The incidence of biopsy-proven acute rejection was lower in the TAC-SRL2 mg group (15.7%) compared with the TAC-SRL0.5 mg (25.2%, p = 0.003) and the TAC-MMF groups (22.3%, p = 0.036). Six-month graft survival was 91.0% (TAC-SRL2 mg), 92.6% (TAC-SRL0.5 mg) and 92.4% (TAC-MMF); the respective values for patient survival were 98.1%, 97.8% and 97.9%. Thirty-four patients (10.5%), 19 patients (5.8%) and 16 patients (4.9%) in the TAC-SRL2 mg, TAC-SRL0.5 mg and TAC-MMF groups, respectively, discontinued the study because of adverse events. Hyperlipemia was reported more often in the TAC-SRL2 mg group (24.0%) compared with 19.4% (TAC-SRL0.5 mg) and 11.0% (TAC-MMF; p < 0.05). Combining 2 mg sirolimus/day with tacrolimus results in lower rates of acute rejection, but a higher incidence of adverse events.

Kidney transplantation from 1119 deceased donors in Finland, 1991 to 2003: impact of donor factors.

We assessed the effect of donor factors on the recovery and quality of cadaveric kidney transplant function. During 1991 to 2003, 2006 kidney grafts were derived from 1119 heart-beating donors in Finland. The annual mean age of donors increased from 33 to 46 years, with a significant decrease in the proportion of high-energy trauma and gunshot wounds and with an increased proportion of donors with coronary disease, hypertension, or cardiopulmonary resuscitation and surgical/radiological interventions before death. The transplant team's share of kidney retrievals increased from 50% to nearly 100%. In uni- and multivariate analyses all these factors had significant effects on the onset and quality of early graft function; however, this effect practically vanished by 1 year posttransplant. Of all studied donor factors, only donor cytomegalovirus (CMV) status significantly affected long-term survival, with donor CMV-positive grafts having 5% worse survival at 5 years. The 1-year graft survival improved from 90.9% to 96.2% and mean 1-year creatinine decreased from 121 micromol/L to 109 micromol/L during these 13 years, showing that the worsening trends in donors quality were compensated by improvements in other aspects of the process.

Impact of mycophenolate mofetil intolerance on early results of kidney transplantation.

From 1992 to 2003, 407 kidney transplantations were performed on 403 patients using cyclosporine (CyA) or tacrolimus (Tac), mycophenolate (MMF), and steroid immunosuppression. Patient records examined for adverse events (AE) and MMF dose reductions or discontinuations during 100 days posttransplant were correlated with data on rejections, graft function, and survival. AEs occurred in 79.1% of transplantations. Gastrointestinal (GI) symptoms, infections, and cytopenias were common. Surprisingly, in 50% of all transplantations serum alanine transferase (ALAT) was elevated, among 21% the change was over three times the upper limit of normal. Patients with delayed graft function showed increased incidences of GI symptoms and thrombocytopenias. There were more ALAT increases and thrombocytopenias in patients on CyA and more GI symptoms in patients on Tac. In 34% of transplantations, the MMF dose was reduced or discontinued. In CyA patients with MMF reduction by day 21, rejection incidence during the subsequent 21 days was 10% versus 0.6% in patients with full-dose MMF until day 21 (P < .002). Among Tac patients no increased rejection frequency was seen after reducing MMF.

Two decades of experience with cyclosporine in renal transplantation in Helsinki.

We present our experience on cyclosporine (CsA) triple immunosuppression in 2445 cadaveric kidney transplantations performed from 1984 to 2002 in Helsinki. Overall, delayed onset of graft function occurred in 30.2% and acute rejection in 25.6% of the transplantations. The 1-, 5-, and 10-year patient survival was 95.1%, 84.5%, and 69.1%; the graft survival rates were 90.0%, 74.9%, and 56.7%; and the death-censored graft survival, 93.3%, 83.5%, and 72.4%. During the study period, the 5-year patient survival improved from 70.8% to 90.6% and the graft survival from 58.2% to 88.0% with the graft half-life estimate of 1-year survivors improving from 7.6 to 21.8 years. Acute rejection episodes decreased from 33.0% to 19.9% and the calculated creatinine clearance at 1 year improved from 50.3 mL/min to 74.3 mL/min. Mean CsA dose diminished significantly, both at 3 weeks (from 8.2 mg/kg to 4.9 mg/kg) and at 1 year posttransplant (from 3.7 mg/kg to 2.8 mg/kg). In 16.7% of transplantations where azathioprine had to be discontinued early, significantly more rejections occurred (38.0% vs 23.2%) with inferior 1-year graft survival (80.2% vs 94.8%) compared to the transplantations continuing on triple therapy. Among 1-year survivors, the 6-month serum creatinine level was strongly associated with death-censored long-term graft survival. In this material, the CsA dosage at 1 year did not predict long-term graft survival.

Should Helicobacter pylori infection be treated before kidney transplantation?

BACKGROUND: Before the introduction of modern medication for ulcer disease, gastroduodenal complications were often fatal in recipients of kidney transplants. Helicobacter pylori causes gastritis and is an important risk factor for peptic ulcer disease and gastric malignancies. The aim of this study was to evaluate whether H. pylori infection influences the outcomes of kidney transplantation. METHODS: Between 1991 and 1994, serum H. pylori antibodies were determined in samples taken just before transplantation from 500 consecutive recipients of kidney transplants. Clinical data were collected retrospectively by means of questionnaires sent to the patients and from the national kidney transplantation registry. RESULTS: The prevalence of seropositivity of H. pylori was 31% in the 500 renal transplant subjects, and the seropositivity increased with age. There were no differences in patient or graft survival between the seronegative and seropositive patients. During the first 3 months after transplantation, five seronegative and one seropositive patient had gastroduodenal ulcers, with bleeding complications in three of the seronegative ones. After 3 months, there were more ulcers in the seropositive group (6 vs 3%) and more oesophagitis in the seronegative group (9 vs 7%). During the 6-year follow-up, two cases of gastroduodenal malignancies were found in the helicobacter-positive group and none in the seronegative group. CONCLUSIONS: Helicobacter pylori infections did not result in significant postoperative gastric complications. Two of the 155 seropositive patients developed gastroduodenal malignancies.

Platelet-specific alloantigens in cadaveric renal transplantation. A prospective study. Effect of HPA-5b mismatch in acute vascular rejection of renal allografts.

This prospective study comprised 166 renal allograft-recipient pairs that were studied for human platelet alloantigens (HPA) 1-3 and 5, which have been shown to be expressed by adhesion molecules of the vascular endothelium. Four of the five (80%) HPA-5a5a regraft recipients developing acute vascular rejection (AVR) had received an HPA-5b-incompatible graft in contrast to one of the 32 (3%) regraft recipients without rejection. The occurrence of AVR was not explained by the degree of HLA mismatches. All four regraft recipients of an HPA-5b-mismatched graft with AVR were HLA-A3,B7, and the combination of HLA-A3 and/or B7 match and an HPA-5b-mismatched graft was associated with AVR. No antibodies against HPA-5b were detected in the patients with AVR of an HPA-5b-mismatched graft. These preliminary findings suggest that HPA-5b is a minor histocompatibility antigen involved in the development of AVR.

Transplantation of both kidneys from 408 donors; comparison of results.

The outcome of 816 paired kidney transplantations from 408 cadaveric donors was evaluated. The transplantations were divided according to order of transplant surgery into group 1 [mean cold ischemia time (CIT) 22 h] and group 2 (mean CIT 28 h). In group 1 the frequency of delayed onset of graft function (DGF) was 22% versus 35% in group 2 (P < 0.005). The 1-year patient survival and graft survival (GS) in group 1 was 98% and 93% versus 94% (P < 0.005) and 90% in group 2. Hemodialysis patients in group 2 had significantly greater DGF (43%) and poorer GS (88%) than peritoneal dialysis patients and the success of transplantation was particularly poor in recipients over 50 years of age.

Cancer incidence in a kidney-transplanted population.

A study on cancer incidence after kidney transplantation was performed using data of national transplant and cancer registries. Since 1964 up to 30 June 1997, 3440 kidney transplantations were performed on 2890 patients. From 1967 to 1997, 230 posttransplantation malignancies were found in 20,817 patient-years of follow up. The standardised incidence ratio (SIR) was 3.33 compared to the general population. The SIR was highest in skin cancer (39.2). The SIRs were high in cancers of the lip (23.0), thyroid (8.08), kidney (8.0), lower urinary tract (3.2), non-Hodgkin lymphoma (4.8), ovary (3.9) and colon (3.9). Skin cancer and lymphomas had much higher SIRs in men than in women whereas lower urinary tract cancer had a higher SIR in women. During the first 10 follow up years, life-table analysis indicates a higher cancer risk in cyclosporine-treated patients, but this may be biased by their shorter follow up as the overall SIR was equal in both groups. This population study shows the increased incidence of cancer in the transplant population and points out the importance of cancer surveillance in the years following kidney transplantation.