Liver transplantation with grafts from controlled donors after cardiac death: a 20-year follow-up at a single center.

The first liver transplantation (LTx) in Sweden was performed in 1984, but brain death as a legal death criterion was not accepted until 1988. Between November 1984 and May 1988, we performed 40 consecutive LTxs in 32 patients. Twenty-four grafts were from donors after cardiac death (DCD) and 16 grafts from heart-beating donors (HBD). Significantly, more hepatic artery thrombosis and biliary complications occurred in the DCD group (p < 0.01 and p < 0.05, respectively). Graft and patient survival did not differ between the groups. In the total group, there was a significant difference in graft survival between first-time LTx grafts and grafts used for retransplantation. There was better graft survival in nonmalignant than malignant patients, although this did not reach statistical significance. Multivariate analysis revealed cold ischemia time and post-LTx peak ALT to be independent predictive factors for graft survival in the DCD group. In the 11 livers surviving 20 years or more, follow-up biopsies were performed 18-20 years post-LTx (n = 10) and 6 years post-LTx (n = 1). Signs of chronic rejection were seen in three cases, with no difference between DCD and HBD. Our analysis with a 20-year follow-up suggests that controlled DCD liver grafts might be a feasible option to increase the donor pool.

Domino liver transplantation: risks and benefits.

Domino liver transplantation, wherein a patient who himself undergoes liver transplantation in turn donates his liver to another recipient, has been performed since the mid-1990 s. Although livers from a handful of metabolic disorders cured by liver transplantation have been used for domino transplantation, familial amyloidotic polyneuropathy (FAP) livers are by far the most common source. FAP is an inherited disorder never presenting its clinical manifestation before the age of 15. In many carriers, the genetic disorder never manifests during lifetime. Thus, only a proportion of patients with FAP develop disease symptoms, which has been the rationale for using such livers for other patients on the waiting list for liver transplantation. According to the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR), only 2 out of more than 500 patients so far have developed symptoms after domino liver transplantation using an FAP liver. Domino recipients with nonmalignant indications for liver transplantation show excellent long-term survivals. With careful selection of recipients, the procedure helps to reduce the organ shortage and the time on the waiting list for patients with malignant disorders.

Liver transplantation for familial amyloidotic polyneuropathy (FAP): a single-center experience over 16 years.

Orthotopic liver transplantation (LTx) is currently the only available treatment that has been proven to halt the progress of familial amyloidotic polyneuropathy (FAP). The aim of this study was to assess mortality and symptomatic response to LTx for FAP. All 86 FAP patients transplanted at our hospital between April 1990 and November 2005 were included in the study. Five patients underwent retransplantation. The 1-, 3- and 5-year patient survival rates in patients transplanted during 1996-2005 were 94.6%, 92.3% and 92.3%, respectively, a significant difference from the rates of 76.7%, 66.7% and 66.7%, respectively, during 1990-1995 (p = 0.0003). Multivariate analysis revealed that the age at the time of LTx (>or=40 years), duration of the disease (>or=7 years) and modified body mass index (mBMI) (<600) were independent prognostic factors for patient survival. A halt in the progress of symptoms was noted in most patients, but only a minority experienced an improvement after LTx. To optimize the posttransplant prognosis, LTx should be performed in the early stages of the disease, and close post-LTx monitoring of heart function by echocardiography and of heart arrhythmia by Holter ECG is mandatory.

Sirolimus experience at a Swedish transplantation center.

Sirolimus is an interesting drug due to its original mechanism of action and because it seems to lack the nephrotoxicity associated with calcineurin inhibitors. During the past 10 years, sirolimus has undergone several clinical trials. Beginning with phase I studies, our first patient given sirolimus was enrolled in 1993, after which we participated in sirolimus phase II trials and finally conducted the large phase III study that led to registration of sirolimus in the European Union (EU) in 2001. Altogether, 111 patients have been treated with sirolimus in our department. Initially, we participated in clinical trials evaluating sirolimus in combination with cyclosporine, but later we focused on studies using sirolimus as base therapy. We found sirolimus to be an effective immunosuppressant lacking several of the disturbing side effects associated with calcineurin inhibitors. It has a high antirejection efficacy and yields excellent survival results, with better renal function than that achieved by calcineurin inhibitors. The main side effects, hyperlipidemia and leukothrombocytopenia, are usually easily manageable. Sirolimus presents an alternative to prophylactic immunosuppression with calcineurin inhibitors and, in the field of transplantation, it represents a welcome addition to the immunosuppressive armamentarium.

Identification of the nonclassical HLA molecules, mica, as targets for humoral immunity associated with irreversible rejection of kidney allografts.

BACKGROUND: A substantial portion of kidney allografted patients experience early acute rejection episodes and even irreversible rejections in the early posttransplantation period. The presence of HLA alloantibodies before grafting is associated with early immunological complications, but in many patients rejections and graft loss occur even in the absence of such antibodies. METHODS: In this study, 748 serum samples taken before and at various time points after kidney transplantation from 139 patients were investigated for the presence, frequency, and specificity of kidney microvascular endothelial cell (KMEC)-reactive antibodies using major histocompatability class (MHC) I-related chain A (MICA) transfected cells and flow cytometry, antibody blocking experiments, and Western blotting. The ability of MICA-specific antibodies to fix complement and to induce a prothrombotic phenotype in KMECs was investigated. RESULTS: A polymorphic, 62 kDa nonclassical HLA class I molecule is identified as a new target molecule for reactivity in sera from patients with irreversible rejections. Specific blocking and transfection experiments verified the target molecule as MICA. A significant correlation was established for pre- or posttransplantation MICA humoral immunity and graft loss (P<0.001). MICA-specific antibody titers increased in the posttransplantation period and were present before any signs of clinical rejection. MICA antibody-containing patient sera induced a prothrombotic phenotype in KMECs. CONCLUSION: The increasing polymorphism detected at the MIC loci combined with the results of this study suggest that typing for the MIC loci and crossmatching for the detection of anti-MIC antibodies before transplantation should be used routinely. A better recipient-donor selection based on a negative crossmatch for both anti-donor HLA and MICA antibodies will decrease early graft rejections and losses.

Urinary tract infections following renal transplantation.

The incidence of urinary tract infections (UTIs) in 363 adult renal transplant recipients transplanted during the period 1990-96 has been analysed. UTI occurred in 96 patients (26%), most frequently during the first year after transplantation. Female recipients had significantly more UTI than male recipients (49% vs. 14%, p < 0.0001). There was no difference in the incidence of UTI between recipients receiving pig-tail catheters as ureteral stents or not, the figures being 21% vs. 28%, respectively. Age had no influence on the incidence of UTI. In 341 patients treated with cyclosporine the incidence of UTI was 28%, while in 15 patients treated with FK-506 only 1 patient (7%) had a UTI (ns). The majority of organisms cultured were gram-negative (76%), with approximately 1/3 being Escherichia coli and 1/5 being Enterococcus and Klebsiella/Enterobacter. The bacterial spectrum was not influenced by the recipient's age. UTI had no effect on the number of rejections, or on graft and patient survival in living donor transplant recipients. No significant difference was found in graft and patient survival rates at 3 yr between patients who had UTI or no UTI.

Prognostic significance of pathological chest radiography in transplant patients affected by cytomegalovirus and/or pneumocystis carinii.

PURPOSE: In order to evaluate the prognostic significance of chest film findings in connection with cytomegalovirus (CMV) and/or pneumocystis carinii infection (PC), a retrospective review was made of the pulmonary charts of 274 recipients of kidney and/or pancreatic grafts transplanted between April 1987 and December 1990. MATERIAL, METHODS AND RESULTS: Positive laboratory findings for CMV and/or PC were seen in 92 patients. In 77 patients only CMV was found, 13 patients had both CMV and PC, and 2 patients had only PC. In 57 patients a chest examination was performed. The films were reviewed by 2 radiologists independently. In 32 patients normal chest film findings were seen, while 25 patients demonstrated pathological changes. Of the patients with pathological changes 3 had only pleuritis while the remaining 22 demonstrated parenchymal infiltrations. No deaths occurred among patients infected with CMV and/or PC, when the chest film findings were normal or pleuritis only was seen, but there were 9 deaths in the group of patients with parenchymal infiltrations. Of the patients who died, 2 had only CMV, 5 had both CMV and PC, and 2 had only PC. The overall mortality, regardless of radiological findings, did not exceed 3% in patients with CMV only, but increased to 38% in patients with both CMV and PC. In patients with parenchymal infiltrations the corresponding mortality figures were increased to 18% and 56%, respectively. CONCLUSION: We conclude that a radiologically verified pneumonia related to the infectious agent influences the prognosis, and that CMV pneumonia has a better prognosis than PC pneumonia.

Renal fibrosis in cyclosporin A-treated renal allograft recipients: morphological findings in relation to renal hemodynamics.

Nineteen nondiabetic kidney graft patients treated with cyclosporin A for 2 years underwent percutaneous renal allograft biopsy as well as renal hemodynamic examination. Renal allograft fibrosis was quantitatively evaluated as the relative volume of the renal cortical interstitium (VV %) and as the interstitium/tubuli ratio (I/T ratio). The histological changes were then classified into four groups, depending on the degree of interstitial fibrosis. The glomerular filtration rate (GFR), renal plasma flow (RPF), renal blood flow (RBF), filtration fraction (FF), and fractional clearance of sodium, potassium, phosphate, chloride, osmoles, and free water clearance were determined in all patients and in 13 healthy controls. Kidney graft recipients had significantly lower GFR, lower RPF, and lower RBF than the healthy controls (P < 0.001 for all comparisons) while FF was similar in patients and controls. Transplant recipients had a significantly higher fractional excretion of sodium, potassium, chloride, and phosphate than controls. All except one patient had clearly increased VV values, indicating increased interstitial fibrosis. The mean VV in renal allograft patients was 35% +/- 10% (normal < 16% +/- 5%) and the I/T ratio was 1.07 +/- 0.60 (normal < 0.24 +/- 0.08). No correlation was found between the quantitative or semiquantitative biopsy analysis and any renal hemodynamic parameter measured. We conclude that renal function is significantly decreased in kidney graft recipients, but that adaptive tubular changes occur in the graft. Interstitial renal fibrosis was common but did not correlate to any renal functional parameter.

Consistent absorption of cyclosporine from a microemulsion formulation assessed in stable renal transplant recipients over a one-year study period.

To evaluate the pharmacokinetic properties of the new microemulsion formulation of cyclosporine (Sandimmun Neoral), a double-blind, prospective study in stable renal transplant recipients was performed. The patients were randomized on a 4:1 basis either to receive Sandimmun Neoral (n = 45) or continue on regular Sandimmun (n = 12). Before randomization, a steady-state pharmacokinetic profile study was performed in all patients while they were still on regular Sandimmun. Pharmacokinetic assessments were then performed after 8 and 12 weeks and after 1 year. A milligram-to-milligram dose conversion was shown to be adequate to maintain the patients within a predefined target therapeutic window. Changes in pharmacokinetic parameters after conversion to Sandimmun Neoral were consistent with an increased rate and extent of cyclosporine absorption from the Neoral formulation. This was reflected by a shorter time to reach peak concentration and also by a mean increase in peak concentration by 67%, and an overall mean increase in drug exposure (area under the curve) by 34%. These findings were also confirmed 1 year after conversion. Furthermore, significantly reduced intraindividual variability in pharmacokinetic parameters was found, as well as improvements in the correlation between trough concentrations and area under the curve after conversion to Sandimmun Neoral. In conclusion, our results indicate an improved and consistent absorption of cyclosporine from the Neoral formulation, which should make clinical management easier and safer.

Evolution of diabetic nephropathy in kidney grafts. Evidence that a simultaneously transplanted pancreas exerts a protective effect.

Thirty-six renal transplant biopsies were obtained from 20 diabetic patients 1-6.5 years after successful combined pancreatic and renal transplantation (PKtx). An additional 36 renal transplant biopsies were obtained from 30 diabetic recipients 1-6.8 years after kidney transplantation only (Ktx). Light microscopic lesions indicating diabetic nephropathy were evaluated by a semiquantitative score ranging from 0 to 9. Within 2.5 years after transplantation, light microscopy showed no or only slight diabetic changes in both groups (nephropathy score = 0-2). Later, a nephropathy score > or = 3 was seen in only 1 of 15 biopsies (6.7%) in the combined PKtx group, but in 11 of 24 biopsies (45.8%) in the Ktx group (P < 0.05). Twenty-eight of the biopsies from the PKtx group and 26 of them from the Ktx patients were examined with electron microscopic morphometry to evaluate the glomerular basement membrane thickness (BMT) and the relative volume of the mesangial tissue (Vv). Of the biopsies taken < 2 1/2 years after transplantation in PKtx patients, and of those similarly taken in the Ktx patients, 93.8% vs. 88.9% had BMT values within 2 SD of the normal (NS). Of the kidney biopsies taken > or = 2.5 years after transplantation, 91.7% in the PKtx group still had a normal BMT, while only 35.3% of the biopsies in the Ktx group had a normal BMT (P < 0.01). In the PKtx group, the Vv was normal in 12/16 (75.0%) of the biopsies taken < 2 1/2 years after transplantation, and in 9/11 (81.8%) of the biopsies obtained > or = 2.5 years after transplantation. In contrast, the Vv was normal in only 1/9 (11.1%) and 2/17 (11.8%) of correspondingly obtained biopsies from Ktx patients (biopsies < 2.5 years after transplantation, P < 0.01, and biopsies > or = 2.5 years after transplantation, P < 0.001, respectively). We conclude that a functioning pancreatic transplant can prevent or reduce the various signs of diabetic nephropathy that eventually develop in diabetic patients with a kidney graft only.

Effect of reduced cyclosporin dosage on long-term renal allograft histology.

The effect of different doses of cyclosporin (CyA) on the occurrence of histological lesions in renal allograft biopsies was investigated 2 years after transplantation. Biopsy findings were compared in three different groups of patients. In group 1, patients were immunosuppressed with CyA and prednisolone according to an early, high-dosage schedule (initial CyA dose 15-17.5 g/kg body weight); in group 2, they were treated with a medium CyA dose (initial dose 12 mg/kg), together with prednisolone; and in group 3, patients were given triple drug therapy consisting of low doses of CyA (initial dose 8 mg/kg), together with both azathioprine and prednisolone. Interstitial fibrosis and tubular atrophy were common findings in all groups, and on the basis of all biopsies, no difference could be found between the groups with respect to the relative volume of the renal cortical interstitium, which was used as a quantitative parameter for interstitial fibrosis. Likewise, no difference was found with respect to serum creatinine levels. When grafts that showed signs of rejection (usually vascular rejection) in the biopsy were excluded (two in group 1, six in group 2, and ten in group 3), the mean interstitial volume was significantly lower in group 3 (triple drug therapy) than in the other groups. The serum creatinine levels were also significantly lower in group 3 than in group 1. Thus, chronic renal lesions could be ameliorated when CyA doses were lowered, but this appeared to entail an increased risk of acute or chronic vascular rejection.

Immunopathological patterns in long-term renal allografts.

Forty-eight consecutive core needle biopsies obtained 12-158 months after transplantation from 48 human renal allografts were analyzed. A conventional histological investigation and an immunohistochemical analysis of various markers of the immune system were performed, as well as cytological analyses of simultaneously obtained fine-needle aspiration biopsies. Findings were compared in grafts with excellent or reduced function and in patients who were immunosuppressed with azathioprine or cyclosporine. All the patients with excellent renal graft function (serum creatinine level less than or equal to 120 mumol/L) showed a normal picture with respect to both FNAB pattern and immunohistology, irrespective of the type of immunosuppression. Thus, the presence of inflammatory cell infiltration in a long-term renal graft suggests a pathological process of potential clinical significance. Biopsies from CsA-treated patients with reduced renal graft function (serum creatinine greater than 120 mumol/L) showing either a normal picture or focal interstitial fibrosis on histological examination were also usually normal with respect to both FNAB cytology and the immunohistological pattern. Five of 36 biopsies with reduced function showed an immunohistochemical pattern with signs of immune activation indistinguishable from those seen in early acute rejection. In cases with histological signs of chronic rejection, the immunopathological pattern varied, which suggests that different pathogenetic mechanisms were involved.