Decreasing incidence of cancer after liver transplantation-A Nordic population-based study over 3 decades.

Cancer remains one of the most serious long-term complications after liver transplantation (LT). Data for all adult LT patients between 1982 and 2013 were extracted from the Nordic Liver Transplant Registry. Through linkage with respective national cancer-registry data, we calculated standardized incidence ratios (SIRs) based on country, sex, calendar time, and age-specific incidence rates. Altogether 461 cancers were observed in 424 individuals of the 4246 LT patients during a mean 6.6-year follow-up. The overall SIR was 2.22 (95% confidence interval [CI], 2.02-2.43). SIRs were especially increased for colorectal cancer in recipients with primary sclerosing cholangitis (4.04) and for lung cancer in recipients with alcoholic liver disease (4.96). A decrease in the SIR for cancers occurring within 10 years post-LT was observed from the 1980s: 4.53 (95%CI, 2.47-7.60), the 1990s: 3.17 (95%CI, 2.70-3.71), to the 2000s: 1.76 (95%CI, 1.51-2.05). This was observed across age- and indication-groups. The sequential decrease for the SIR of non-Hodgkin lymphoma was 25.0-12.9-7.53, and for nonmelanoma skin cancer 80.0-29.7-10.4. Cancer risk after LT was found to be decreasing over time, especially for those cancers that are strongly associated with immunosuppression. Whether immunosuppression minimization contributed to this decrease merits further study.

Pediatric organ transplantation and risk of premalignant and malignant tumors in Sweden.

Increased cancer risks are well documented in adult organ transplant recipients. However, the spectrum of malignancies and risk in the pediatric organ transplant population are less well described. We identified all solid organ transplanted patients aged <18 in Sweden between 1970-2007 (n = 536) in the National Patient Register and linked to the Cancer Register. Nationwide rates were used to calculate standardized incidence rate ratios and 95% CI estimating the association between transplant and cancer during maximum 36 years of follow-up. Nearly 7% of pediatric solid organ transplant recipients developed a premalignant or malignant tumor during follow-up. Transplantation was associated with an increased risk of any cancer (n = 24, SIR = 12.5, 95% CI: 8.0-18.6): non-Hodgkin lymphoma (NHL) (n = 13, SIR = 127, 95% CI: 68-217), renal cell (n = 3, SIR = 105, 95% CI: 22-307), vulva/vagina (n = 3, SIR = 665, 95% CI: 137-1934) and nonmelanoma skin cancers (n = 2, SIR = 64.7, 95% CI: 7.8-233.8). NHL typically appeared during childhood, while other tumors were diagnosed during adulthood. Apart from short-term attention toward the potential occurrence of NHL, our results suggest cancer surveillance into adulthood with special attention to skin, kidneys and the female genitalia.

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.

Simultaneous Pancreas-Kidney Transplant From Donors After Brain Death vs Donors After Circulatory Death: A Single-Center Follow-up Study Over 3 Decades.

BACKGROUND: Despite an increase in the number of pancreas transplants in the Scandiatransplant region in the last decade, there continues to be a gap between demand and supply of transplantable organs. This imbalance has encouraged the transplant community to consider new sources of grafts, such as the reintroduction of donors after circulatory death (DCD) who were the standard donors in our center before 1988. MATERIAL AND METHODS: In this long-term follow-up study, we compare 44 consecutive, simultaneous pancreas kidney transplants performed at Karolinska University Hospital between 1986 and 1991: 21 patients received DCD grafts and 23 received grafts from donors after brain death. RESULTS: Both groups had similar donor and recipient characteristics, but cold ischemia times were significantly shorter in the DCD group. Warm ischemia times were very short compared with other studies on DCDs. Patient and graft survival rates were similar in both groups. CONCLUSION: This study suggests that controlled DCD pancreas and kidney grafts transplanted simultaneously can be a feasible option for reducing organ shortage without any negative impact on the long-term results.

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.

Changing donation pattern in central Sweden.

Since 1990, the Organisation for Organ donation in Central Sweden has registered the numbers of donations at the various hospitals in the area. During this period, a significant decrease in donation rate was observed in the large hospitals, while there was an increase in donation rate in the smaller hospitals. Taken together, the small hospitals are now at least as important as the large hospitals. Possible reasons for the observed change in donation pattern are discussed.

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.

Adipocyte-derived hormones in heroin addicts: the influence of methadone maintenance treatment.

Heroin addiction markedly affects the nutritional and metabolic status and frequently leads to malnutrition. The aim of our study was to compare circulating concentration of adipose tissue-derived hormones leptin, adiponectin and resistin in 12 patients with heroin addiction before and after one-year methadone maintenance treatment with the group of 20 age- and body mass index-matched healthy subjects. Basal serum leptin and adiponectin levels in heroin addicts were significantly decreased (3.4+/-0.4 vs. 4.5+/-0.6 ng/ml and 18.9+/-3.3 vs. 33.9+/-3.1 ng/microl, respectively; p 0.05) while serum resistin concentrations were increased compared to healthy subjects (10.1+/-1.2 vs. 4.6+/-0.3 ng/ml; p 0.05). Moreover, positive correlation of serum leptin levels with body mass index was lost in the addicts in contrast to control group. One year of methadone maintenance treatment normalized serum leptin, but not serum adiponectin and resistin concentrations. In conclusion, circulating concentrations of leptin, adiponectin and resistin are markedly altered in patients with chronic heroin addiction. These alterations appear to be relatively independent of nutritional status and insulin sensitivity.

Percutaneous needle biopsy of the renal allograft. A clinical safety evaluation of 1129 biopsies.

In many transplant centers there is a reluctance to perform percutaneous core needle biopsies in renal allografts for fear of complications that may jeopardize the graft. We have evaluated the safety of percutaneous renal allograft biopsy by retrospectively studying 1129 biopsy specimens in 513 patients between 1974 and 1988. All biopsies were performed with a conventional 2.0 mm TruCut disposable needle (Travenol Labs.; Deerfield, IL) without radiographic aid for localization of the kidney. Kidney tissue was obtained in 1095 cases (97.0%). In 1037 biopsies (91.9%) enough renal tissue for histological evaluation was obtained. In 34 biopsies (3.0%) no renal tissue and in 58 (5.1%) only renal medulla was found. All the complications were demonstrated by with macroscopic bleeding into the urinary tract system. Thirty-two patients (2.8%) developed hematuria requiring hospitalization and some type of active treatment (catheter-à-demeure, n = 14; cystoscopy, n = 11; percutaneous nephrostomy, n = 3; surgery, n = 4). On 8 biopsy occasions blood transfusion was required. Three graft removals (0.3%) were attributed to the procedure of biopsy for emergency diagnostic purposes. All three grafts were severely damaged by rejection and had little or no function. No grafts were lost among the biopsies taken for long-term follow-up. No deaths occurred. Biopsies yielding only renal medulla were found to carry a greater risk of bleeding than adequate biopsy specimens (P less than 0.001), as did biopsies from transplants with acute vascular rejection. Conversely, biopsies taken for routine check-ups of long-term renal allografts were associated with a lower risk than biopsies taken because of poor or deteriorating renal function (P less than 0.05). An analysis of 340 biopsies, taken in accordance with a protocol during periods of stable renal function, revealed no deterioration in graft function at 1 and 12 months after the biopsy. In this study, we have found that conventional percutaneous needle biopsy of the renal allograft involves a certain risk of complications, even including graft loss. We have also defined a number of risk factors for such complications. However, we think that the benefits outweigh the risks, and needle biopsy should therefore remain an important diagnostic tool among all the others in the posttransplantation management of the renal transplant recipient.

Autonomic system dysfunction and polyneuropathy in nondiabetic uremia. A one-year follow-up study after renal transplantation.

Polyneuropathy and autonomic dysfunction were studied in 15 patients with nondiabetic terminal uremia before renal transplantation and again at 6 and 12 months after the transplantation. Beat-to-beat variation of the electrocardiogram (ECG) relative to mean beat interval was used as an observation of the function of the parasympathetic vagal reflex arc. Marked autonomic dysfunction--i.e., reduced beat-to-beat variation and a mild diffuse polyneuropathy--was found. The neuropathy was mainly of axonal type, but a slowing of conduction velocities was also found. The latter was markedly improved after transplantation and is suggested to be caused by a toxic metabolic factor, possibly causing nodal dysfunction. Action potential amplitudes and autonomic function did not improve during the study. This implies a structural damage that is not repaired in 12 months. Neurological examination should be included in the care of patients with uremia, and the results should be one of the factors considered when transplantation is discussed.

Nosocomial Legionnaires' disease following renal transplantation.

A cluster of five cases of Legionnaires' disease in renal transplant patients is described. They were treated with erythromycin and rifampicin, and all five survived. Two of them had rejected their grafts prior to their Legionella pneumonia; two rejected their transplants after reduction of immunosuppressive therapy to combat the infection. L pneumophila was present in the water distribution system of the hospital. Eradication measures included flushing the water pipes to the transplantation ward with hot and hyperchlorinated water, raising the warm water temperature to 60 degrees C, and installing ultraviolet (UV) irradiation units on the warm and cold water pipes to the ward. These measures were successful in that no new cases of legionellosis occurred after wards. L pneumophila could subsequently not be demonstrated by culture in plastic shower hoses supplied with UV-irradiated water. L pneumophila could be demonstrated by direct fluorescent antibody technique, but nonspecific reactions cannot be excluded. A higher prevalence of elevated L pneumophila antibody titers was observed in patients nursed for more than four weeks in the hospital than in patients with a shorter hospital stay, in hospital staff members, or in the general population. It seems that, with appropriate control measures, transplantation activities need not be discontinued in the presence of a minor cluster of Legionnaires' disease in renal transplant patients.

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.

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.

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.

Hyperlipidemia in renal transplant recipients treated with sirolimus (rapamycin).

BACKGROUND: Sirolimus is an interesting immunosuppressive drug that does not seem to cause nephrotoxicity, neurotoxicity, or diabetogenicity, as commonly seen in patients treated with cyclosporine or tacrolimus. In this report, we describe a possible association between sirolimus and observed hyperlipidemia. METHODS: Serum levels of triglycerides and cholesterol were analyzed in 11 patients who participated in a pilot study evaluating the effect of oral sirolimus or placebo combined with cyclosporine and corticosteroids on the occurrence of acute renal transplant rejection. RESULTS: In four of nine patients given sirolimus, significantly increased serum triglyceride levels were seen, with peak levels occurring 2-4 months after transplantation and ranging between 11.7 and 42.0 mmol/L (reference value <2.2 mmol/L). In two patients given placebo, the serum triglyceride levels remained below 5.0 mmol/L. After reduction or discontinuation of sirolimus, the serum triglyceride levels decreased within 1-2 months and after 1-8 months levels had returned to their pretransplant values. A significant increase in serum cholesterol levels was seen in one of nine patients given sirolimus. CONCLUSION: It seems that long-term treatment with sirolimus in combination with cyclosporine and corticosteroids may increase the risk of hypertriglyceridemia.

Fine-needle aspiration cytology and conventional histology in 200 renal allografts.

The diagnoses in 200 parallel fine-needle and core biopsies taken in acute renal allograft dysfunction, reduced function in long-term allografts, or in well-functioning grafts were compared. Fine-needle aspiration biopsy (FNAB) was found to be a reliable diagnostic tool with both a high sensitivity and specificity in acute cellular rejection (81 and 92%, respectively) and in normal kidney grafts (78 and 82%). On the other hand, the method was less valuable in the diagnosis of vascular rejection or interstitial fibrosis. Further evaluation is needed regarding the diagnostic implications of isometric vacuolization of tubular cells in FNAB specimens as a marker for acute cyclosporine nephrotoxicity.

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.

Long-term acyclovir prophylaxis in bone marrow transplant recipients and lymphocyte proliferation responses to herpes virus antigens in vitro.

In this randomized double-blind and placebo controlled trial of 6 months' prophylaxis with acyclovir (ACV) in 42 bone marrow transplant (BMT) recipients, patients receiving ACV had fewer herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections during the prophylaxis compared to the placebo treated patients (P less than 0.05). During the first 6 months after the prophylaxis had been discontinued the frequency of clinical HSV reactivations was low both in the ACV (1/13) and in the placebo (1/13) treated patient groups. Altogether the ACV treated patients had significantly fewer HSV reactivations during the first year after BMT (P less than 0.05). The HSV-specific lymphocyte proliferation response was also lower in the ACV treated group at 3, 6 and 12 months after BMT (P less than 0.05). VZV infections recurred rather frequently, however, after discontinuation of ACV prophylaxis. Therefore no difference was found in the number of VZV infections during the first year after BMT. The VZV-specific lymphocyte proliferation response was significantly lower in the ACV treated group only at 6 months (P less than 0.05). ACV prophylaxis had no effect on the frequency of CMV infections; CMV-specific lymphocyte proliferative responses were not decreased.

A simple radioassay for 25-hydroxycholecalciferol without chromatography.

A simple method to assay 25-hydroxycholecalciferol in human plasma without chromatography is described. The method includes ammonium sulphate precipitation of 25-hydroxycholecalciferol bound to plasma-transport globulins as a purification step, extraction with toluene and saturation analysis utilizing human osteomalacic plasma for competitive protein-binding assay. The criteria of reliability of the method are reported.

Galactosyl hydroxylysine in assessment of Paget's bone disease.

Urinary galactosyl hydroxylysine/creatinine ratio (GHL) was used to assess rates of bone collagen degradation and the activity of the pagetic lesion as well as for monitoring the rate and degree of suppression of bone resorption over 1 year in patients treated with 30 mg of intravenous pamidronate for 3 consecutive days. The clinical utility of GHL was compared with that of urinary hydroxyproline/creatinine and deoxypyridinoline/creatinine and with bone isoenzyme of serum alkaline phosphatase. The results suggest that GHL is a quantitative marker of the activity of Paget's bone disease. GHL is less sensitive than hydroxyproline, deoxypyridinolone and bone alkaline phosphatase in monitoring treatment of Paget's disease. The assay of GHL is easier, faster and less costly than that of hydroxyproline or deoxypyridinoline and it can be easily standardized.