Comprehensive Complication Index to Monitor Morbidity and Mortality After Liver Transplantation in Primary Sclerosing Cholangitis.

OBJECTIVE: The objective of this study was to investigate the short-term and long-term morbidity after liver transplantation (LTx) in patients with primary sclerosing cholangitis (PSC). BACKGROUND: PSC is a common indication for LTx in Scandinavia. Recently, research has focused on long-term survival and morbidity. The Comprehensive Complication Index (CCI) precisely describes postsurgical complications, by considering both number and severity. PATIENTS AND METHODS: Two patient groups were compared: those with classical PSC symptoms (n=148) and those with increased risk of cholangiocarcinoma (n=51, premalignant group). Two CCI scores were calculated, at 1-year post-LTx and a cumulative overall score at the latest follow-up. In addition, we investigated factors potentially related to high CCI. RESULTS: The 1-year median CCI were 29.6 and 26.2 in the classical and premalignant groups, respectively ( P =0.308). The median overall CCI were 43.2 and 46.8 ( P =0.765), respectively. Patient survival was significantly lower in patients with 1-year CCI>42. The most common complications associated with low survival were cholangitis, infections, and hypertension. One-year and overall CCI were similar between sexes and different types of biliary anastomosis. Patients with pre-LTx Model for End-stage Liver Disease scores >20 had higher 1-year and overall CCI (36.2 and 52.6, respectively) than those with lower Model for End-stage Liver Disease scores. Both low (<22) and high (>25 kg/m 2 ) body mass indices were associated with high overall 1-year and overall CCI (50.9 and 41.8, respectively), but median body mass indices were associated with significantly lower 1-year and overall CCI (38.4, P =0.023). CONCLUSIONS: The previously determined 1-year CCI cutoff of 42 could significantly predict survival post-LTx. Mortality and morbidity were not significantly different between the PSC groups analyzed.

The first 10 years of simultaneous pancreas-kidney transplantation in Finland.

INTRODUCTION: Simultaneous pancreas-kidney transplantation (SPK) is an option for patients with type 1 diabetes (T1D) and kidney failure but can be associated with a high complication rate. Here we describe our 10-year experience since the launch of the SPK program. METHODS: This retrospective study included consecutive patients with T1D receiving SPK from March 14, 2010 to March 14, 2020 at Helsinki University Hospital. Portocaval anastomosis (i.e., systemic venous drainage) and enteric exocrine drainage were used. A specific team was trained for both pancreas retrieval and transplantation, postoperative care was standardized to include somatostatin analogues, antimicrobial treatment, and preoperatively initiated chemothrombopropylaxis. During program maturation donor criteria were expanded and logistical processes improved to minimize cold ischemia time. Clinical data were collected from a nationwide transplantation registry and patient records. RESULTS: A total of 166 SPKs were performed (median 2 per year in the first 3 years, 17.5 per year for the following 4 years, and 23 per year for the past 3 years). Seven patients (4.1%) died with a functioning graft with a median 43 months follow-up. One-year pancreas graft survival was 97.0%, 3-year pancreas graft survival was 96.1% and 5-year was 96.1%. Mean HbA1c was 36 mmol/mol (SD 5.57) and creatinine was 107 µmol/L (SD 34.69) at 1-year after transplantation. All kidney grafts were functioning at the end of follow-up. Complications required re-laparotomy in 39 (23%) patients, mostly due to a pancreas graft related problem (N = 28). No pancreas or kidney graft failure from thrombosis occurred. CONCLUSION: A planned, step-wise development of an SPK program offers a safe and effective treatment for patients with T1D and kidney failure.

Gamma-glutamyltransferase predicts macrovesicular liver graft steatosis - an analysis of discarded liver allografts in Finland.

OBJECTIVE: Liver-transplantation activity is limited by the shortage of grafts. Donor-liver macrovesicular steatosis predisposes to ischemia-reperfusion injury and is associated with reduced graft survival. The increasing prevalence of fatty-liver disease underlines the importance of identifying macrovesicular steatosis in potential donor livers. We analyzed liver grafts discarded for transplantation, and particularly the role of gamma-glutamyltransferase (GGT) in predicting graft steatosis. METHODS: One-hundred sixty rejected cadaveric-donor liver grafts were studied. Donor selection was based on clinical data, and macroscopic graft inspection. Discarded grafts were biopsied at procurement of non-liver organs. RESULTS: The most common reasons for discarding the graft were abnormal liver tests, ultrasound-verified steatosis and history of harmful alcohol use. GGT correlated moderately with macrovesicular steatosis (r = 0.52, p < 0.001), but poorly with microvesicular steatosis (r = 0.36, p < 0.001). Increased correlation between GGT and macrovesicular steatosis was observed among alcohol abusers (r = 0.67, p < 0.001). Area under the curve (AUC) of GGT for predicting >30% macrovesicular steatosis was 0.79 (95% CI 0.71-0.88), and for >60% steatosis, 0.79 (95% CI 0.68-0.90). The optimal GGT-cut off for detecting >30% and >60% macrovesicular steatosis were, respectively, 66 U/L (sensitivity 76% and specificity 68%) and 142 U/L (sensitivity 66% and specificity 83%). Among alcohol users, a GGT value >90 U/L showed 100% sensitivity for >60% macrovesicular steatosis. AUC for GGT in predicting fibrosis Stages 2-4 was 0.82 (95% CI 0.71-0.92, p < 0.001, optimal cut off 68, sensitivity 92%, specificity 61%). CONCLUSIONS: Abnormal liver values, steatosis and harmful alcohol use were the main reasons for discarding liver-graft offers in Finland. GGT proved useful in predicting moderate and severe liver graft macrovesicular steatosis.

Association Between Pre-Transplant Oral Health and Post-Liver Transplant Complications.

Oral disease is linked with systemic inflammation and various systemic conditions, including chronic liver disease. Liver transplantation (LT) candidates often need dental infection focus eradication, and after LT, there is high risk of many inflammation-related complications. We studied whether pre-LT dental status is associated with the occurrence of post-LT complications. This study included 225 adult LT recipients whose teeth were examined and treated before LT, and 40 adult LT recipients who did not have pre-LT dental data available. Data on post-LT complications were collected from the national liver transplant registry and followed up until the end of July 2020. Worse pre-LT dental status was associated with a higher risk of acute rejection post-LT compared to patients with good dental status. Worse dental status was also associated with higher 1-year-post-LT ALT levels and lower albumin levels. In conclusion, poor pre-LT oral health seems to associate with an increased risk of post-LT acute rejection and with elevated ALT levels and decreased albumin levels, suggesting an effect on post-LT liver health. Therefore, prevention and treatment of oral and dental diseases should be promoted early in the course of liver disease.

Enhanced recovery protocol in laparoscopic liver surgery.

INTRODUCTION: Enhanced recovery protocols (ERP) accelerate recovery and shorten postoperative hospital stay. This increased knowledge of ERPs has also gradually implemented into liver surgery. However, in laparoscopic liver surgery (LLS), the experience of optimized perioperative care protocols is still limited. METHODS: We prospectively studied the implementation of multimodal ERP principles to LLS in the first 100 consecutive patients. Opioid-sparing multimodal pain management was applied together with early mobilization already in the postoperative care unit (PACU). Drains and catheters were avoided and per oral intake was initiated promptly. Primary pain control was achieved with iv NSAIDS, low-dose opioid and corticosteroids. Combination of per oral ibuprofen and long-acting tramadol was routinely administered shortly after operation. The multiprofessional adherence to the protocol was also evaluated. RESULTS: Investigated LLS was performed during Aug 2016-Apr 2019. Operations were done due to malignancy in 83 (83%) of cases, mostly for colorectal liver metastases (n = 52, 52%). Forty-eight (48%) of the operated patients were female. Median age was 65 years (range 17-91). The American Society of Anaesthesiologists Physical Status (ASA) classification median was three. Median postoperative hospital stay was 2 days (range 1-8 days). More than seventy percent of patients were discharged by the second postoperative day and nearly ninety percent by the third postoperative day. Complications after surgery were few. The new ERP elements were adopted in most of the cases. CONCLUSIONS: ERP was introduced safely and effectively after LLS. The adherence to the ERP was good. Routine discharge 1-2 days after LLS is realistic and achievable.

Activin inhibition limits early innate immune response in rat kidney allografts-a pilot study.

Activins are members of the transforming growth factor-beta (TGF-ß) superfamily of cytokines. They play critical roles in the onset of acute and chronic inflammatory responses. The aim of this study was to investigate how activin inhibition affects acute kidney injury and inflammation after transplantation. The study was carried out in kidney transplantation and renal ischemia-reperfusion models in the rat. Soluble activin type 2 receptor (sActRIIB-Fc) was used to inhibit activin signaling. Transplantation groups were as follows: (i) cyclosporine A (CsA) (ii) CsA + sActRIIB-Fc, (iii) CsA+ inactive protein control Fc-G1. IRI groups were as follows: (i) no treatment, (ii) sActRIIB-Fc. Serum activin B concentration was significantly elevated after transplantation and IRI, whereas activin A was produced locally in renal allografts. Activin inhibition efficiently limited neutrophil, macrophage, and dendritic cell infiltration to the allografts measured 72 h after transplantation. In addition, sActRIIB-Fc treatment modulated serum cytokine response after transplantation and reduced the early accumulation of fibroblasts in the graft interstitium. In conclusion activin inhibition reduces the innate immune response early after renal transplantation in the rat. It also limits the accumulation of fibroblasts in the graft suggesting that activins may be involved in the fibrogenic signaling already early after kidney transplantation.

Optimized recovery programs in gastrointestinal surgery.

Optimized or enhanced recovery programs have been applied to intestinal surgery already for a long time. They are being widely initiated also within bariatric, hepatic and pancreatic surgery. The programs aim at an increasingly better well-being of surgical patients by avoiding procedures which slow down the recovery and favoring those that promote it. Informing the patient is also an essential part of the programs. Effective pain management avoiding opioids, early started oral nutrition, and mobilization immediately after the operation prevent postoperative decreased intestinal motility and nausea. At best, the programs will guarantee the patients' excellent recovery and shorten the length of stay on the ward.

Intensive perioperative simvastatin treatment protects from chronic kidney allograft injury.

BACKGROUND/AIMS: Ischemia-reperfusion injury (IRI) and innate immune response augment adaptive immunity and may also trigger repair processes that lead to uncontrolled fibrosis and atherosclerosis as seen in chronic allograft injury. Simvastatin has been shown to protect from renal IRI in several experimental studies. The aim of this study was to examine the effect of donor simvastatin pretreatment and early initiation of recipient simvastatin treatment on chronic kidney allograft injury. METHODS: A rat renal transplantation model was used. Simvastatin was administered perorally for donor (5 mg/kg) and/or for recipient (2 mg/kg) 2 hours before transplantation and/or as daily treatment starting on the first postoperative day (2 mg/kg/day). The study included 5 groups: (1) no simvastatin, (2) donor pretreatment, (3) daily recipient treatment, (4) donor pretreatment + daily recipient treatment and (5) donor pretreatment + recipient pretreatment + daily recipient treatment. The grafts were recovered at day 90 for histopathological and immunohistochemical analysis. Kidney function was followed weekly with serum creatinine, and 24-hour urine protein was measured 60 and 90 days after transplantation. RESULTS: We found that donor and recipient simvastatin pretreatment combined with daily recipient treatment reduced graft inflammation and chronic allograft injury. Treatment using only statins started after transplantation reduced inflammation to some extent, but did not affect chronic kidney allograft injury. Pretreatment using only donor statins impaired graft function and increased proteinuria. CONCLUSION: Our data suggest that perioperative recipient statin treatment reduces inflammation and may protect the graft in the long term.

Sirolimus inhibits lymphangiogenesis in rat renal allografts, a novel mechanism to prevent chronic kidney allograft injury.

Lymphangiogenesis occurs in renal allografts and it may be involved in the maintenance of the alloreactive immune response and thus participate in the development of chronic kidney allograft injury. Sirolimus (SRL) has been shown to inhibit lymphangiogenesis. The aim of this study was to describe lymphangiogenesis and its regulation during the development of chronic kidney allograft injury and to investigate the effect of SRL on allograft lymphangiogenesis and chronic kidney allograft injury. A rat renal transplantation model was used. Allografts treated with cyclosporine A or with SRL were analyzed in various time points. Syngenic transplantations were used as controls. Kidney function was followed with serum creatinine. Histology was analyzed by Chronic Allograft Damage Index (CADI). Immunohistochemistry was used to detect lymphatic vessels, VEGF-C and VEGFR-3. In cyclosporine-treated allografts VEGF-C/VEGFR-3 pathway was strongly upregulated leading to extensive lymphangiogenesis 60 days after transplantation. Lymphangiogenesis correlated positively with the CADI score. Sirolimus efficiently inhibited lymphangiogenesis, improved graft function and attenuated the development of chronic kidney allograft injury when compared with cyclosporine. In conclusion, lymphangiogenesis is associated with chronic kidney allograft injury and SRL is a potent inhibitor of lymphangiogenesis in renal allografts. Inhibition of lymphatic proliferation could mediate the nephroprotective properties of SRL.

Histopathological Helsinki score of colorectal liver metastases predicts survival after liver resection.

Several perioperative scoring systems have been created to predict outcomes in metastatic colorectal cancer; however, these rarely include histological parameters. We evaluated histological factors used for patients with liver metastases operated between 2000 and 2019 and compared the results with the Fong score. Many scoring models for overall disease-free survival (DFS) were established and compared using multivariate Cox proportional hazard models. Statistically significant predictors at a 5% level in the univariate analysis were included in the multivariate models using the backward and forward selection methods. Per these models, we established a score of eight histological factors. We defined low-, intermediate-, and high-risk groups and compared them using the Kaplan-Meier survival and receiver operating characteristics (ROC) analyses. The histological score's accuracy was compared with the modified Fong clinical risk score. The following factors constituted the Helsinki score: advanced pT stage, node-positive primary, ≥2 metastases, size >50 mm, vitality >30%, margin <5 mm, vascular invasion and biliary invasion. The high-risk group had significantly worse DFS and overall survival. In ROC analyses, the Helsinki score was slightly better than the modified Fong clinical risk score. Helsinki score challenges physicians to acknowledge histological factors as important outcome measures.

[Incarcerated Spigelian hernia]. / Kureutunut Spigelin tyrä.

Incarcerated Spigelian hernia is a rare cause of abdominal pain requiring emergency surgery. It occurs in the lower abdomen between abdominal musculature in the region of Spigelian aponeurosis. On the basis of incidental findings in laparoscopy the frequency of this hernia is less than 2%. Spigelian hernias are often completely symptomless, but they are associated with the risk of intestinal incarceration. Owing to its rare occurrence, incarcerated Spigelian hernia is difficult to diagnose, which may delay the treatment.

Early short-term imatinib treatment is sufficient to prevent the development of chronic allograft nephropathy.

BACKGROUND: Chronic allograft nephropathy (CAN), now defined as interstitial fibrosis and tubular atrophy not otherwise specified, is a near universal finding in kidney grafts by the end of the first decade posttransplantation. Platelet-derived growth factor (PDGF) is a major mitogen mediating mesenchymal cell proliferation in CAN. Here, we investigated whether early short-term PDGF inhibition with imatinib could prevent CAN. METHODS: Kidney transplantations were performed from Dark-Agouti (DA) to Wistar-Furth (WF) rats and syngenic controls were done between DA rats. Allografts were immunosuppressed with cyclosporine. One group was also treated with imatinib for the first 30 days after transplantation. Serum creatinine levels were measured once a week. Grafts were harvested 90 days after transplantation. RESULTS: In control allografts, moderate to intense chronic changes were seen, whereas in syngenic grafts, no changes were seen. The early imatinib treatment prevented the development of CAN significantly compared to control allografts. Only few histological changes were seen. Fibrogenic growth factor ligand and receptor induction as well as inflammatory cell response was significantly inhibited by imatinib. Creatinine values of imatinib-treated allografts were also significantly lower compared to controls. CONCLUSIONS: We show that short-term imatinib treatment is sufficient to prevent CAN significantly, indicating that early PDGF induction has an important role in the pathogenesis of CAN. Here, we provide preclinical work that will need to be confirmed in patients with CAN.

FK778 ameliorates post-transplant expression of fibrogenic growth factors and development of chronic rejection changes in rat kidney allografts.

BACKGROUND: Acute rejection is the major risk factor for the development of subsequent chronic allograft nephropathy (CAN), which is the primary reason for late allograft loss in kidney transplantation. Platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) are the main mitogens mediating mesenchymal cell proliferation. Their early post-transplant induction may start cascades leading to the development of CAN. An immunosuppressive drug, FK778, inhibits de novo pyrimidine biosynthesis and several receptor tyrosine kinases (RTKs). Here we investigated its effects on acute and chronic rejection as well as post-transplant PDGF and TGF-beta expression in combination therapy with calcineurin inhibitors (CNIs). METHODS: Kidney transplantations were performed from DA to WF rats. Syngenic DA-DA grafts were used as controls. Allografts were immunosuppressed with a combination of FK778 (10 mg/kg/day p.o.) and CsA (1.5 mg/kg/day s.c.) or tacrolimus (Tac) (1.5 mg/kg/day p.o.). Grafts were harvested 5 and 90 days after transplantation for histology and immunohistochemistry (PDGF-A, PDGF-B, PDGFR-alpha, PDGFR-beta, TGF-beta, TGF-betaR). The dose response of FK778 on acute rejection was studied with monotherapy of 5, 10 and 20 mg/kg/day. Chronic changes were scored according to the Chronic Allograft Damage Index (CADI). RESULTS: FK778 ameliorated the early post-transplant inflammatory response dose dependently. Additive effects were seen with FK778 and CNIs. Significantly lower CADI scores were seen in combination therapy of FK778 and CNIs compared with CNI monotherapies. FK778 also significantly reduced both early and late PDGF and TGF-beta expression when combined with CNIs. CONCLUSIONS: These results indicate that FK778 could prevent the development of CAN and be a promising therapy also in clinical kidney transplantation.

Severe allograft rejection in an intestinal transplant patient following oral immunoglobulin treatment for chronic norovirus infection: a case report.

In an intestinal transplant patient under triple immunosuppression therapy with tacrolimus levels >10 ng/L, a 2-day oral immunoglobulin therapy given as treatment for chronic norovirus infection was temporally closely associated with the development of severe steroid-resistant acute graft rejection, thus suggesting that oral immunoglobulin might be able to promote a rejection response.

Oral Platelet-Derived Growth Factor and Vascular Endothelial Growth Factor Inhibitor Sunitinib Prevents Chronic Allograft Injury in Experimental Kidney Transplantation Model.

BACKGROUND: Expression of both platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) is increased during the development of chronic rejection which remains the major reason for late allograft loss in clinical kidney transplantation. Sunitinib is a tyrosine kinase inhibitor which inhibits both VEGF and PDGF receptors. Here we investigated its effect on the development of chronic rejection. METHODS: Rat aortic denudation model was used to define sunitinib dose. In vitro studies were done to investigate the effect of sunitinib on smooth muscle cell proliferation and migration. Kidney transplantations were performed from dark agouti rat strain (DA) to Wistar furth rat strain rats and syngenic DA-DA grafts were used as controls. Allografts were immunosuppressed either with cyclosporine or with cyclosporine and sunitinib. Grafts were harvested at 5 and 90 days for histology and immunohistochemistry. Serum creatinine levels were measured weekly to monitor graft function. RESULTS: Sunitinib decreased neointimal formation and smooth muscle cell proliferation and migration in a dose-dependent manner. Sunitinib was well tolerated and almost completely prevented chronic rejection changes and preserved significantly better renal graft function after transplantation. Sunitinib also inhibited chronic PDGF-A and -B and VEGF-A and -B expressions. CONCLUSIONS: These results demonstrate that combined inhibition of PGDF and VEGF with sunitinib prevents chronic rejection changes in experimental kidney transplantation which indicates that sunitinib could be a potential intervention also in clinical kidney transplantation.

Epidermal growth factor receptor inhibition with erlotinib ameliorates anti-Thy 1.1-induced experimental glomerulonephritis.

BACKGROUND: Mesangial proliferative glomerulonephritis is a common glomerular disorder that may lead to end-stage renal disease. Epidermal growth factor (EGF) plays an important role in the regulation of cell growth, proliferation, and differentiation and in the pathology of various renal diseases. Erlotinib is a novel, oral, highly selective tyrosine kinase inhibitor of the EGF receptor. It is clinically used to treat non-small cell lung and pancreatic cancers. Here, we investigated the effect of erlotinib on the progression of mesangioproliferative glomerulonephritis in an experimental model. METHODS: Mesangial glomerulonephritis was induced with anti-rat Thy-1.1 antibody in male Wistar rats weighing 150-160 g. Rats were treated with erlotinib (10 mg/kg/day p.o.) or vehicle only (polyethylene glycol). Native Wistar rat kidneys were used as histological controls. Serum creatinine levels were measured at day 7. Kidneys were harvested 7 days after antibody administration for histology. RESULTS: Native controls showed no histological signs of glomerular pathology. In the vehicle group, intense glomerular inflammation developed after 7 days and prominent mesangial cell proliferation and glomerular matrix accumulation was seen. Erlotinib was well tolerated and there were no adverse effects during the follow-up period. Erlotinib significantly prevented progression of the glomerular inflammatory response and glomerular mesangial cell proliferation as well as matrix accumulation when compared with the vehicle group. Erlotinib also preserved renal function. CONCLUSION: These results indicate that erlotinib prevents the early events of experimental mesangial proliferative glomerulonephritis. Therefore, inhibition of the EGF receptor with erlotinib could prevent the progression of glomerulonephritis also in clinical nephrology.

Epidermal growth factor receptor inhibition by erlotinib prevents vascular smooth muscle cell and monocyte-macrophage function in vitro.

INTRODUCTION: Vascular smooth muscle cells (VSMCs) and monocyte-macrophages play a central role during the development of chronic allograft injury, which still remains an important challenge in organ transplantation. Inflammation, fibrosis and accelerated arteriosclerosis are typical features for chronic allograft injury. Growth factors participate in cell proliferation, differentiation and migration in this pathological process. OBJECTIVE: Here we studied the role of epidermal growth factor receptor (EGFR) in VSMC and monocyte-macrophage function in vitro. EGFR inhibition by erlotinib, a selective EGF tyrosine kinase inhibitor, was studied in VSMC proliferation and migration as well as monocyte-macrophage proliferation and differentiation. MATERIALS AND METHODS: Rat coronary artery SMCs were used for VSMC studies. As a model for monocyte-macrophage proliferation and differentiation human monocytic cell line U937 was used. Phorbol ester TPA was used to induce these cells to differentiate into macrophages. RESULTS: Platelet-derived growth factor (PDGF)-B, a known VSMC inducer, caused 2.1-fold stimulation in VSMC proliferation compared to non-stimulated VSMC. Erlotinib prevented this VSMC proliferation in a dose-dependent manner, p < 0.001 in all groups compared to controls. PDGF-B stimulation increased VSMC migration to 2.5-fold when compared with non-stimulated cells. Erlotinib decreased VSMC migration dose-dependently and this effect was significant with all doses, p < 0.05. Erlotinib inhibited dose-dependently the proliferation of U937 monocytic cells, p < 0.001. Erlotinib prevented also TPA-induced macrophage differentiation in a dose-dependent way, p < 0.05. DISCUSSION: Erlotinib significantly prevents VSMC proliferation and migration in vitro. Erlotinib inhibited also significantly both monocyte proliferation and differentiation. Our data suggest that EGFR inhibition in VSMC and monocyte function has beneficial effects on chronic allograft injury.

Chronic allograft nephropathy is prevented by inhibition of platelet-derived growth factor receptor: tyrosine kinase inhibitors as a potential therapy.

BACKGROUND: Chronic allograft nephropathy (CAN) is the primary reason for late allograft loss in kidney transplantation, and currently there is no treatment available for it. Platelet-derived growth factor (PDGF) is suggested to be a major mitogen mediating mesenchymal cell proliferation in CAN. It has been shown that PDGF is already induced at acute renal allograft rejection, indicating a link between acute rejection and subsequent development of CAN. However, the definite effect of PDGF on the pathogenesis of CAN is still unknown. We investigated the role of PDGF in CAN by inhibiting PDGF by imatinib (STI571), a selective PDGF receptor tyrosine kinase inhibitor. METHODS: Kidney transplantations were performed from Dark Agouti (DA) to Wistar-Furth rats, and syngenic control transplantations were performed from DA to DA rats. All allograft recipients were immunosuppressed with cyclosporine A (1.5 mg/kg/day subcutaneously). One group of the animals was also treated with imatinib (10 mg/kg/day orally). Serum creatinine levels and cyclosporine A concentrations were measured once per week until the animals were killed. Grafts were harvested 5 and 90 days after transplantation for histology and immunohistochemistry. RESULTS: Only very few histologic chronic changes, similar to syngenic grafts, were seen in imatinib-treated allografts compared with control allografts. Creatinine values of imatinib-treated allograft recipients and infiltration of inflammatory cells, PDGF ligand, and receptor induction were also at the same level as in syngenic grafts. CONCLUSIONS: Our results demonstrate that imatinib prevents CAN almost completely, indicating that PDGF plays an important role in its pathogenesis. On the basis of our findings, imatinib could be a potential intervention in preventing CAN in clinical kidney transplantation.

Leflunomide analogue FK778 is vasculoprotective independent of its immunosuppressive effect: potential applications for restenosis and chronic rejection.

BACKGROUND: Leflunomide (LFM) inhibits experimentally both acute and chronic allograft rejection. The inhibition of dihydroorotate dehydrogenase (DHODH) in pyrimidine synthesis is suggested to be the major immunosuppressive mechanism. The mechanism of its vasculoprotective effect is not known, although it may be linked to inhibition of receptor tyrosine kinases (RTK). Here, we have investigated whether sufficient vasculoprotective effect could be obtained upon administration of FK778, a LFM analogue with shorter half-life, and compared the dose response with that of a known platelet-derived growth factor RTK inhibitor, imatinib, after endothelial injury in vivo. METHODS AND RESULTS: Wistar rats were used for aorta denudations. The rats remained untreated or received either FK778 or imatinib (STI571) at decreasing oral doses from 10 mg/kg per day. Half of the animals in both treatment groups also received uridine to reverse DHODH activity. Morphometric analysis was done after 14 day follow-up. In the untreated group, moderate neointima formation was detected. FK778 almost completely inhibited intimal formation, with or without uridine addition (P<0.05). Imatinib also inhibited neointima formation (P<0.05), whereas exogenous uridine reversed its effect. CONCLUSIONS: Our results demonstrate that FK778 inhibits neointima formation by way of a mechanism that is independent of DHODH inhibitory activity on vascular smooth muscle cell. Interestingly, the effect of imatinib was inhibited by uridine, suggesting that part of its action on vascular stenosis could be mediated through inhibition of pyrimidine synthesis.