Large-scale changes in marine and terrestrial environments drive the population dynamics of long-tailed ducks breeding in Siberia.

Migratory animals experience very different environmental conditions at different times of the year, i.e., at the breeding grounds, during migration, and in winter. The long-tailed duck Clangula hyemalis breeds in the Arctic regions of the northern hemisphere and migrates to temperate climate zones, where it winters in marine environments. The breeding success of the long-tailed duck is affected by the abundances of predators and their main prey species, lemmings Lemmus sibiricus and Dicrostonyx torquatus, whose population fluctuation is subject to climate change. In the winter quarters, long-tailed ducks mainly eat the blue mussel Mytilus edulis. We examined how North-west Siberian lemming dynamics, assumed as a proxy for predation pressure, affect long-tailed duck breeding success and how nutrient availability in the Baltic Sea influences long-tailed duck population size via mussel biomass and quality. Evidence suggests that the long-tailed duck population dynamics was predator-driven on the breeding grounds and resource-driven on the wintering grounds. Nutrients from fertilizer runoff from farmland stimulate mussel stocks and quality, supporting high long-tailed duck population sizes. The applied hierarchical analysis combining several trophic levels can be used for evaluating large-scale environmental factors that affect the population dynamics and abundance of migrants from one environment to another.

Primary Outcome of Laparoscopic Colorectal Resections in a Northern Finnish Hospital: A Single Center Study.

BACKGROUND AND AIMS: Over the past decades, laparoscopic colorectal surgery has become widely used for various indications. Large multicenter studies have demonstrated that laparoscopy has clear advantages over open surgery. Compared to open procedures, laparoscopy decreases perioperative blood loss, post-operative pain, and hospitalization time, but provides equivalent long-term oncological and surgical results. Most studies have been conducted in high-volume institutions with selected patients, which may have influenced the reported outcome of laparoscopy. Here, we investigated the primary outcome of all laparoscopic colorectal resections performed between 2005 and 2015 in a low-volume center. MATERIALS AND METHODS: This retrospective study included bowel resections performed between 2005 and 2015 in the Lapland Central Hospital. Data were retrieved from electronic patient registries, and all operations that began as a laparoscopy were included. Patient records were investigated to determine the primary surgical outcome and possible complications within the first 30 days after surgery. RESULTS: During 2005-2015, 385 laparoscopic colorectal resections were performed. Indications included benign (n = 166 patients, 43.1%) and malignant lesions (n = 219 cases, 56.9%). The median patient age was 68 years, and 50.4% were male. The median American Society of Anesthesiologist score was III, and 48.5% of patients had an American Society of Anesthesiologist class of III or IV. The median hospital stay after surgery was 6 days (interquartile range: 3.8). The conversion rate to open surgery rate was 13%. The total surgical complication rate was 24.2%, and re-operation was required in 11.2% of patients. A total of 26 patients had anastomotic leakage, of which 16 required re-operations. The 30-day mortality was 0.8%. CONCLUSION: Our results showed that laparoscopic colorectal surgery in a peripheral hospital resulted in primary outcome rates within the range of those reported in previous multicenter trials. Therefore, the routine use of laparoscopic colorectal resections with high-quality outcome is feasible in small and peripheral surgical units.

The effect of low-temperature pretreatment on the solubilization and biomethane potential of microalgae biomass grown in synthetic and wastewater media.

Microalgae have been suggested as a sustainable raw material for biofuel production in the form of methane via anaerobic digestion. Here, pretreatments at 60-80°C were investigated, aiming to study the impact of algae culture media on biomethane potential and pretreatment efficiency. Chlorella vulgaris and mixed culture of native algae species (dominating by Scenedesmus sp.) were grown in synthetic medium, wastewater (sterilized and non-sterilized) and digestate from anaerobic digestion of pulp and paper biosludge (sterilized and non-sterilized). The biomethane potential for native microalgal biomass varied between 154 and 252LCH4kg-1 VS depending on culture media. The efficiency of the low-temperature pretreatment (80°C, 3h) for solubilization (9-12%) of C. vulgaris and native algae biomass was similar for algae grown in sterilized and non-sterilized wastewater media. The pretreatment increased the biomethane potential of native algae biomass by 11-24%.

Mesophilic anaerobic digestion of pulp and paper industry biosludge-long-term reactor performance and effects of thermal pretreatment.

The pulp and paper industry wastewater treatment processes produce large volumes of biosludge. Limited anaerobic degradation of lignocellulose has hindered the utilization of biosludge, but the processing of biosludge using anaerobic digestion has recently regained interest. In this study, biosludge was used as a sole substrate in long-term (400 d) mesophilic laboratory reactor trials. Nine biosludge batches collected evenly over a period of one year from a pulp and paper industry wastewater treatment plant had different solid and nutrient (nitrogen, phosphorus, trace elements) characteristics. Nutrient characteristics may vary by a factor of 2-11, while biomethane potentials (BMPs) ranged from 89 to 102 NL CH4 kg(-1) VS between batches. The BMPs were enhanced by 39-88% with thermal pretreatments at 105-134 °C. Despite varying biosludge properties, stable operation was achieved in reactor trials with a hydraulic retention time (HRT) of 14 d. Hydrolysis was the process limiting step, ceasing gas production when the HRT was shortened to 10 days. However, digestion with an HRT of 10 days was feasible after thermal pretreatment of the biosludge (20 min at 121 °C) due to enhanced hydrolysis. The methane yield was 78 NL CH4 kg(-1) VS for untreated biosludge and was increased by 77% (138 NL CH4 kg(-1) VS) after pretreatment.

Long-term thermophilic mono-digestion of rendering wastes and co-digestion with potato pulp.

In this study, mono-digestion of rendering wastes and co-digestion of rendering wastes with potato pulp were studied for the first time in continuous stirred tank reactor (CSTR) experiments at 55°C. Rendering wastes have high protein and lipid contents and are considered good substrates for methane production. However, accumulation of digestion intermediate products viz., volatile fatty acids (VFAs), long chain fatty acids (LCFAs) and ammonia nitrogen (NH4-N and/or free NH3) can cause process imbalance during the digestion. Mono-digestion of rendering wastes at an organic loading rate (OLR) of 1.5 kg volatile solids (VS)/m(3)d and hydraulic retention time (HRT) of 50 d was unstable and resulted in methane yields of 450 dm(3)/kg VS(fed). On the other hand, co-digestion of rendering wastes with potato pulp (60% wet weight, WW) at the same OLR and HRT improved the process stability and increased methane yields (500-680 dm(3)/kg VS(fed)). Thus, it can be concluded that co-digestion of rendering wastes with potato pulp could improve the process stability and methane yields from these difficult to treat industrial waste materials.

Mesophilic and thermophilic anaerobic laboratory-scale digestion of Nannochloropsis microalga residues.

This paper studies methane production using a marine microalga, Nannochloropsis sp. residue from biodiesel production. Residue cake from Nannochloropsis, oils wet-extracted, had a methane potential of 482LCH4kg(-1) volatile solids (VS) in batch assays. However, when dry-extracted, the methane potential of residue cake was only 194LCH4kg(-1) VS. In semi-continuous reactor trials with dry-extracted residue cake, a thermophilic reactor produced 48% higher methane yield (220LCH4kg(-1)VS) than a mesophilic reactor (149LCH4kg(-1)VS). The thermophilic reactor was apparently inhibited due to ammonia with organic loading rate (OLR) of 2kgVSm(-3)d(-1) (hydraulic retention time (HRT) 46d), whereas the mesophilic reactor performed with OLR of 3kgVSm(-3)d(-1) (HRT 30d). Algal salt content did not inhibit digestion. Additional methane (18-33% of primary digester yield) was produced during 100d post-digestion.

The effect of organic loading rate and retention time on hydrogen production from a methanogenic CSTR.

The possibility of shifting a methanogenic process for hydrogen production by changing the process parameters viz., organic loading rate (OLR) and hydraulic retention time (HRT) was evaluated. At first, two parallel semi-continuously fed continuously stirred tank reactors (CSTR) were operated as methanogenic reactors (M1 and M2) for 78 days. Results showed that a methane yield of 198-218 L/kg volatile solids fed (VS(fed)) was obtained when fed with grass silage at an OLR of 2 kgVS/m³/d and HRT of 30 days. After 78 days of operation, hydrogen production was induced in M2 by increasing the OLR from 2 to 10 kgVS/m³/d and shortening the HRT from 30 to 6 days. The highest H2 yield of 42 L/kgVS(fed) was obtained with a maximum H2 content of 24%. The present results thus demonstrate that methanogenic process can be shifted towards hydrogen production by increasing the OLR and decreasing HRT.

Biogas from energy crops--optimal pre-treatments and storage, co-digestion and energy balance in boreal conditions.

The objective of this research was to evaluate the biogas production from crops in boreal conditions, focusing on the optimal pre-treatment and storage methods, co-digestion and energy balance of farm-scale crop based biogas plants. Alkaline treatments offered some potential for improving the methane yield from grass and sugar beet tops. The results show that the CH4 yield of energy crops can be maintained by appropriate ensiling conditions for even after 11 months in ambient conditions. The CH4 yield was best preserved with wet grass mixture without additives. Co-digestion of manure and crops was shown to be feasible with feedstock volatile solids (VS) containing up to 40% of crops. The highest specific methane yields of 268, 229 and 213 l CH4 kg(-1) VSadded in co-digestion of cow manure with grass, sugar beet tops and straw, respectively, were obtained during feeding with 30% of crop in the feedstock, corresponding to 85-105% of the total methane potential in the substrates as determined by batch assays. The energy output:input ratio of farm-scale grass silage based biogas plant varied significantly (3.5-8.2) with different assumptions and system boundaries being lowest when using only inorganic fertilizers and highest when half of the heat demand of the system could be covered by metabolic heat.

Co-digestion of grass silage and cow manure in a CSTR by re-circulation of alkali treated solids of the digestate.

Three laboratory, continuously stirred tank reactors (CSTRs) co-digesting grass silage and cow manure (forming 30% and 70% of substrate volatile solids (VS), respectively) were operated to evaluate the effects of re-circulating an alkali-treated and untreated solid fraction of the digestate back to the reactors. The CSTRs were operated at an organic loading rate (OLR) of 2 kg VS m(-3) day(-1) and hydraulic retention time (HRT) of 20 days with a semi-continuous mode of feeding. The feasibility of co-digestion with substrate VS containing 30% VS of crop was reinforced, resulting in average specific methane yield of about 180-185 1 CH4 kg(-1) VS. Re-circulation of the solid fraction of digestate back to the reactors in both alkali-treated and untreated forms decreased the methane yield by 11% and 21%, respectively, and resulted in operational problems such as scum formation and accumulation of the reactor materials. Batch studies were conducted to evaluate (i) the methane potentials of the solid fraction of digestate, and whole digestate with alkali treatments ranging from 20-60 g NaOH kg(-1) VS of substrate, and (ii) methane potentials of the accumulated reactor materials as top, middle and bottom layers. The solid fraction of digestate treated with 20 g NaOH kg(-1) VS showed higher specific methane yield (340 l CH4 kg(-1) VS) than the higher range of alkali treatments. The bottom layers of the control reactor and the reactor fed with alkali-treated solids gave a higher specific methane yield (93 and 85 l CH4 kg(-1) VS, respectively), and all three layers of untreated solids gave similar methane potentials.

Methane oxidation in a boreal climate in an experimental landfill cover composed from mechanically-biologically treated waste.

The present study evaluated microbial methane (CH4) oxidation in a boreally located outdoor landfill lysimeter (volume 112 m3, height 3.9 m) filled with mechanically-biologically treated waste (MBT residual) and containing a cover layer made from the same MBT residual. The calculations based on gas emission and pore gas measurements showed that, between April and October 2005, a significant proportion (> 96%) of the methane produced (< 23 l CH4 m(-2) d(-1)) in the lysimeter was oxidized. Methane was oxidized mainly at the depths of 35-75 cm, as indicated by the upward decrease both in the methane concentration and in the methane-to-carbon dioxide ratio in the pore gas. Lower methane oxidation (< 0.8 CH4 m(-2) d(-1); this was < 22% of the methane produced) was observed only during the coldest time of the year (January 2006), apparently due to the fall in temperature at the depths of 25-70 cm (from 9-25 degrees C during April to October to 2-9 degrees C in January). Unexpectedly, the highest methane oxidation potential (MOP) was observed in samples from the top layer where exposure to methane was low. Overall, the results show that MBT residual is a suitable support medium for methane oxidation in landfill covers in field conditions in a boreal climate.

Screening for potential fermentative hydrogen production from black water and kitchen waste in on-site UASB reactor at 20 degrees C.

The potential of black water and a mixture of black water and kitchen waste as substrates for on-site dark fermentative hydrogen production was screened in upflow anaerobic sludge blanket reactors at 20 degrees C. Three different inocula were used with and without heat treatment. With glucose, the highest specific hydrogenogenic activity was 69 ml H2 g volatile solids(-1) d(-1) in batch assays and the highest hydrogen yield 0.44 mol H2 mol glucose(-1) in upflow anaerobic sludge bed reactor. The mixture of black water and kitchen waste degraded readily into volatile fatty acids in the reactors, thus showing potential for hydrogen production. In the conditions applied, however, the highest end product was propionate and no hydrogen was produced. Black water alone apparently contained too little readily soluble carbohydrates for hydrogen producing bacteria, and little VFA and no hydrogen was produced.

Anaerobic digestion of grass silage in batch leach bed processes for methane production.

Anaerobic digestion of grass silage in batch leach bed reactors, with and without a second stage upflow anaerobic sludge blanket (UASB) reactor, was evaluated. Sixty six percent of the methane potential in grass was obtained within the 55 days solids retention time in the leach bed-UASB process without pH adjustment, whereas in the one-stage leach bed process 20% of the methane potential in grass was extracted. In two-stage operation, adjustment of the pH of influent to the leach bed reactor to 6 with HCl led to inhibition of both hydrolysis/acidogenesis and methanogenesis. In the leach bed-UASB process 39% of the carbohydrates and 58% of the acid soluble lignin were solubilised within the 49 days of operation, whereas Klason lignin was most recalcitrant. The methane potential of the digestates varied from 0.141 to 0.204 m3 CH4 kg(-1) added volatile solids.

Effects of solid-liquid separation on recovering residual methane and nitrogen from digested dairy cow manure.

The feasibility of optimizing methane and nitrogen recovery of samples obtained from farm biogas digester (35 degrees C) and post-storage tank (where digested material is stored for 9-12 months) was studied by separating the materials into different fractions using 2, 1, 0.5 and 0.25 mm sieves. Mass-balances revealed that digested material mainly consists of <0.25 mm (60-69%) and >2 mm (18-27%) fractions, while fractions between 2 and 0.2 mm made the rest. Incubation of solid fractions >0.25 mm of digester material at 35 degrees C resulted in specific methane yields of 0.060-0.085 m(3)kg(-1) volatile solids (VS) during initial 30-50 d and 0.16-0.18 m(3)kg(-1)VS at the end of 340 d incubation. Similarly, fractions >0.25 mm of post-storage tank material produced 0.055-0.092 m(3)kg(-1)VS and 0.13-0.16 m(3)kg(-1)VS of methane after 30-50 d and after 250 d, respectively. Methane yields for fractions <0.25 mm of post-storage tank was 0.03 m(3)kg(-1)VS after 30-50 d and 0.05 m(3)kg(-1)VS after 250 d compared to 0.20 m(3)kg(-1)VS and 0.41 m(3)kg(-1)VS, respectively for the same fraction of digester material. Separation of digested cow manure into solids and liquid fractions to recover methane may be feasible only for post-storage tank material and not for digester material. Nitrogen management would not be feasible with neither material as total nitrogen and ammonium-nitrogen concentrations were equally distributed among the segregated fractions.

Landfill gas upgrading with countercurrent water wash.

A pilot-scale countercurrent absorption process for upgrading landfill gas to produce vehicle fuel was studied using absorption and desorption units and water as absorbent. The height-to-diameter ratio of the absorption column used was 3:1 instead of the more conventionally used 20:1 ratio, and a higher pressure was used along with a lower water flow rate. The effects of pressure (10-30 bar) and water and gas flow-ratios on the upgrading process were studied. Methane content in the product gas increased to near or above 90% with both gas flows (50 and 100 l/min) used at over 20 bar pressure with 10 l/min water flow and at 30 bar pressure with 5l/min water flow. Carbon dioxide content with these upgrading parameters ranged from 3.2% to 4.8%. The remaining fraction of the product gas was nitrogen (from 6% to 7%), while hydrogen sulphide was removed to below the detection limit with all of the upgrading parameters used. The methane content of exhaust gas increased with increasing pressure. In conclusion, the pilot-scale gas upgrading process studied here appears to be able to produce gas with high energy content (>90% methane), apparently suitable as vehicle fuel, from landfill gas.

Enumeration of methanotrophic bacteria in the cover soil of an aged municipal landfill.

The enumeration of methanotrophic bacteria in the cover soil of an aged municipal landfill was carried out using (1) fluorescent in situ hybridization (FISH) with horseradish peroxidase-labeled oligonucleotide probes and tyramide signal amplification, also known as catalyzed reporter deposition-FISH (CARD-FISH), and (2) most probable number (MPN) method. The number of methanotrophs was determined in cover soil samples collected during April-November 2003 from a point with low CH(4) emission. The number of types I and II methanotrophs obtained by CARD-FISH varied from 15 +/- 2 to 56 +/- 7 x 10(8) cells g(-1) absolute dry mass (adm) of soil and methanotrophs of type I dominated over type II. The average number of methanotrophs throughout the cover soil profile was highest during May-September when the cover soil temperature was above 13 degrees C. Methanotrophs accounted for about 50% of the total bacterial population in the deepest cover soil layer owing to higher availability of substrate (CH(4)). A lower number of methanotrophs (7 x 10(2) to 17 x 10(5) cells g(-1) adm of soil) was determined by the MPN method compared to the CARD-FISH counts, thus confirming previous results that the MPN method is limited to the estimation of the culturable species that can be grown under the incubation conditions used. The number of culturable methanotrophs correlated with the methane-oxidizing activity measured in laboratory assays. In comparison to the incubation-based measurements, the number of methanotrophs determined by CARD-FISH better reflected the actual characteristics of the environment, such as release and uptake of CH(4), temperature, and moisture, and availability of substrates.

Anaerobic on-site treatment of kitchen waste in combination with black water in UASB-septic tanks at low temperatures.

Anaerobic on-site treatment of a mixture of black water and kitchen waste (BWKW) was studied using two-phased upflow anaerobic sludge blanket (UASB) septic tanks at the low temperatures of 20 and 10 degrees C. Black water (BW) was also treated alone as reference. The two-phased UASB-septic tanks removed over 95% of total suspended solids (TSS) and 90% of total chemical oxygen demand (COD(t)) from both BWKW (effluent COD(t) 171-199mg/l) and BW (effluent COD(t) 92-100mg/l). Also, little dissolved COD (COD(dis)) was left in the final effluents (BW 48-70mg/l; BWKW 110-113mg/l). Part of total nitrogen (N(tot)) was removed (BW 18% and BWKW 40%) and especially at 20 degrees C ammonification was efficient. A two-phased process was required to obtain the high removals with BWKW at 10 degrees C, while with BW a single-phased process may have sufficed even at 10 degrees C. BWKW also produced more methane than BW alone. Sludge in phases 1 of BW and BWKW treatment was not completely stabilised after 198d of operation.

Early short-term platelet-derived growth factor inhibition prevents the development of chronic allograft nephropathy in experimental rat kidney transplantation.

Chronic allograft nephropathy (CAN) remains the primary reason for late allograft loss in kidney transplantation. Platelet-derived growth factor (PDGF) is a major mitogen mediating mesenchymal cell proliferation in CAN. When administered continuously the PDGF receptor tyrosine kinase inhibitor imatinib prevents the development of CAN and restores kidney function in experimental kidney transplantation. Herein we investigated whether early short-term imatinib treatment prevented CAN. Kidney transplantations were performed from DA to WF rats and syngenic controls were done between DA rats. Allograft recipients were immunosuppressed with cyclosporine (CsA; 1.5 mg/kg/d sc). One group of allografts was also treated with imatinib (10 mg/kg/d po). Serum creatinine levels were measured once a week. Grafts were harvested 90 days after transplantation for histology and immunohistochemistry (PDGF-AA, -BB, PDGFR-alpha, -beta). Histological changes were scored according to the Chronic Allograft Damage Index (CADI). Among syngenic grafts, no signs of CAN were observed, namely, CADI 0.3 +/- 0.2 (mean +/- SEM). Control allografts showed moderate to intense chronic changes, CADI 6.5 +/- 1.3. Early short-term imatinib treatment significantly prevented the development of CAN compared with control allografts. Only a few histological changes were seen, namely, CADI 3.3 +/- 1.4. Compared with control allografts PDGF ligand and receptor induction was significantly inhibited by imatinib to nearly the same level as in syngenic grafts. Creatinine values of imatinib-treated allografts were also lower than control allografts. Our results demonstrated that early short-term imatinib treatment significantly prevented CAN. This indicated that early PDGF induction has an important role in the pathogenesis of CAN.

Vascular endothelial growth factor (VEGF) ligand and receptor induction in rat renal allograft rejection.

BACKGROUND: Acute rejection is the single most important risk factor for the subsequent development of chronic allograft nephropathy (CAN), which is still the primary reason for late allograft loss in kidney transplantation. Vascular endothelial growth factor (VEGF) is a proangiogenic factor that has an important role in the development and maintenance of physiological endothelium. While its role has been characterized in the pathology of diabetic nephropathy and preeclampsia, its role in the development of acute and chronic allograft rejection remains unclear. METHODS: Kidney transplantations were performed from DA to WF rats and syngeneic control transplantations were performed between DA rats. Normal kidneys were used as controls to evaluate physiological VEGF and VEGFR-1 expression. Allografted rats were immunosuppressed with cyclosporine (CsA) (1.5 mg/kg/d subcutaneously); and no immunosuppression was given to syngeneic grafts. Grafts were harvested at 5 and 90 days after transplantation for histology and immunohistochemistry (VEGF, VEGFR-1). RESULTS: In normal kidneys VEGF ligand and receptor expression was almost nonexistent. Only mild glomerular, arterial, and tubular VEGF expression was seen. In syngeneic grafts, no histological signs of acute or chronic rejection were seen, whereas characteristics of both acute and chronic rejection were seen in CsA-treated allografts. Altough VEGF expression was increased in syngenic grafts when compared to controls it still remained mild in both the early and the late posttransplant period. In CsA-treated allografts moderate VEGF expression was seen already 5 days after transplantation; the expression increased at 90 days after transplantation. The same pattern was also discovered for VEGFR-1 expression although the difference was not as remarkable after 5 days. CONCLUSIONS: Our results demonstrated that VEGF ligand and receptor expression was increased in both acute and chronic rejection. Our data suggested that VEGF may have an important role in the pathology of chronic rejection. Based on our findings VEGF inhibition could be a potential intervention to prevent CAN in clinical kidney transplantation.

The effect of leflunomide analogue FK778 on development of chronic rat renal allograft rejection and transforming growth factor-BETA expression.

BACKGROUND: Chronic allograft nephropathy (CAN) remains the primary reason for late allograft loss in kidney transplantation. Transforming growth factor beta (TGF-beta) is a major mitogen mediating mesenchymal cell proliferation and epithelial to mesenchymal cell transition in CAN. FK778, an analogue of an active metabolite of leflunomide, is a promising immunosuppressive drug that inhibits de novo pyrimidine biosynthesis. Herein we investigated the effect of FK778 on development of chronic rejection and TGF-beta expression in combination with calcineurin inhibitors cyclosporine (CsA) and tacrolimus (Tac). METHODS: Kidney transplantations were performed from DA to WF rats and syngeneic control transplantations between DA rats. Allografts were immunosupressed alone with CsA (1.5 mg/kg/d subcutaneously) or Tac (1.5 mg/kg/d orally) or with combinations of FK778 (10 mg/kg/d orally) and CsA or Tac. No immunosuppression was given to syngeneic grafts. Grafts were harvested 90 days after transplantation for histology and immunohistochemistry (TGF-beta, TGF-betaR1). The chronic changes in allografts were scored according to the Chronic Allograft Damage Index (CADI). RESULTS: No histological signs of chronic rejection were seen in syngeneic grafts. According to CADI, moderate chronic changes were seen in grafts treated only with CsA or Tac. In both groups the changes typically associated with CAN were significantly ameliorated with FK778. CsA-treated grafts showed intense posttransplant expression of TGF-beta and TGF-betaR1 after 90 days. In grafts treated with Tac monotherapy this expression was substantially lower. FK778 markedly reduced the expression of TGF-beta and TGF-betaR1 when combined with calcineurin inhibitors and lesser expression was demonstrated with the combination of FK778 and Tac. CONCLUSIONS: Our results demonstrated that FK778 is a potent immunosuppressive drug having synergistic effects with calcineurin inhibitors. When combined with CsA or Tac, it decreased posttransplant TGF-beta ligand and receptor expression. Our data also showed that FK778 prevented chronic changes typically associated with CAN. Taken together our results suggested that FK778 could be a promising therapy for CAN in clinical kidney transplantation.

The effect of FK778 on acute rat renal allograft rejection and expression of platelet-derived growth factor and transforming growth factor-beta.

BACKGROUND: Acute rejection is the single most important risk factor for the development of subsequent chronic allograft nephropathy (CAN). Both platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta) are major mitogens mediating mesenchymal cell proliferation and epithelial to mesenchymal cell transition. Early posttransplant induction of these growth factors may start molecular mechanisms leading to CAN. A new promising immunosuppressive drug, FK778, is an analogue of the active metabolite of leflunamide, which inhibits de novo pyrimidine biosynthesis. Herein we investigated the effect of FK778 on acute rejection and on the expression of PDGF and TGF-beta both alone and in combination with cyclosporine (CsA) or tacrolimus (Tac). METHODS: Kidney transplantations were performed from Dark Agouti (DA) to Wistar-Furth (WF) rats with syngeneic controls between DA rats. No immunosuppression was given to syngeneic grafts. Allografts were immunosuppressed with FK778 alone or in combination with CsA or Tac. Grafts were harvested on day 5 for histology and immunohistochemistry (PDGF-A, -B, PDGFR-alpha, -beta, TGF-beta1, and TGF-betaR1). RESULTS: FK778 ameliorated the inflammatory response and reduced PDGF and TGF-beta expression in a dose-dependent manner. It also showed synergy with calcineurin inhibitors, an effect that was stronger with Tac than with CsA. CONCLUSIONS: Our results indicated that FK778 decreased PDGF and TGF-beta expression early in acute rejection, suggesting it to be a promising therapy for CAN.