The Effect of α-Melanocyte Stimulating Hormone on Renal Ischemia Reperfusion Injury

Purpose: In ischemia-reperfusion induced renal injuries, cytokines, chemoattractant chemokines, adhesion molecules and nitric oxide play an important role. α-Melanocyte stimulating hormone (α-MSH) is a potent anti-inflammatory cytokine so the therapeutic effect of α-MSH on an ischemia-reperfusion induced acute renal failure is to be evaluated. Methods: 40 male Spraque-Dawley rats were prepared for the experiment, they were classified into three classes (Sham, ischemic control and α-MSH injection). Both renal pedicles were clamped for 45 minutes. α-MSH (50㎍) was injected intravenously three times, immediately before ischemia and reperfusion and 18 hour after reperfusion. Serum creatinine and histologic changes were analyzed between groups (Sham (n=6), ischemic control group (n=15), and α-MSH group (n=19)). Results: Serum creatinine level decreased significantly at 24 hours after reperfusion in α-MSH treated animals (SCr24 0.78±0.23㎎/dL 4.21±1.14㎎/dL, 3.01±1.19㎎/dL, repectively (P=0.008)), especially serum creatinine level at 48 hours after reperfusion much more dicreased in α-MSH group (SCr48 0.67±0.16㎎/dL, 4.21±2.03㎎/dL, 1.15±1.11㎎/dL, repectively (P=0.004)). Tubular neccrosis and neutrophil infiltration decreased signigicantly in α-MSH treated group (P=0.001). Mortality was noted 33.3% only at ischemic conrol group. Conclusion: we demonstrate the fact that α-MSH has protective role on ischemic renal injury and improves survival rates.ope

Polyomavirus-associated Nephropathy after Renal Transplantation

The first clinical infections with polyomavirus (PV) were demonstrated in 1971, when BK virus was isolated from the urine after a kidney transplant recipient and JC virus from the brain of a patient who died of progressive multifocal leukoencephalopathy. Polyomavirus-associated nephropathy (PVAN) has become an important cause of allograft dysfunction and loss in kidney transplantation since first recognized in kidney transplant recipient with PVAN in 1995. Most cases of PVAN are caused by polyomavirus hominis type 1, known as BK virus and arise while the patient in on triple immunosuppressive combinations, often comprising tacrolimus and/or mycophenolate mofetil plus corticosteroids. Significant progress has been made, particularly in the area of diagnostic methods for PV, facilitating diagnosis, screening and monitoring of PV infection. Definitive diagnosis of PVAN requires allograft kidney biopsy. Immunologic control of PV replication can be achieved by reducing, switching, and discontinuing of the immunusuppressive agents. Cidofovir and leflunomide are used empirically in the treatment of PVAN. However, these antiviral agents are not approved for PVAN. Recently, investigational use at low-dose cidofovir (0.25~0.33㎎/㎏ intravenously biweekly) without probenecid should be considered for the treatment of cases refractory to decreasedmaintenance immunosuppression. PVAN had a serious consequence of kidney transplantation that increasingly cause for chronic allograft kidney loss. Despite reduction in immuosuppression, suppression, allograft kidney loss occurred in 46% of transplant recipients with PVAN. PVAN recurred in 15% of retransplantations compared with 5% of primary kidney transplantations. However, retransplantation is not contraindicated for transplant recipient in whom a first allograft kidney lost due to PVAN. Recently, preemptive retransplantation can be considered in patients with allograft loss due to PVAN.ope

The Role of HMGB1 and the Effect of Ethyl Pyruvate on Ischemia and Reperfusion Injury of Rat Kidney

Purpose: High mobility group box-1 (HMGB1) was identified as a DNA binding protein that functions as a co-factor for proper transcriptional regulation in somatic cells. Extra- cellular HMGB1 acts as a potent pro-inflammatory cytokine that contributes to the pathogenesis of diverse inflammatory and infectious disorders. Ethyl pyruvate (EP), a stable aliphatic ester derived from pyruvic acid is the first described pharmacological inhibitor for HMGB1 secretion. We designed this study to identify the change of HMGB1 expression in rat kidney tissues of ischemia reperfusion injury and the effect of EP on the expression of HMGB1. Methods: Sprague-Dawley rats (200∼300 g) were subjected to 40 minutes of renal warm ischemia. The animals were divided into three groups: sham group without warm ischemia, the EP group (EP given before ischemia), and the ischemic control group. Kidneys were harvested and serum creatinine, IL-1 and IL-6 were measured at 6hours, 1 day, 3 days and 5 days after reperfusion. Immunohistochemical stain of HMGB-1 was done. Results: Serum creatinine and IL-1 level were elevated in ischemic control group and EP injection group. In EP injection group, serum creatinine and IL-1 level were lower than the ischemic control group. In the rat 40 minutes ischemia reperfusion model, HMGB1 expression was increased at 6 hours after reperfusion. which was decreased gradually at 1 day, 3 days, and 5 days after reperfusion. HMGB1 expression was more distinct at outer medullary area. intraperitoneal EP injection has no effect on the expression of HMGB1. Conclusion: From these results, we deduced a conclusion that the preventive effect of EP on the rat kidney ischemia reperfusion injury is not by the decreased expression of HMGB1 but by the prevention of the release of the HMGB1.ope

Recurrent Urinary Tract Obstruction Due to Long-Coiled Transplant Ureter and Extrinsic Ureteric Compression

Urinary tract complications, manifesting as leakage or obstruction, generally occur in 3.0~13% of renal recipients. Most complications occur at the ureterovesical anastomosis and are secondary to technical causes and ureteric ischemia. Ultrasound and computed tomographic images are described in a recipient who underwent oversea deceased donor renal transplantation and presented with recurrent ureteral obstruction and hydronephrosis secondary to combination of unusually located transplant kidney, long-coiled ureter, ureteric compression and ischemia of the transplant ureterope

Effects of Mycophenolic Acid and Rapamycin on Toll-Like Receptor Expression in Hypoxic Human Proximal Tubular Epithelial Cells

Background: Toll like receptor (TLR), an element of innate immunity, is upregulated by Ischemia/reperfusion (IR) injury and may be involved in adaptive immune response. Immunosuppressive agents may increase or attenuate IR injury and TLR expression. To explore the involvement of TLRs in hypoxic tubular injury and modification by mycophenolic acid (MPA) rapamycin (RAP), this study examined TLR expression in hypoxia-induced human renal proximal tubular epithelial cells (HK-2). Methods: HK-2 cells were cultured in keratinocyte-SFM media supplemented with epidermal growth factor and bovine pituitary extract. The Induction of hypoxia was achieved using GasPak pouch system. TLR 2, 3, and 4 mRNA expression was analyzed by real time RT-PCR using SYBR green and TLR 4 protein expression was evaluated by Western blot analysis. MPA at concentration of 100 nM and 1uM and RAP at concentration of 20, 50, and 100 nM were added to culture medium. Results: TLR4 but noTLR2 or TLR3 mRNA expressions increased in hypoxic HK-2 cells at 24 and 48 hrs. TLR4 protein expression also increased in hypoxic HK-2 cells at 24 and 48 hrs. MPA (100 nM and 1uM) and RAP (20, 50, and 100 nM) decreased hypoxia-induced TLR4 mRNA expression in HK-2 cells compared to normoxia at 24 hrs. However, TLR4 protein expression was decreased only by RAP at 20 and 50 nM. Conclusions: The results suggest that RAP may modify hypoxic renal tubular damage by decreasing TLR4-mediated inflammatory and immune reactionsope

Clinical Outcome of Renal Transplantation in Patients with Positive Pretransplant Hepatitis B Surface Antigen

Purpose: The natural history of renal transplant recipients with positive HBs Ag is still unclear and unpredictable. Liver-related morbidity and mortality after long-term immunosuppression need clinical challenges. We retrospectively investigated the clinical outcome of pre-transplant HBs Ag positive renal recipients in a single transplant center located in endemic area. Methods: After excluding post-transplant de novo HBV infected, and peri-transplant anti-hepatitis C virus positive recipients, the clinical outcome of 1,816 recipients was examined by the nature of pre-transplant HBs Ag positivity. Results: Pre-transplant HBs Ag positivity was documented in 61 recipients (M/F=47/14). During mean follow up of 71.61±54.14 months, 24 recipients died (6 by infection, 12 by hepatic failure, 2 by hepatocellular carcinoma, 2 by other malignancies, 1 by suicide, 1 by gastrointestinal bleeding). In 14 recipients (58.3%), death was related to liver-associated reasons. The 10-year patient survival rates in HBs Ag negative and positive groups were 90.0% and 62.6%, respectively (P＜0.0001). The 10-year graft survival rates in HBs Ag negative and positive groups were 82.0% and 55.6%, respectively (P＜0.0001). When pre-transplant HBV DNA viral load by PCR was positive or when the level of post-transplant HBV-DNA viral load flared up, we started lamivudine therapy since 1997. Seventeen recipients received daily 100 mg lamivudine. The mean duration of patients survival with (n=17) and without (n=44) lamivudine therapy was 104.3±45.6 and 59.0±51.2 months, respectively (P=0.003). The 10-year patient survival rates in patients with and without lamivudine therapy were 80.7% and 55.4%, respectively (P=0.0698). Conclusion: Overall patient and graft survival in patients with positive pre-transplant HBs Ag was lower than negative recipients. Although, statistically not significant, lamivudine therapy showed a marginally positive impact on the survival of patients with pre-transplant positive HBs Ag.ope

Clinical Application of Mammalian Target of Rapamycin Inhibitor in Kidney Transplantation

Mammalian target of rapamycin inhibitors (mTOR-I)* is a novel immunosuppressive agent that has the variable action mode, such as anti-fibroblastic, anti-tumor and anti-atherosclerotic effect, but doesn`t have a nephrotoxicity. Since March 2006, two types of mTOR-I, sirolimus and everolimus, are clinically available in Korea. In this article, we summarize the pharmacologic characteristics of mTOR-I and review the clinical application of mTOR-I as the component of immunosuppressive regimen after kidney transplantation. Sirolimus and everolimus share the same action mode resulting in an arrest of cell cycle (G1 to S phase arrest). Despite the similarities of chemical structure between sirolimus and everolimus, there are remarkable pharmacokinetic differences between the two molecules. In summary, the half-life and time to reach steady state of everolimus is shorter than those of sirolimus. Therefore, there are significant difference in administration interval and mode. Four types of clinical application of mTOR-I were tried in de Novo renal transplant recipients; (1) for replacement of calcineurin inhibitor (CNI), (2) for replacement of antimetabolites, (3) in combination CNI with low dose mTOR-I versus high dose mTOR-I, (4) standard dose CNI plus low dose mTOR-I versus low dose CNI plus high dose mTOR-I. Generally, mTOR-I shows superior results in graft survival rate, acute rejection free rate and graft renal function (eGFR), but shows inferior results in maintenance rate of regimen and occurrence of side effect (such as proteinuria, wound healing problem and dyslipidemia). Conversion from CNI to mTOR-I was tried in recipients with de Novo post-transplant malignancy or chronic allograft dysfunction. These clinical trial data suggest that mTOR-I may be useful in management of selective type of post-transplant malignancy (such as non-melanoma skin cancer, Kaposi`s sarcoma and post-transplant lymphoproliferative disease) or chronic allograft dysfunction with CNI nephrotoxicity. Clinical application of mTOR-I makes variable combination of immunosuppressive agent possible. Therefore, it is possible to make the selective or tailored immunosuppressive regimen that yields the best outcome with minimal adverse effect.ope

Treatment of Acute and Chronic Wound in Immunodeficiency Patients Using Easyef® (EGF)

Purpose: The mechanism of wound healing is a complex process which includes coagulation, inflammation, fibroplasias and scar remodeling phase. Various factors, such as immune status of host, growth factors and many enzymes play significant roles in wound healing process. Especially those who are immunosuppressed have reduced humoral immunity leading to blockade in inflammatory phase and decreased secrection of various growth factors, resulting in delayed wound healing. We tried to accelerate the wound healing process in the immunosuppressed patients by introducing the exogenous growth factors. Methods and Results: From March 2004 to February 2005, ten patients who were administered with immunosuppressant medications or had undergone long-term immuno-deficit state were treated with EGF. Patients had an average of 9×6㎝ skin defect due to either trauma or infection, and with good wound care and twice-a-day application of Easyef® (human recombinant epidermal growth factor, Dae-Woong), complete healing was achieved in all wounds in an average of 3 months. Conclusion: The treatment of wound with application of epidermal growth factor can be a method of choice in treating wounds in the immunosuppressed patients.ope

Risk Factors Affecting Long-Term Outcome in Kidney Re-Transplantation Recipients

Purpose: The aims of this study were to review the result of kidney re-transplantation in comparison with first kidney transplantation, and to identify the prognostic factors affecting long-term outcome at a single center. Methods: Between April 1979 and January 2006, the total number of renal allografts was 2,495. Among these, 159 cases received second (155 cases) or third (4 cases) transplantation. Demographic characteristics and clinical outcomes of both groups were compared. And we examined the risk factors affecting long-term outcome in re-transplantation recipients. Results: The mean duration of previous graft survival in re-transplantation group was 86.1±51.4 (0~215) months. Major cause of the previous graft failure was chronic rejection (n=88, 55.3%). One-, 5-, and 10-year graft survivals of the re-transplantation group and the first transplantation group were 94.1%, 88.9%, 76.0% and 96.0%, 84.8%, 69.1%, respectively without significant difference (P=0.2203). In uni-variate survival analysis, acute rejection experienced group, elderly recipient more than 50 years old, and female gender group showed significant inferior graft survival rate compared to control group. Previous graft survival duration didn`t cause significant graft survival difference. Multivariate survival analysis also confirmed that the episodes of acute rejection within 12 months after transplantation (P=0.035, Odd ratio=2.514), elderly recipient more than 50 years old (P=0.002, odd ratio=3.734), and female gender (P=0.005, Odd ratio=3.692) were statistically significant independent risk factors affecting graft survival in kidney re-transplantation. Conclusion: Long-term outcomes after kidney re-transplantation were not different from that of first kidney transplantation. Therefore, renal re-transplantation could be the treatment of choice even in recipients with previous failed renal allograft.ope

Long-term Effect of Steroid-free Immunosuppressive Protocol in Kidney Transplantation

Purpose: Early experience of steroid-free immunosuppressive protocol for kidney transplant recipient was unsatisfactory due to a remarkable incidence of acute rejection. We also attempted steroid-free protocol in 1990, and experienced painful early result. Therefore, steroid-free protocol have not been tried since 1990. Now, we retrospectively reviewed our experience of steroid-free protocol which was performed in 1990, and verified the long-term effect of steroid-free protocol. Methods: Among 149 recipients who underwent living donor kidney transplantation in 1990, 48 recipients with stable graft function were enrolled in this study. Cyclosporine and steroid were administrated as a maintenance immunosuppressive regimen without induction immunosuppression such as anti-lymphocyte antibodies. Steroid was gradually reduced for 6~8 weeks at 2~3 month after transplantation. If acute rejection or graft dysfunction was developed during tapering period or after cessation, steroid was restarted. And such tapering failure and restart group were defined as steroid-free failure group. We compared the clinical outcomes of steroid-free trial group compared with non-trial (control) group. Results: 17 (35.4%) of 48 recipients failed in steroid-free protocol finally. Acute rejection was the most common cause of steroid-free failure by 11 (64.7%) recipients, and most failure (12 recipients, 70.6%) occurred within 1 year after transplantation. Therefore failure group showed significant inferior graft survival rate than steroid-free group (35.3% versus 80.7%, P=0.001). The overall steroid-free trial group showed similar graft survival rate compared with control group. But the steroid-free group showed superior graft survival rate than control without statistical significance (80.7% versus 60.4%, P=0.383). And also showed lower incidence of post-transplant diabetes, hypertension, hyperlipidemia and bone disease without or with significance. Conclusion: The steroid-free protocol without addition of other immunosuppressive agent causes high incidence of acute rejection and poor graft survival. Hwoever, success group to steroid-free protocol shows beneficial effect in graft survival rate and post-transplant complications.ope