Cause Of Graft Failure Research Articles

31-P

Aim Chronic rejection (CR) remains the leading cause of graft failure after renal transplantation. We previously showed preoperatively sensitized patients who remain sensitized posttransplant have poor graft survival due to CR. In an effort to reduce CR, we implemented a strategy that scored ‘sensitization risk’ at the time of transplant and preemptively treated patients with 3 or more points with IVIG and plasmapheresis. We report the impact of this protocol upon 3 year clinical outcome. Methods All patients received deceased donor kidneys. Sensitization points were determined at time of transplant for the following parameters: PRA >50% with DSA (1 point), FCXM >100 MCS (1 point), FCXM >200 MCS (2 points), delayed graft function (1 point). Patients with 3 points were preemptively treated with 150 mg/kg IVIG and plasmapheresis thrice weekly for 2 weeks. Immunosuppression was same in all patients. Results Of 235 recipients, 36 received preemptive treatment (Treated) and 199 did not (Control). Groups were similar (p = ns) in terms of patient age (48 vs. 52 yrs), gender (47 vs. 56% male), ethnicity (85 vs. 69% African American) and HLA mismatch (4.5 vs. 4.6). In contrast, Treated patients had significantly (p Conclusions Sensitized patients with positive FCXM and DSA at transplant are most susceptible to chronic rejection. By combining a simple point-based algorithm for sensitization status and preemptive treatment, we have improved 3 year graft survival in this high risk group.

Human Leukocyte Antigen and Major Histocompatibility Complex Class I-Related Chain A Antibodies After Kidney Transplantation in Turkish Renal Transplant Recipients

BackgroundThis study was designed to determine whether human leukocyte antigen (HLA) and major histocompatibility complex class I chain-related A (MICA) antibody (Ab) production during the first 6 months posttransplantation correlated with long-term graft survival and rejection rate. The study group included 147 first transplantations from either living related (LRDs) or deceased donors (DDs) who were divided into two subgroups: rejection (RG, n = 28) and nonrejection (NRG, n = 119). Serum samples (n = 441) collected from each patient on posttransplant days 30, 90, and 180 were tested for HLA and MICA Ab using the Luminex technique. ResultsAmong 82 Ab-positive patients (55.8%), 40 had both HLA and MICA, 33 only HLA, and 9 only MICA Ab in the posttransplant period. The rates of HLA class I, class II, or both Ab positivities were greater in the RG than the NRG (P = .011, .037, and .0275, respectively). At 180 days posttransplant, 64.3% of patients in the RG had Ab and 41.2% in the NRG (P = .0349). The data for the LRD (n = 116) group were similar to those for the entire group; whereas there was no significant difference in Ab positivity between RG and NRG patients who received organs from DDs. There was no significant difference with respect to HLA class II and/or MICA Ab positivity between RG and NRG among patients who lacked HLA class I Ab. DiscussionWe confirmed that HLA and MICA Ab may be harmful posttransplant, promoting rejection processes and representing an important cause of graft failure. HLA class II and MICA Ab positivities were only important predictors of graft failure when present together with HLA class I positivity. Patients who developed HLA alone or both HLA and MICA Ab rejected their grafts more frequently than Ab-negative recipients.

A Case of Acute Antibody-Mediated Rejection Developed after Pretreatment with Rituximab and Plasma Exchange in a Highly-Sensitized Recipient with a Deceased Donor Kidney

Acute antibody-mediated rejection is the major cause of graft failure in the early stage of kidney transplantation. Preoperative treatment and early diagnosis of acute rejection is very important to prevent graft loss in sensitized patients. High panel reactive antibody (PRA) means a likelihood of acute rejection, and the recipient of high PRA needs adequate pretreatment for kidney transplantation. However, there is not sufficient time and chances for desensitization in deceased kidney transplants. We report a successful renal transplant outcome in a 47-year-old-woman with high PRA levels (Class I 97.5%, Class II 36.7%). The cross match was negative on the CDC (ELISA) and flowcytometric methods. Plasma exchange was performed on the recipient before transplantation (fresh frozen plasma replacement, 1.3 plasma volume) and immediately after plasma exchange she was given 200 mg of rituximab. She received basiliximab and methyl prednisolone induction therapy and was maintained on steroids, mycophenolate mofetil, and tacrolimus. Graft function was normal immediately after transplantation, but decreased urinary output and elevated serum creatinine was noted on POD 5. On POD 6, a graft biopsy revealed acute cellular rejection (Type IIa) and antibody-mediated rejection (Type II). On 9∼13 days after transplantation, additional plasma exchange was performed every other day, and steroid pulse therapy was performed 3 times. After normalization of urinary output and serum creatinine, the patient was discharged and is being followed up on. In conclusion, immunologically careful preparation and pretransplant treatment may be needed on the negative cross match in cadaveric kidney recipients with high levels of PRA.

Mycophenolate mofetil inhibits hepatitis C virus replication in human hepatic cells

Hepatitis C virus (HCV) infection is the most common indication for liver transplantation and the major cause of graft failure. A widely used immunosuppressant, cyclosporine A (CsA), for people who receive organ transplantation, has been recognized to have the ability to inhibit HCV replication both in vivo and in vitro. In this study, we investigated the effects of several other immunosuppressants, including mycophenolate mofetil (MMF), rapamycin and FK506, on HCV replication in human hepatic cells. MMF treatment of hepatic cells before or during HCV infection significantly suppressed full cycle viral replication, as evidenced by decreased expression of HCV RNA, protein and production of infectious virus. In contrast, rapamycin and FK506 had little effect on HCV replication. Investigation of the mechanism(s) disclosed that the inhibition of HCV replication by MMF was mainly due to its depletion of guanosine, a purine nucleoside crucial for synthesis of guanosine triphosphate, which is required for HCV RNA replication. The supplement of exogenous guanosine could reverse most of anti-HCV effect of mycophenolate mofetil. These data indicate that MMF, through the depletion of guanosine, inhibits full cycle HCV JFH-1 replication in human hepatic cells. It is of interest to further determine whether MMF is indeed beneficial for HCV-infected transplant recipients in future clinical studies.

Hepatic artery thrombosis and liver malignancy in pediatric liver transplantation

BackgroundHepatic artery thrombosis (HAT) remains a significant cause of graft failure and mortality after pediatric liver transplantation. Conditions not associated with hepatic failure, such as liver tumors, may be more prone to thrombotic problems after transplant. We hypothesized that liver transplant for hepatic malignancies may be associated with increased rates of HAT in the posttransplant period. MethodsWe conducted a retrospective review of pediatric patients (age, 0-21 years) who underwent primary liver transplantation at a free-standing children's hospital from 1990 to 2009. We reviewed cause of underlying liver disease, age, sex, weight, occurrence of HAT, use of antiplatelets and anticoagulants perioperatively, as well as reintervention, retransplant, and death. ResultsA total of 129 children underwent 146 liver transplants, and 15 (12%) patients developed HAT. Nine liver transplants were performed for hepatic malignancy, and 4 (44%) of these patients developed HAT (relative risk, 4.85; 95% confidence interval, 1.9-12.2; P = .0015). All 4 children with hepatic malignancy and HAT required reintervention, including 3 retransplants (75%). One of these patients died. ConclusionsHepatic artery thrombosis occurs approximately 5 times more often and appears to be more morbid in children with hepatic malignancy after transplantation. Prospective evaluation of prophylactic anticoagulation regimens in the setting of hepatic malignancy requiring transplantation is warranted.

Glaucoma in penetrating keratoplasty: risk factors, management and outcome

Glaucoma is a leading cause for graft failure. This retrospective study analyzes the risk factors, graft status, and treatment modalities in patients with post-penetrating keratoplasty glaucoma. A retrospective analysis of case records of 1,848 penetrating keratoplasties carried out between 2000 and 2005 was performed. A total of 160 patients (160 eyes) with post-penetrating keratoplasty glaucoma were included; 112 cases were primary grafts, 48 repeated grafts. The assessment included the pre-operative history of corneal disease and glaucoma, the lens status, and the anesthesiological techniques. Furthermore, the response to anti-glaucoma treatment, graft failure, and endothelial cell loss was evaluated. The incidence of post-penetrating keratoplasty glaucoma was 8.7 % (160/1,848). Preoperative glaucoma was the most important risk factor (62/160). Half of the patients (81 patients) responded to medical therapy (51 %) and the other half of patients (79 patients) to surgical therapy (49 %); of the latter, filtering surgery were performed in 16 %, cyclodestructive procedures in 66 % and both in 16 %. One patient received a glaucoma implant and cyclodestructive procedures (1 %). After 24 months, clear grafts were achieved in 94 eyes (59 %). Visual acuity after 24 months of 20/200 (logMAR 1.0) or better was achieved in 77 eyes (46 %) and of 20/50 (logMAR 0.4) in 33 eyes (21 %). Careful and ongoing observation of IOP, especially in the first year after PK, is recommended for patients after penetrating keratoplasty and prompt treatment of IOP elevation when indicated. Early filtering surgery with a better outcome than other surgery procedures should be preferred if medical treatment is not sufficient. Despite anti-glaucoma therapy, good visual outcome can remain beyond expectations despite a clear graft. While there is a potential option for graft exchange, damage to the optic nerve from end-stage glaucoma leads immutably to visual loss.

491 Differential Effect of Everolimus and Metabolic Risk Factors on Early vs. Late Progression of Allograft Vasculopathy: Dissecting Two Faces of the Same Disease

Coronary allograft vasculopathy (CAV) is the main cause of graft failure after heart transplantation (HT). Clinical trials showed that everolimus (EVE) prevents early CAV. However, if this property can be replicated in clinical practice and on long-term CAV progression is unexplored.

Right hepatic artery thrombosis in an essential polycythemia vera patient following pancreato-biliary surgery for severe pancreatitis

Hepatic artery thrombosis (HAT) remains one of the major causes of graft failure and mortality in liver transplant recipients. But it is a very rare in non-transplantation patient with the complication of HAT. We reported herein a case of successful urokinase intra-arterial thrombolytic treatment for HAT in an essential polycythemia vera patient following pancreato-biliary surgery. This patient underwent debridement and T-tube drainage in common bile duct for severe pancreatitis and acute suppurative obstructive cholangitis. Significant elevation of liver transaminases and white blood cell counts was noted 30 days after operation and HAT was confirmed by CT-angiography and digital subtracted angiography. Apart from malena and malaise, this patient had scarcity of evident symptoms. The only obvious risk factor relating to HAT is thrombocytosis. This patient was continuously characterized by an excess of platelets from its admission to the onset of HAT. This patient was treated successfully with continuous transcatheter arterial thrombolysis using urokinase. The symptom including malena and malaise disappeared 3 days after thrombolysis. And the patient was treated with hydroxyurea for polycythemia vera thereafter. In conclusion, physicians should be alerted that HAT can be happened in non-transplantation patients especially in those of having hypercoagulability.

Efficacy and Safety of Long-term Corticosteroid Eye Drops after Penetrating Keratoplasty: A Prospective, Randomized, Clinical Trial

Endothelial rejection remains a major cause of graft failure after penetrating keratoplasty (PKP). Topical corticosteroids are the gold standard for preventing rejection; however, protocols for corticosteroid treatment have been diverse. The aim of the present study was to examine the efficacy and safety of long-term use of corticosteroid eye drops after PKP in a randomized, clinical trial. Randomized, nonblinded, clinical trial. We enrolled 42 patients (21 males and 21 females) with a mean age of 65.3 years who underwent PKP and maintained graft clarity for >1 year with topical steroid eye drops. Patients were randomly assigned to 1 of 2 groups: Administration of 0.1% fluorometholone 3 times a day (steroid group) or discontinuation of steroid eye drops (no steroid group). All patients were followed for 12 months. Proportion of eyes without endothelial rejection and the proportion of eyes with clear grafts and the incidence of local or systemic side effects. Of the initial 42 patients, 4 in the steroid group and 6 in the no steroid group did not complete the trial. Of the patients who completed the trial, 1 patient in the steroid group and 6 in the no steroid group developed endothelial rejection at an average of 5.2±4.5 (mean ± standard deviation) months after study enrollment. The difference in the incidence of rejection between groups was found to be significant by both chi-square (P = 0.027) and Kaplan-Meier analyses (log-rank test, P = 0.032). No difference was observed between the 2 groups in visual acuity, intraocular pressure, epithelial damage, tear-film break-up time, cataract progression, infection, or incidence of systemic side effects. Prolonged use of 0.1% fluorometholone was beneficial for the prevention of rejection after PKP. Because no adverse consequences were noted, we recommend continuing use of the low-dose corticosteroids, even in non-high-risk cases.

Influence of Metabolic Syndrome on Development of Cardiac Allograft Vasculopathy in the Transplanted Heart

Cardiac allograft vasculopathy (CAV) is the main cause of graft failure and death 1 year after heart transplantation (HTx). Metabolic syndrome (MS) increases the risk of cardiovascular events by endothelial dysfunction. The purpose of this study was to determine if patients with MS developed a higher risk of CAV 1 year after HTx. Since January 2004 until April 2009, 155 HTx patients were recruited. Cardiopulmonary transplants were excluded (12 patients), as well as retransplants (5 patients), pediatric transplants (11 patients), patients who refused to participate (3 patients), and those who died during the first year (35 patients). The final analysis included 89 patients. MS was diagnosed when Adult Treatment Panel III modified and revised criteria were met, before HTx or after the first 3 months. CAV was diagnosed through intravascular ultrasound performed 1 month and 1 year after HTx. CAV was defined as an intimal thickening ≥ 0.5 mm in the follow-up with regard to the one of the basal study. Development of CAV was significantly higher in patients with MS (59% vs. 19%, P<0.0001). Patients with more criteria of MS had a higher development of CAV: no criteria (4%); one criterion (4%); two criteria (47%); three criteria (62%); four criteria (75%); and five criteria (100%). Variables related to CAV in a multivariate analysis were MS (odds ratio [OR] 7.97; 95% confidence interval [CI]: 2.77-22.96; P<0.001), donor's age (OR 1.07; 95% CI: 1.01-1.13; P=0.019), low high-density lipoprotein cholesterol (OR 0.26; 95% CI: 0.09-0.71; P=0.009), and hypertriglyceridemia (OR 4.08; 95% CI: 1.45-11.50; P=0.008). Presence of MS distinguishes a subgroup of patients with high risk of developing CAV. Narrow and personalized monitoring of these patients would be recommendable.

Saphenous vein graft disease: causes, prevention, and contemporary treatment strategies

Coronary bypass graft surgery provides symptomatic relief and a long life expectancy for most patients with coronary artery disease who have suitable vessels. Although arterial conduits are becoming more popular, saphenous vein grafts (SVG) are still frequently used in coronary artery bypass surgery since they are readily available, especially in emergency situations. However, SVG tend to degenerate over time, as nearly half of them develop significant stenosis and nearly 40% of them become completely occluded within a decade. Treatment options for SVG failure include redo-surgery, percutaneous intervention, and/or medical therapy. However, challenges in maintaining graft patency (as a predictor of long-term survival) and interventional complications (e.g., distal embolization, ''no-reflow,'' and higher rates of periprocedural myocardial infarction) are still ongoing problems for cardiologists and cardiovascular surgeons. This review discusses the possible causes of graft failure and the contemporary approaches for improving outcomes in patients undergoing coronary artery bypass graft surgery with at least one SVG.

Iatrogenic Aortocoronary Arteriovenous Fistula following Coronary Artery Bypass Surgery: A Case Report and Complete Review of the Literature.

The case of a patient who presented with angina following a coronary artery bypass (CABG) operation during which the left internal mammary artery was inadvertently anastomosed to a cardiac vein is presented. The literature concerning previously reported cases of aortocoronary arteriovenous fistulas (ACAVF) due to inadvertent grafting of a coronary vein is reviewed and the significance of this complication is discussed. ACAVF due to inadvertent grafting of a coronary vein is a rare complication of CABG and may be a more common cause of graft failure than has previously been recognized. Distortion of cardiac anatomy, the presence of epicardial fat, and an intramyocardial course of the artery intended for grafting are predisposing factors. Some patients present with angina pectoris and heart failure whereas others have no symptoms. The diagnostic test of choice is coronary angiography. Cardiac MRI and CT have a limited role due to the smaller size and the more clearly defined course of these fistulas. Asymptomatic patients are simply observed since spontaneous closure of these fistulas is reported. Symptomatic patients can be treated with combined medical management and percutaneous methods.

Long‐Term Outcomes of Patients Treated with Primary Stenting for Transplant Renal Artery Stenosis: A 10‐year Case Cohort Study

The purpose of the present study was to evaluate graft and patient survival and long-term outcomes of primary endoluminal stenting (PES) as an initial treatment for transplant renal artery stenosis (TRAS). From December 1999 to March 2010, 744 consecutive patients undergoing renal transplantation were enrolled. Patients were divided into one of two groups: the study group, comprised of 18 patients who underwent PES for TRAS > 60%, and a control group, including the remaining 726 recipients who did not develop TRAS post-transplantation. Primary outcome measures were death-censored graft failure and all-cause mortality. The immediate and long-term effects of PES were evaluated by assessing blood pressure (BP) control and biochemical graft function. The technical success rate for PES was 100%, and minor complication occurred in only one case (5.6% of the study group). With a mean follow-up of 7.1 ± 3.7 and 6.9 ± 2.4 years in the study and control groups, respectively, 4 patients in the study group and 113 patients in the control group reached the primary outcome (log rank P = 0.418). The reduction in stenosis resulted in immediate improvement in BP control and graft function, which persisted throughout the 6 year follow-up period. Restenosis occurred in only one patient (5.6%), but restenosis was not the cause of graft failure. This study indicated that both the long-term graft and patient survival were as good in TRAS patients treated with PES as in patients without TRAS. The data also supported the use of PES as an initial treatment for TRAS.

Laparoscopic Roux-en-Y gastric bypass in a morbidly obese patient with renal transplant: A case report

Renal transplant is the only curative treatment for end-stage renal disease. As diabetes and obesity are the major causes of graft failure and post-transplant complication, it is important to manage obesity in patients with renal transplant. Herein, we report a case of a morbidly obese renal-transplant patient with poorly controlled diabetes who received bariatric surgery. A 34-year-old obese Taiwanese man with type 2 diabetes had end-stage renal disease that had progressed since 2008, when he had commenced hemodialysis (January 2008) and had a renal transplant (July 2008). Because of persistent obesity and poorly controlled diabetes, he received LRYGB at Chiayi Christian hospital on 18 August 2010. In the month that followed, he lost 10 kg. His serum creatinine decreased to 1.11 mg/dL (1.4 mg/dL, preoperative) and his hemoglobin A1c decreased to 8.5% (10.4%, preoperative). These results indicate that, in obese renal transplant patients, LRYGB may be employed to treat obesity, control diabetes and stabilize or improve the renal function.

Inhibition of Mitogen Activated Protein Kinase Activated Protein Kinase II with MMI-0100 reduces intimal hyperplasia ex vivo and in vivo

Vein graft intimal hyperplasia remains the leading cause of graft failure, despite many pharmacological approaches that have failed to translate to human therapy. We investigated whether local suppression of inflammation and fibrosis with MMI-0100, a novel peptide inhibitor of Mitogen Activated Protein Kinase Activated Protein Kinase II (MK2), would be an alternative strategy to reduce cell proliferation and intimal hyperplasia. The cell permeant peptide MMI-0100 was synthesized using standard Fmoc chemistry. Pharmacological doses of MMI-0100 induced minimal human endothelial and smooth muscle cell proliferation (30% and 12% respectively). MMI-0100 suppressed IL-6 expression to control levels, without effect on IL-8 expression. MMI-0100 caused sodium nitroprusside induced smooth muscle cell relaxation and inhibited intimal thickening in human saphenous vein rings in a dose-dependent fashion. In a murine aortic bypass model, MMI-0100 reduced intimal thickness in vein grafts by 72%, and there were fewer F4/80-reactive cells in vein grafts treated with MMI-0100. MMI-0100 prevents vein graft intimal thickening ex vivo and in vivo. These results suggest that inhibition of MK2 with the cell-permeant peptide MMI-0100 may be a novel strategy to suppress fibrotic processes such as vein graft disease.

Treatment of Early Hepatic Artery Thrombosis After Liver Transplantation

Introduction Early hepatic artery thrombosis remains one of the major causes of graft failure and mortality in liver transplant recipients. It is the most frequent severe vascular complication after orthotopic liver transplantation (OLT) accounting for >50% of all arterial complications. Most patients need to be considered for urgent liver retransplantation. Materials and Methods Among 911 OLTs in 862 from 1989 to 2011, we observed 23 cases (2.6%) of acute early hepatic artery thrombosis. Seventeen patients were qualified immediately for liver retransplantation, and 6 underwent endovascular therapies, including intra-arterial heparin infusion or percutaneous transluminal angioplasty with stent placement. Results Among patients who were assigned to early liver retransplantation, 11/17 survived with 3 succumbling due to postoperative complications, including 1 portal vein thrombosis, and 3 succumbling on the waiting list. All patients who underwent endovascular therapy survived with an excellent result obtained in 1 who underwent treatment <24 hours after arterial thrombosis. In 2 patients we achieved a satisfactory result not requiring retransplantation, but 3 patients assigned to endovascular treatment >24 hours after arterial thrombosis needed to be reassigned to liver retransplantation because of poor results of endovascular treatment. Conclusions Endovascular treatment efforts should be made to rescue liver grafts through urgent revascularization depending on the patient's condition and the interventional expertise at the transplant center, reserving the option of retransplantation for graft failure or severe dysfunction.

Zinc Transporter 8 Autoantibodies Increase the Predictive Value of Islet Autoantibodies for Function Loss of Technically Successful Solitary Pancreas Transplant

Despite the success rate of solitary pancreas transplantation in type 1 diabetes with preserved kidney function has greatly improved in recent years, a residual proportion of failures persists. With the aim of investigating autoimmunity as an unrecognized cause of graft failure, we measured autoantibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 (IA-2A) and the recently discovered zinc transporter 8 antigen (ZnT8A) in 25 recipients of technically successful solitary pancreas transplantation. The overall pancreas graft survival was 92%, 88%, and 80% at 2, 4, and 6 years, respectively. Fourteen patients (56%) had one or more autoantibodies before transplantation, with no effect on subsequent pancreas graft outcome. After transplantation, major autoantibody changes (serum conversion from negative to positive, spreading from one to multiple autoantibodies, or titer increase) were observed in 5 of 25 recipients: in four patients, the autoantibody change was followed by the loss of graft function (95% sensitivity, 80% positive predictive value), with a significantly lower graft survival compared with patients without autoantibodies (P<0.0001). The addition of ZnT8A to GADA and IA-2A increased the number of identified autoantibody changes from three to five of 25 recipients and the number of predicted graft function loss from two to four out of five graft losses. Detection of major autoantibody changes after technically successful solitary pancreas transplantation is predictive of subsequent loss of graft function. ZnT8A in addition to GADA and IA-2A are a useful marker to be included in the screening panel of posttransplant immune monitoring.

Significance of complement split product C4d in ABO-compatible liver allograft: Diagnosing utility in acute antibody mediated rejection

Diagnosis of liver allograft antibody-mediated rejection (AMR) is difficult and requires a constellation of clinical, laboratory and histologic features that support the disease and exclude other causes. Histologic features of AMR may intermix with those of biliary obstruction, preservation/reperfusion injury, and graft ischemia. Tissue examination for complement degradation product 4d (C4d) has been proved to support this diagnosis in other allografts. For this reason, we conducted a retrospective review of all ABO compatible/identical re-transplanted liver patients with primary focus on identifying AMR as a possible cause of graft failure and to investigate the utility of C4d in liver allograft specimens. We reviewed 193 liver samples obtained from 53 consecutive ABO-compatible re-transplant patients. 142 specimens were stained with C4d. Anti-donor antibody screening and identification was determined by Luminex100 flow cytometry. For the study analysis, patients were stratified into 3 groups according to time to graft failure: group A, patients with graft failure within 0–7 days ( n = 7), group B within 8–90 days ( n = 13) and C > 90 days ( n = 33). Two patients (3.7%) met the diagnostic criteria of acute AMR. Both patients experienced rapid decline of graft function with presence of donor specific antibodies (DSA), morphologic evidence of humoral rejection and C4d deposition in liver specimens. C4d-positive staining was identified in different medical liver conditions i.e., acute cellular rejection (52%), chronic ductopenic rejection (50%), recurrent liver disease (48%), preservation injury (18%), and hepatic necrosis (54%). Univariate analysis showed no significant difference of C4d-positive staining among the 3 patients groups, or patients with DSA ( P > .05). In conclusion, AMR after ABO-compatible liver transplantation is an uncommon cause of graft failure. Unlike other solid organ allografts, C4d-positive staining is not a rugged indicator of humoral rejection, thus, interpretation should be done with caution to avoid diagnostic dilemmas.

Histopathological findings of failed grafts following Descemet’s stripping automated endothelial keratoplasty (DSAEK)

PurposeTo study the histopathological findings of the early cases of failed DSAEK grafts and to analyze the causes of graft failure. MethodsRetrospective study of 13 failed DSAEK grafts (four grafts submitted alone with no host cornea) of 12 patients. The histopathologic features are correlated with the clinical and operative findings. ResultsSignificant attenuation of the endothelial cells found in 10/13 cases (77%), retained recipient Descemet’s membrane in 7/13 (54%), variability of graft thickness in 5/13 (38%) and two of these had stromal irregularity. Retrocorneal fibrous membrane along the donor’s Descemet’s membrane was found in 4/13 (31%) resulting in endothelial detachment in one case. Eight of the nine host cornea–graft specimens were found to have: total graft-cornea detachment (in one), subtotal in four and partial (⩽50% of graft length) in three. The detached flaps showed infection at the interface of the graft–host cornea in two, epithelial ingrowth and fibrous proliferation along the anterior stromal surface of the graft (one case each). An additional histopathological finding was secondary amyloid deposition within the host stroma (in one). ConclusionIrregular or thick graft, graft–host interface fibrous/epithelial ingrowth, and infection all predispose to DSAEK failures related to graft detachment. Endothelial cells attenuation and retrocorneal fibrous membrane are major causes for primary graft failure.

Everolimus and Minimization of Cyclosporine in Renal Transplantation: 24-Month Follow-Up of the EVEREST Study

The association of cyclosporine A (CsA) with everolimus can exert synergistic effects on the alloimmune response. CsA inhibits the synthesis of interleukin-2 while everolimus inhibits the response to interleukin-2. Moreover, the interaction with CsA increases the bioavailability of everolimus (1). These data suggest that it is possible to reduce the doses of both drugs when given in combination. Previously, we reported the 1-year results of a randomized trial in 285 de novo renal transplants, 278 from deceased donors (2). Patients of group A received low-concentration CsA (C2 maintenance levels 350–500 ng/mL) plus everolimus (C0 levels 3–8 ng/mL), while patients of group B received very low-concentration CsA (C2 maintenance levels 150–300 ng/mL) and everolimus at higher target levels (C0 8–12 ng/mL). One-year graft survival rate was better in group B (98% vs. 90%; P=0.007). The mean serum creatinine levels at 1 year were, respectively, 1.51±0.55 mg/dL and 1.55±0.62 mg/dL. After the 1-year study was completed, 215 patients (110 in group A and 115 in group B) accepted to enter the extension study and to continue the study treatment up to 2 years. At 24 months, the mean everolimus dosages were 1.45±0.6 mg/day in group A (blood levels 6.17±2.1 ng/mL) and 2.24±1.1 mg/day in group B (blood levels 8.15±3.5 ng/mL), and the dosages of CsA were 1.62±0.5 mg/kg/day (C2 levels 407.6±159 ng/mL) and 1.38±0.7 mg/kg/day (C2 blood levels 330.7±159 ng/mL), respectively; the prednisone dosages were 5.14±1.28 mg/day in group A and 4.91±1.10 mg/day in group B. Four deaths (two in group A and two in group B) occurred within 6 months since transplantation; another patient of group A died after the first year because of myocardial infarction. Fifteen grafts were lost in group A and six in group B (P=0.043). In group A, only one graft was lost after the first year because of recurrent focal glomerular sclerosis. In group B, three failures occurred in the second year; two because of chronic rejection and one because of infection. The 24-month graft survival, including death as a cause of graft failure, was 87.4% in group A and 94.4% in group B (P=0.048). Acute rejection after the first year occurred in just one patient of group B. The cumulative probability of biopsy-proven rejection at 2 years was 15.0% in group A and 15.7% in group B. The mean levels of serum creatinine at 24 months were 1.45±0.5 mg/dL in group A and 1.52±0.7 mg/dL in group B (P=not significant [NS]). Mean glomerular filtration rate according to Nankivell et al. (3) was 65.8±19.7 mL/min in group A versus 61.8±22.0 mL/min in group B. The slopes of serum creatinine and glomerular filtration rate between 6 months and 2 years were practically flat (data not shown). At 24 months, systolic blood pressure was 135.6±16.1 mm Hg in group A and 135.8±18.8 mm Hg in group B; diastolic blood pressure was 81.2±9.8 mm Hg in group A versus 81.7±10.4 mm Hg in group B. Most patients were on antihypertensive medication. Mean hemoglobin levels were 13.1±1.6 g/dL in group A and 13.0±1.7 g/dL in group B. Plasma cholesterol levels were 228.0±41 mg/dL in group A and 235.1±54.5 mg/dL in group B (P=NS). Triglycerides levels were 193.3±84.9 mg/dL versus 224.4±120.6 mg/dL (P=NS). 3-hydroxy-3-methyl-glutaryl-Co (HMG-CoA) reductase inhibitors were administered in 83% of patients in both groups. Proteinuria more than 0.2 g/day occurred in 13 patients of group A (9.1%) and in 20 of group B (14.1%). The overall incidence of infections requiring hospitalization was similar in the two groups (10.5% in group A and 14.5% in group B). Diabetes was diagnosed in 7 (4.9%) patients in group A and in 13 patients (9.2%) in group B (P=NS). One patient (0.7%) in group A and three patients in group B (2.1%) developed nonmelanoma skin cancer. Twelve patients (four in group A and eight in group B) discontinued treatment because of adverse events after the first year (Table 1).TABLE 1: Adverse events leading to discontinuation of treatment between the first and the second yearFrom these results, it is possible to conclude that minimal doses of CsA in association with everolimus may offer excellent graft survival and stable renal function at 2 years. Claudio Ponticelli1 Maurizio Salvadori2 Maria Piera Scolari3 Franco Citterio4 Paolo Rigotti5 Antonella Veneziano6 Marta Bartezaghi6 on behalf of EVEREST Study 1Division of Nephrology Humanitas Scientific Institute Rozzano (Milano), Italy 2Division of Nephrology Careggi Hospital Firenze, Italy 3Renal Transplant Unit S. Orsola Malpighi University Hospital Bologna, Italy 4Department of Surgery Catholic University Hospital Roma, Italy 5Surgery Division Policlinic University Hospital Padova, Italy 6Medical Department Novartis Italy Origgio (Varese), Italy