Excellent outcomes of ABO-incompatible kidney transplantation: a single-center experience

Introduction

Due to the severe shortage of deceased donors in Japan, ABO-incompatible living donor kidney transplantation has been performed since the late 1980s. Excellent long-term outcomes have been achieved; the rates of graft survival among these patients are currently similar to those of recipients of ABO-compatible grafts. Our single-center experience describing the immunosuppressive protocols, complications, and grafts survivals is documented in this study.

Patients and Methods

Among 123 patients with end-stage renal disease who underwent living donor kidney transplantation between January 1999 and December 2010, 25 cases were ABO-incompatible grafts. All of these patients were followed until August 2011. Analyzing these patients, we focused on their immunosuppressive protocols, complications, and graft survivals.

Results

Patient and graft survival rates were 100%. One patient experienced antibody-mediated rejection and an intractable acute cellular rejection episode, 1 patient an antibody-mediated rejection, and 6 patients had acute cellular rejection episodes. However, there were no severe complications.

Conclusion

Although ABO-incompatible kidney transplantation is a high-risk procedure, a short-term graft survival rate of 100% may be expected due to recent significant improvements in desensitization and recipient management.     

Decrease of blood type antigenicity over the long-term after ABO-incompatible kidney transplantation

Background

Few studies have investigated the changes in the antigenicities of the transplanted organs after transplantation.

Methods

We examined, by immunohistochemical assay, the changes in expression of the blood-type antigens on the transplanted kidneys over the long-term after ABO-incompatible kidney transplantation with A- or B-antigen incompatibility (blood type A to B and B to A). The subjects were six patients, including one case with graft loss, who had received ABO-incompatible kidney allografts more than ten years previously. As normal controls, four cases of ABO-compatible transplantation during the same period, including two recipient/donor pairs each with blood group A1 and blood group B were enrolled.

Results

Expression of the blood-type A or B antigens decreased gradually to 91.8% during the first three months after transplantation, 85.8% during the first five years, 64.1% during the first ten years, and 57.6% over ten years after transplantation on average in ABO-incompatible transplant recipients. In one patient with graft loss due to severe antibody-mediated rejection, the donor's type B blood-type antigens on the transplanted graft had changed but partially to the recipient's blood-type A antigen by 2582 days after the transplantation, suggestive of the occurrence of blood-type chimerism on the endothelium. In ABO-compatible transplant recipients, such changes in expression were not observed. The average percentage of blood-type antigen-positive vessels at more than ten years after the renal transplantation was 99.8%.

Conclusions

Decrease in the expression of the donor's blood-type antigen on the endothelium of the graft has been considered as one of the mechanisms underlying the accommodation occurring over the long-term after ABO-incompatible kidney transplantation. On the other hand, establishment of antigenic chimerism on the graft endothelium could be one of the hallmarks of the immunological reaction associated with antibody-mediated rejection.     

ABO-Incompatible Kidney Transplantation: First Cases in Turkey

Introduction

ABO compatibility has been believed to be necessary in kidney transplantation (Ktx) to prevent acute antibody-mediated rejection. However, developments in immunosuppression and immunoadsorption techniques have overcome acute antibody-mediated rejection caused by ABO incompatibility. Herein, we have presented the first ABO-incompatible Ktx cases in Turkey. All recipients did not have an ABO-compatible donor but presented significant dialysis inadequacy due to vascular access problems.

Method

Five dialysis patients with blood groups O or B underwent kidney transplantation from living related donors of blood group type A1 or AB between march 23, 2007 and August 16, 2007. All patients received Rituximab (375 mg/m²) at 3-4 weeks before the Ktx. Additionally, we started tacrolimus (0.15 mg/kg), mycophenolate mofetil (2 × 1 g), and simvastatin (1 × 20 mg) 1 week before the operation. Immunoadsorption therapy employing a specific filter (Glycosorbs) to remove anti-A or anti-B antibodies was continued until the titers were <1/4. After the Ktx, we again performed immunoadsorption if the anti-A or the anti-B antibody titer was >1/8 during the first postoperative week and >1/16 at the second postoperative week. We used 2 standard hemodialysis machines with a connection line to perform immunoabsorption and dialysis during the same session.

Results

Acute humoral and cellular rejection was not detected. During the follow-up 1 patient was lost due to a cardiovascular complication. Mean creatinine level was 1.1 ± 0.3 mg/dL. These first ABO-incompatible transplantation cases in Turkey suggest that this source may represent an effective approach to overcome the organ shortage.     

Fat extravasation due to unreamed and experimentally reamed intramedullary nailing of the sheep femur

Aim

To compare systemic fat extravasation in unreamed and experimentally reamed nailing.

Methods

An osteotomy was created in the proximal third of the femoral shaft in 16 sheep, and intramedullary pressure increase and fat extravasation were monitored for the two nailing techniques.

Results

The highest intramedullary pressures, median 2700 mmHg, and highest percentages of fat extravasation, peaking at almost 90% of fat, were found for the unreamed nailing technique. The values for the reamed group were significantly lower.

Conclusions

The extravasation of intramedullary fat can be attributed to the great increase in intramedullary pressure that occurs during unreamed nailing. Correctly performed intramedullary reaming with the new reaming system produces lower pressures and much less systemic fat extravasation, reducing the risk for fat embolism.     

Impact of Intraportal Donor-Specific Leukocyte Transfusion for Adult ABO-Incompatible Liver Transplantation

Introduction

We have reported that repeated donor-specific leukocyte transfusions (DSLT) via the portal vein allow rapid reduction of immunosuppressants and decrease the occurrence of acute cellular rejection. Herein, we examined the immunological benefits of DSLT in adult ABO-incompatible living donor liver transplantation (LDLT).

Materials and Methods

Ten adult patients (MELD score, 19.4 ± 7.3; range, 12-29) underwent LDLT from ABO-incompatible donors from August 2003 to November 2007. The antirejection therapy included multiple perioperative plasmaphereses, splenectomy, and quadruple immunosuppression. In addition to these conventional approaches, we performed 4 intraportal administrations of DSLT after transplantation.

Results

There was no humoral rejection in any patient. Two patients experienced mild cellular rejection requiring steroid pulse therapy. Both donor-specific immunoglobulin (Ig)M and IgG A/B antibodies in all patients decreased following transplantation by 16 fold. By flow cytometry, donor type of CD56+NK T cells existed in the liver graft showing macrochimerism at 1 month after liver transplantation. Furthermore, interleukin (IL)-10 production of Th2 type cytokines was up-regulated after transplantation. Three patients died of sepsis and infection. The 5-year survival rate was 70% by the Kaplan-Meier method.

Conclusion

Adult ABO-incompatible liver transplantation can be performed with acceptable patient and graft survival rates with a low risk of antibody-mediated rejection using intraportal administration of DSLT. Donor type CD56+NK T cells may induce tolerance by a veto or an anti-idiotype network mechanism.     

Kidney transplantation of living unrelated donor-recipient combinations

Introduction

According to the Japanese renal transplant registry in 2009, there were 1123 living kidney transplantations (LKT), including 35% from spouses (husband/wife). Up to the present in Japan, biologically living unrelated donors (LURD) are most frequently spouses. This study summarized our experience with LURD, especially spousal, kidney transplantation.

Patients and methods

We performed 112 cases of LKT between April 2003 and March 2011, including 44 (39%) from spouses and two from other LURD. The other 66 cases received kidneys from living related donors (LRD). We divided the patients into two groups: 44 patients (group 1) received kidneys from spouses (LURD) and 66 (group 2) from LRD. During the induction phase, tacrolimus or cyclosporine, mycophenolate mofetil, and methylprednisolone were prescribed for immunosuppression. Basiliximab was administered on postoperative days 0 and 4. In ABO-incompatible LKT, plasmapheresis was performed to remove anti-AB antibodies prior to LKT; splenectomy or rituximab administration, at the time of or before LKT.

Results

Among group 1, one patient died with a functioning graft and one lost her graft. Among group 2, one patient died with a functioning graft and one lost his graft. The incidences of an acute rejection episode were 31.8% and 24.2% in groups 1 and 2, respectively. There were three cases of antibody-mediated rejection in group 1. No patient experienced a lethal infectious complication.

Conclusions

Our results demonstrated that spousal LKT (LURD) was equivalent to LKT from LRD. In response to the shortage of deceased donors, LKT between married couples and from ABO-incompatible donors will spread in Japan.     

Flow Cytometric Detection of Anti-AB Antibody Titers in Blood Group O Recipients of Blood Group A2 Donor Kidneys

Aim

ABO-incompatible kidney transplantation has been accepted for end-stage renal failure patients who have no ready opportunity for a deceased or living donor. Antibody titration for ABO-incompatible renal transplantation is not only difficult but also lacks conformity among laboratories. Herein we analyzed 20 living related renal transplant couples to detect recipient anti-A2 antibody using flow cytometric analysis.

Materials and methods

Patients were admitted to our center for renal transplantation between January 1999 and December 2010. All but four of them had undergone a previous renal transplantation from an ABO-compatible donor but experienced graft failure. All donor blood groups were subtyped by our blood bank using a lectin-based dilution assay. To detect recipient anti-A2 antibody titers we used a tube hemagglutination method. A/B antibody titer analysis by flow cytometry incubated serially diluted serum samples with donor erythrocytes. Each analysis was repeated three times over a 2-week period using an older and the last sera simultaneously.

Results

The 13 male and 7 female patients showed our overall mean age of 32 ± 12 years. All patients had panel-reactive antibody levels below 15%. The level of flow cytometric antibody titers did not vary upon repeated analysis (P = .01). When compared with the tube method there was a discrepancy of the level at which the antibody titer became negative.

Discussion

Flow cytometric antibody titration is a practical and rapid technique to determine the amount of anti-A2 antibody in renal recipients.     

Intravenous landiolol, a novel β(1)-adrenergic blocker, reduces the minimum alveolar concentration of sevoflurane in women

Study Objective

To investigate the effect of intravenous (IV) landiolol, a novel β₁-adrenergic blocker, on the minimum alveolar concentration (MAC) of sevoflurane in adult women.

Design

Prospective, randomized study.

Setting

University hospital.

Patients

42 ASA physical status 1 and 2 women, aged 24-57 years, who were scheduled to undergo elective abdominal surgery.

Interventions

Anesthesia was induced in all patients by vital capacity rapid inhalation induction of sevoflurane. In the landiolol group, administration of landiolol began when patients took a vital-capacity breath: 0.125 mg/kg/min for one minute and then 0.04 mg/kg/min. Normal saline was administered in the control group.

Measurements

MAC was determined by a technique adapted from the conventional up-down method.

Main Results

The MAC of sevoflurane was 2.2% ± 0.2% in the control group and 1.7% ± 0.2% in the landiolol group, a statistically significant difference (P = 0.0005).

Conclusions

IV landiolol reduces the MAC of sevoflurane in women by approximately 20%.     

Inadequate Mycophenolic Acid Exposure and Acute Rejection in Kidney Transplantation

Introduction

The clinical utility of predose levels of mycophenolic acid (MPA) monitoring among patients treated with mycophenolate mofetil (MMF) has been questioned. The aim of this study was to evaluate the impact of adequate MPA levels in the incidence of acute rejection episodes among a cohort of kidney transplant recipients.

Material and Methods

In this retrospective study of 314 consecutive cases treated with tacrolimus, MMF, and steroids, evaluated 12-hour trough MPA samples during the first week as well as at 1, 3, 6, and 12 months as median values.

Results

During the first week, the median values of MPA were 1.6 μg/mL (p25-75 0.7-2.7 μg/mL) on mean doses of 1.84 ± 0.38 g/d. The incidence of acute rejection was 28%. The mean MPA levels during the first week were significantly lower among patients who developed rejection than in nonrejectors (1.5 ± 0.1 vs 2.1 ± 0.1 μg/mL; P < .001). There were no significant differences in trough tacrolimus levels between rejectors and nonrejectors (11.2 ± 0.4 vs 11.6 ± 1.2 μg/mL; P < .78). Logistic regression analysis showed that one of the predictive factors of acute rejection was a 12-hour trough MPA <1.6 μg/mL (relative risk [RR] 2.6; CI [confidence interval] 95% 1.6-4.3; P < .001).

Conclusions

Adequate MPA exposure is important to prevent acute rejection. Taking into account that the routine measurement of the area under the curve of MPA is impractical, at least the follow-up of trough MPA levels may help in the management of renal transplant recipients.     

Use of simulect can reduce the incidence of acute rejection and demonstrates with superior 3-year patient and graft survival rates in renal transplantation

Background

Acute rejection is a major cause of graft loss in renal transplantation. Because the highest risk for acute rejection is in the first month posttransplantation, improved prophylaxis could be most beneficial in this period. Simulect administration provides 30 to 45 days of immunoprophylaxis against acute rejection during the critical period after transplantation.

Objectives

We sought to assess the incidence of acute rejection episodes and the safety and tolerability of Simulect plus Neoral immunosuppression. Patient and graft survival rates up to 3 years posttransplantation were evaluated.

Method

Forty-one transplant recipients received Simulect by intravenous infusion of an initial 20-mg dose on the day of renal transplantation and a second 20-mg dose on day 4 posttransplant. All renal recipients received immunosuppression with Neoral and steroid.

Results

There were eight cases (19.5%) of acute rejection within 1 year. The rejection episodes were easily reversed with steroid pulse therapy in seven patients except for graft loss. The 1-, 2-, and 3-year graft survival rates were 95%, 93%, and 88%, respectively. Overall, the 3-year patient survival rate was 100%.

Conclusions

Simulect in combination with Neoral and steroid-reduced the incidence of acute rejection without an increase in adverse events. The low incidence and severity of acute rejection may have led to the superior 3-year patient and graft survival rates in renal transplantation.     

Surgery improves quality of life in patients with “mild” hyperparathyroidism

Background

Surgical treatment of patients with “classic” hyperparathyroidism improves quality of life, but these benefits to patients with “mild” disease remain unclear.

Methods

The SF-36 Health Survey was administered to 174 patients 1 week before, 1 week after, and 1 year after undergoing parathyroidectomy.

Results

One hundred fifty-one patients completed at least 2 surveys. There were 18 and 133 cases of “mild” and “classic” hyperparathyroidism, respectively. Preoperatively, the groups did not differ significantly in the 10 scales. One year after surgery, patients with “classic” and “mild” disease improved significantly in 9/10 and 10/10 scales, respectively (P < 0.05). Those with “mild” disease had a statistically larger improvement than those with “classic” disease in 4 scales.

Conclusions

Quality of life significantly improved in surgically treated patients with both “mild” and “classic” hyperparathyroidism, supporting surgical treatment of “mild” hyperparathyroidism. Moreover, quality of life may improve more in patients with “mild” rather than “classic” disease.     

Radiofrequency energy delivery to the anal canal: is it a promising new approach to the treatment of fecal incontinence?

Background

The present study was conducted to assess the efficacy and safety of the delivery of radiofrequency energy to the anal canal (the SECCA procedure).

Methods

Eight patients with fecal incontinence underwent the SECCA procedure. The Fecal Incontinence Severity Index (FISI) score and the Fecal Incontinence-related Quality of Life (FIQL) scale were completed at baseline and after the procedure. Anorectal manometry and endoanal ultrasound also were conducted.

Results

Seven of the 8 patients were women, and the median age of the patients was 59 years (range, 28-73 y). The mean FISI score and all of the parameters in the FIQL scale with the exception of the embarrassment scale measured at 6 months after the procedure was not improved significantly. We observed no changes in the anal manometry and endoanal ultrasound parameters. Complications associated with the procedure developed in 7 of the 8 patients, including anal bleeding, anal pain, and anal mucosal discharge.

Conclusions

The FISI score and FIQL scale were not improved significantly after the SECCA procedure, and considerable complications were associated with the procedure.     

When is it reasonable to split pediatric en bloc kidneys for transplantation into two adults?

Background

Traditionally, kidneys from donors ≥60 years old and pediatric kidneys are considered marginal organs for transplantation. Pediatric donor kidneys are underutilized for transplantation into adult recipients due to concern for poor outcomes.

Methods

Using data from the Organ Procurement and Transplant Network, we analyzed patterns of pediatric kidney use (single vs en bloc) in the United States from 1987 to 2007. Using the Cox proportional hazards model, graft outcomes of pediatric donor kidneys transplanted as single vs en bloc grafts from different donor weight groups were compared with renal transplantation from donors ≥60 years old in an attempt to define a pediatric donor weight at which kidneys can be justifiably split to expand the donor pool.

Results

Compared with older donor kidneys, graft failure risk of pediatric single kidneys was consistently lower when the donor weight exceeded 10 kg. On the other hand, graft survival benefit for pediatric en bloc kidneys was evident starting at donor weight ≤10 kg in comparison to older donor kidneys. Pediatric en bloc kidneys performed consistently better than pediatric single kidneys for all donor weight groups.

Conclusions

Splitting of pediatric donor en bloc kidneys for transplantation into 2 adults when the donor weight exceeds 10 kg was associated with acceptable graft outcomes. This practice, along with increased use of small pediatric donor kidneys, may help to alleviate the waiting list burden in renal transplantation.     

Kidney Transplantation in HIV-Positive Patients: Report of Our First 7 Cases

Introduction

Infection with human immunodeficiency virus (HIV) is associated with end-stage renal disease (ESRD). Although many teams initially were reluctant to offer kidney transplantation as a therapeutic option in HIV-positive patients with ESRD, new drug regimens introduced in the late 1990s have dramatically improved the life expectancy in these patients.

Objective

To report the results of the first 7 kidney transplantation procedures in HIV-positive patients at our institution.

Patients and Methods

Patients were selected to minimize the risks of HIV disease progression, opportunistic infections, and tumors. Protease-inhibitor therapies were suspended because of possible interaction with immunosuppression drugs. The induction regimen did not include lymphocyte-depleting drugs. After undergoing transplantation, patients were monitored by the transplantation and infectious disease teams.

Results

To date, all patients are alive with functioning grafts. We did not observe any episodes of acute rejection, and there were few adverse events. Drug tolerance was good for both immunosuppression and antiretroviral therapies.

Conclusion

Kidney transplantation in HIV-positive patients with ESRD is warranted. Provided that patients are carefully selected, good results can be achieved with few adverse events, episodes of acute rejection, and drug interactions. Posttransplantation, these patients must be closely monitored by both the transplantation and infectious diseases teams to ensure optimal management.     

Serum levels of interleukin-9 during acute rejection in liver transplantation

Introduction

Interleukin-9 (IL-9) has been cast as a player in autoimmunity, but its role in liver transplantation remains to be clarified. The aim of our study was to investigate the time course of IL-9 serum levels during hepatic allograft rejection.

Methods

IL-9 serum levels were determined in 34 healthy subjects and 50 hepatic transplant recipients. The patients were divided into two groups: group I was composed of 15 patients with acute rejection episodes, and group II, 35 patients free of this problem. Samples were collected on days 1 and 7 after liver transplantation and on the day of liver biopsy.

Results

The concentrations of IL-9 were similar in the rejection and nonrejection groups over the entire postoperative period. The whole transplant group, including those with stable graft function, showed higher IL-9 serum levels than the controls at all times after liver transplantation.

Conclusions

These preliminary results suggest a lack of participation of IL-9 in human liver allograft rejection.     

Early Sirolimus Therapy in Renal Transplant Recipients at High Risk: Is It Justified?

Background

We studied early sirolimus (SRL) therapy in renal transplant recipients at high risk after administration of antithymocyte globulin or interleukin-2 receptor blockade induction.

Patients and Methods

In 45 patients, SRL therapy was started within 1 month after transplantation. The primary indications for conversion of treatment from calcineurin inhibitors (CNIs)-mycophenolate mofetil (MMF)-steroid to SRL-MMF-steroid were biopsy-proved rejection (after treatment), CNI toxicity, CNI elimination, and acute tubular necrosis. Pediatric, geriatric, and other patients with medical comorbidities were not excluded.

Results

Post-SRL rejection episodes were reported in 22.2% of recipients including 15.6% who were resistant to steroid therapy. Mean (SD) follow-up after SRL therapy was 59.9 (8.1) months. Proteinuria greater than 2 g/d (P = .001), leukopenia (P < .001), hyperlipidemia (P < .001), and transaminases values (P = .02) increased significantly after SRL therapy. Graft survival was 88.8%, and patient survival was 93.3%. There was significant improvement in serum creatinine concentration and estimated creatinine clearance by the end of the study (P < .001). A high incidence of adverse effects and infections was noted post-SRL therapy, and the drug was discontinued in 31% of patients because of multiple adverse effects. At multivariate analysis, age, hypertension, nutritional status, bone marrow suppression, hyperlipidemia, and graft dysfunction were identified as risk factors for worse graft and patient outcome.

Conclusion

Early treatment with combined SRL-MMF-steroid may be effective as a CNI-free immunosuppression regimen in patients at high risk; however, there is a high rate of adverse effects during long-term follow-up.     

C4D Immunostaining in Surveillance Endomyocardial Biopsies From Well-Functioning Heart Allografts

Objective

The meaning of biopsy C4d detection in heart allografts without dysfunction or morphologic changes suggesting antibody-mediated rejection (AMR) is not clear. The aim of this study was to search for an association between C4d detection in allograft biopsies of well-functioning hearts without changes suggestive of AMR, and clinical outcomes.

Methods

Endomyocardial protocol biopsies from 44 heart transplant patients with well-functioning grafts and without changes suggesting AMR were performed at 1 month and 1 year after transplantation and analyze the presence of C4d deposition using immunohistochemistry. Two-year follow-up was based on clinical parameters and echocardiographic information. Heart graft function was categorized as good vs. poor. The presence of C4d, using diverse schemes to graduate the extension of the deposition, was correlated with clinical graft outcomes.

Results

C4d deposition was observed in the capillary walls of 33 biopsies (37.5%; n = 25 patients; 56.8%). No biopsy had diffuse (>50%) immunostaining. Six patients presented with multifocal capillary C4d immunostaining in at least 1 biopsy. Capillary positivity for C4d (if focal or multifocal) showed no statistical association with cellular rejection or graft function. Perimyocytic C4d detection was neither associated with rejection nor graft outcome.

Conclusion

Our work failed to demonstrate an association between C4d detection in protocol biopsies of heart grafts and clinical outcomes. The clinical utility of C4d staining in solid organ transplantation may vary by organ. Our results suggest that C4d did not have clinical utility in surveillance biopsies of well-functioning heart grafts without morphological changes suggesting AMR.     

Psychiatric and psychosocial predictors of medical outcome after liver transplantation: a prospective, single-center study

Objective

Recognizing the potential impact of psychiatric and psychosocial factors on liver transplant patient outcomes is essential to apply special follow-up for more vulnerable patients. The aim of this article was to investigate the psychiatric and psychosocial factors predicted medical outcomes of liver transplanted patients.

Methods

We studied 150 consecutive transplant candidates, attending our outpatient transplantation clinic, including 84 who had been grafted 11 of whom died and 3 retransplanted.

Results

We observed that active coping was an important predictor of length of stay after liver transplantation. Neuroticism and social support were important predictors of mortality after liver transplantation.

Conclusion

It may be useful to identify patients with low scores for active coping and for social support and high scores for neuroticism to design special modes of follow-up to improve their medical outcomes.