S Fuchinoue

Improved Outcomes of Renal Transplantation from Cardiac Death Donors: A 30‐Year Single Center Experience

Outcomes of renal transplantation from donation after cardiac death (DCD) donors over 30 years were analyzed. Between 1975 and 2004, 256 renal transplantations from DCD donors were performed. The recipients were divided into four groups according to a time period as follows: 1975–1979 (Group 1; n = 18), 1980–1989 (Group 2; n = 81), 1990–1999 (Group 3; n = 84) and 2000–2004 (Group 4; n = 73). Of the 256 transplanted kidneys from DCD donors, 38 (15%) functioned immediately after transplantation. The incidence of delayed graft function (DGF) was 72%. Warm ischemic time and total ischemic time were 7.4 ± 9.4 min and 11.9 ± 5.6 h, respectively. The overall graft survival rates at 1, 5 and 10 years were 80%, 72% and 53%, respectively. Graft survival rates in each group have continually improved over time (5‐year graft survival; 23% vs. 64% vs. 74% vs. 91%, respectively). However, there was no significant difference in graft survival rates between the groups of patients who survived with a functioning graft for more than 1 year. A multivariate Cox regression analysis showed acute rejection and donor age to be independently associated with graft outcome. DCD donors are a valuable source of kidneys for transplantation with promising long‐term outcomes.

How Do Living Kidney Donors Develop End-Stage Renal Disease?

The clinical course and risk factors for developing end‐stage renal disease (ESRD) after heminephrectomy in living kidney donors have scarcely been investigated. We reviewed medical records and identified eight case donors who developed chronic kidney disease (CKD) stage 5 or ESRD, and subsequently investigated the association between postoperative clinical courses and changes in renal function. To conduct a case‐control study, we also selected a control group comprising 24 donors who had maintained stable renal function and were matched for age, sex and follow‐up time since donation. Except for one donor who developed ESRD caused by a traffic accident, none of the donors developed progressive renal dysfunction immediately after donation. Their renal functions remained stable for a long period of time, but started to decline after developing new comorbidities, especially risk factors known as progression factors (proteinuria or hypertension) or accelerating factors (cardiovascular [CV] event or infection) of CKD. As compared with the control donors, incidence of postoperative persistent proteinuria, acute CV event, severe infection and hospitalization due to accelerating factors of CKD were significantly higher in the case donors. These results suggest the importance of long‐term (more than 10 years) follow‐up of donors with special attention on the risk factors of CKD.

Thickening of the peritubular capillary basement membrane is a useful diagnostic marker of chronic rejection in renal allografts.

In kidney transplantation, the multilayering of the peritubular capillary basement membrane (MLPTC) in electron microscopy (EM) has been recognized as a feature of chronic rejection (CR). In this study, thickening of the peritubular capillary (PTC) basement membrane was evaluated by light microscopy (LM) to determine whether it corresponds to the MLPTC in EM and whether it can be used as a diagnostic marker of CR. Forty‐eight patients with late renal allograft were divided into chronic allograft nephropathy (CAN) with CR (Group 1, n = 23), CAN without CR (Group 2, n = 19) and CAN‐free (Group 3, n = 6). The thickening of the PTC basement membrane (ptcbm) was scored from grades 0 to 2 (ptcbm score), and the MLPTC thickness was measured in EM. Interobserver agreement on ptcbm scores was statistically significant (Kappa coefficient = 0.63). LM and EM lesions corresponded very well. The ptcbm score was highest in Group 1, and ptcbm2 corresponded closely with CR. Group 1 showed significantly thicker MLPTC than Groups 2 and 3. The results validated the usefulness of the ptcbm score and suggested that the thickening of the PTC basement membrane can be a novel diagnostic marker of CR.

Glomerular Expression of Plasmalemmal Vesicle-Associated Protein-1 in Patients with Transplant Glomerulopathy

Transplant glomerulopathy (TG) is a prominent feature of chronic rejection that is characterized by double contours of the glomerular capillaries (GC). In this report, we demonstrate that one of the histopathological features of TG is a phenotypic change of glomerular endothelial cells which is illustrated by increased caveolae formation. To verify the endothelial changes in this disease, we examined the expression of plasmalemmal vesicle‐associated protein‐1 (PV‐1), a glycoprotein associated with plasmalemmal vesicles (caveolae), in the glomeruli of TG patients using pathologische anatomie Leiden‐endothelium (PAL‐E) antibody. Twenty‐six cases of chronic allograft nephropathy (CAN) with TG were examined, compared with 16 cases of CAN without TG, type I MPGN (4 cases), and transplant glomerulitis (8 cases). Overall, 24 of 26 (92.3%), 4 of 16 (25%), 0 of 4, 0 of 8 cases were PAL‐E‐positive for GC, respectively. Further, the extent of glomerular PAL‐E expression was positively correlated with both the grade of TG (rs= 0.72, p = 0.0003) and proteinuria (g/day) (rs= 0.51, p = 0.02). A correlation was not observed between glomerular PAL‐E positivity and peritubular capillary C4d deposits (Yetes chi = 0.23, p = 0.89). In summary, the present study demonstrates expression of PV‐1 in the GC of TG which is correlated with the grade of TG and proteinuria.

Histological analysis of late renal allografts of antidonor antibody positive patients with C4d deposits in peritubular capillaries

Abstract:  The association of humoral immunity with late renal allograft dysfunction has recently been recognized, and many reports have revealed C4d deposits in peritubular capillaries (C4d in PTC), and the presence of serum antidonor HLA antibody in patients suffering from graft dysfunction, long time after transplantation. In this study, morphological changes in renal allograft biopsies more than 1 year after transplantation in 14 patients with C4d in PTC and serum antidonor antibody were investigated for the presence of chronic rejection (CR). In addition to the light microscope study, an electron microscope study was done to evaluate the multilayering of the peritubular capillary basement membrane (MLPTC). Histologically, only seven of 14 patients met the criteria of CR, and 71.4% (5/7) of CR patients had episodes of acute humoral rejection (AHR), coexisting with acute tubulointerstitial rejection. Peritubular capillaritis was observed in all patients, although it differed in severity. Transplant glomerulitis and interstitial inflammation were also observed in many patients: 71.4% (10/14) and 92.9% (13/14) respectively. MLPTC was observed in 12 patients (85.7%), but the severity of the MLPTC did not reflect the severity of peritubular capillaritis or any other histological features. The long‐term outcomes of the patients CR, especially those with episodes of AHR, were poor, and two of them lost their graft functions. On the other hand, patients without CR had relatively favourable outcomes. In conclusion, we confirmed the diverse morphological changes of late renal allografts, which cannot be categorized as chronic humoral rejection (CHR), and such patients who do not have typical morphological changes such as CHR, should be followed‐up on a long‐term basis in order to clarify the significance of C4d on PTC in late renal allografts.

Assessment of Viability of Pancreas Transplants From Non–Heart-Beating Cadaver

THE program of combined pancreas–kidney transplantation from non–heart-beating cadaver donors was introduced in 1990 at Tokyo Women’s Medical College. In case of pancreas transplantation, especially from non– heart-beating cadavers, it is extremely important to minimize warm ischemia and assess the viability of pancreas graft. In the present paper, the methods of assessment of the pancreatic graft viability were investigated.

NEO RED CELL AS AN ORGAN PRESERVATION SOLUTION

Neo red cell (NRC) was derived from outdated human red cells. The following experimental work has been done in order to investigate if NRC is valid for organ preservation. Hearts were obtained from male Lewis rat (250-350 g body weight). Heart transplantation was performed as Ono-Lindseys method after 1, 3, 6, 12 and 24 hours simple cold storage. Rats were divided into two groups. Group 1; original NRC as preservation solution, Group 2; modified NRC (NRC suspended with UW solution) as preservation solution. After 1, 3, and 6 hour cold ischemic storage, the transplanted hearts in both groups showed contraction immediately after declamping the aorta and the pulmonary artery. After 12 and 24 hour preservation, the transplanted hearts in group 2 showed contraction. Myocardial ATP levels after 6, 12, 24 hours cold storage compared with 0 hour were 62.3%, 28.3%, 32.8% in group 1 respectively. On the contrary, myocardial ATP levels were 87.2%, 57.6%, 52.2% in group 2 respectively. After 24 hour preservation, pathological change was not remarkable between the two groups. Results of the prolonged preservation time and the myocardial ATP changes suggest that there is a possibility for effective use of NRC not only as blood substitute but also organ preservation solution.

Modified Hemoglobin Solution as Possible Perfusate Relevant to Organ Transplantation

A modified hemoglobin solution (- conjugate solution, PHP solution) has very interesting characteristics such as oxygen-carrying property without corpuscular components. Experimental use of the PHP solution has shown promising possibilities as a perfusate relevant to organ transplantations. 1) Elongation of warm ischemic time in canine kidneys: Dogs survived even with the unilateral kidneys which had been exposed up to 4.5 hour warm ischemia and, thereafter, perfused with the PHP solution. 2) Elongation of perfusion preservation period of canine livers: Dogs survived with the transplanted livers which had been perfused for 48 hours with the PHP solution. 3) Successful perfusion of rat small intestine: Lewis rat intestines perfused and preserved for 12 hours with the PHP solution showed a higher survival rate compared with those with Collins or UW solution. 4) Removal of antibodies: By exchange transfusion with a total of 30-60 ml of the PHP solution, a Lewis rat hematocrit lowered to 5% while IgG went down to nil from 8970 mg/dl, IgA to 28 mg/dl from 118 mg/dl and IgM to 190 mg/dl from 897 mg/dl. This technique is expected to be applicable for removal of the naturally existing antibodies in xenotransplantation.

Successful Third Kidney Transplantation With Intensive Immunosuppression in a Highly Sensitized Recipient

HLA sensitization associated with previous kidney transplantation is a major drawback to retransplantation. Recently we successfully performed a third graft using intensive immunosuppression for a highly sensitized recipient. The patient was a 31-year-old man who had previously undergone a living donor graft from his father at our institute in 1999. His kidney graft function had deteriorated due to chronic allograft nephropathy, returning to hemodialysis therapy in 2005. He received a second graft from a deceased donor in another country on August 14, 2006. It rejected on postoperative day 3 possibly due to acute accelerated rejection. He was offered a third kidney from his brother. Panel-reactive antibody (PRA) tested before the third procedure revealed positive class I (88%) and class II (96%) PRAs. Mycophenolate mofetil (MMF) was started 3 weeks before the third transplantation, and preoperative plasmapheresis performed thrice. He underwent the living donor graft on March 9, 2007. Immunosuppression consisted of tacrolimus, MMF, methylprednisolone, and basiliximab. Immediately afterward there was a sudden decrease in allograft blood flow and urine output, implying hyperacute rejection. Following treatment with plasmapheresis and a single dose of rituximab (200 mg), the kidney allograft function recovered, although the PRA at 3 weeks was still positive. Six months posttransplantation, he is well with a creatinine of 0.9 mg/dL. Our protocol may reduce the risk for graft loss in a highly sensitized transplant recipient.

Long Term Liver Preservation Using Artificial Blood Substitutes

Twenty-four hour hypothermic perfusion preservation of the liver was aimed using an artificial blood substitutes. A canine liver was harvested and preserved using originally designed perfusates. In group 1, Perfluorotributylamine solution (Oxypherol solution) was used. In group 2, (Pyridoxylated hemoglobin)-(Polyoxyethylene) conjugate solution (Stabilized Hemoglobin, PHP-1). In group 3 and in group 4, modified Stabilized hemoglobin, PHP-3 and PHP-4 was used. After the preservation, each liver was transplanted orthotopically. Postoperative graft function was estimated the following parameter, such as bile excretion, consciousness level, activated clotting time, and survival rate. In group 1 and group 2, improvement of such factors were not fully observed. On the contrary, in group 3 and 4, complete recovery of the function was seen and in group 4, longer survival was obtained. PHP solution was considered suitable perfusate for liver preservation.