Impact of the Great Eastern Japan Earthquake on transplant renal function in Iwaki city, Fukushima.

Tokiwa-kai group is a urologic and dialysis institution complex located in Iwaki city, Fukushima, Japan, and has performed renal transplantation since 1997. Although water is mandatory for renal transplant recipients, the water supply did not work for approximately a month after the earthquake in Iwaki city. Moreover, after the Fukushima Daiichi nuclear accident struck Iwaki city, there was a critical shortage of food and medical supplies, including immunosuppressant drugs. Therefore, we investigated the impact of the Great Eastern Japan Earthquake on transplant renal function. We followed 30 patients who underwent renal transplantation before the Great Eastern Japan Earthquake. There were 19 males and 11 females with a mean age of 47 years. All recipients were not injured by the earthquake or the tsunami. Of the 30 recipients, 1 lost his renal graft at 12 months after the earthquake, and 1 has deterioration of graft function with a serum creatinine level of 5.5 mg/dL. Their creatinine levels before the earthquake were 2.79 mg/dL and 3.78 mg/dL, respectively. The other recipients have good graft function with a mean creatinine level of 1.5 mg/dL. All recipients did not experience any rejection episode after the earthquake. The shortage of water and food after the Great Eastern Japan Earthquake exacerbated the renal graft function, especially in the recipients with the lower graft function.

Analysis of renal transplant protocol biopsies in ABO-incompatible kidney transplantation.

Numerous studies have shown that protocol biopsies have predictive power. We retrospectively examined the histologic findings and C4d staining in 89 protocol biopsies from 48 ABO-incompatible (ABO-I) transplant recipients, and compared the results with those of 250 controls from 133 ABO-compatible (ABO-C) transplant recipients given equivalent maintenance immunosuppression. Others have shown that subclinical rejection (borderline and grade I) in ABO-C grafts decreased gradually after transplantation. In our study, however, subclinical rejection in the ABO-I grafts was detected in 10%, 14% and 28% at 1, 3 and 6-12 months, respectively. At 6-12 months, mild tubular atrophy was more common in the ABO-C grafts whereas the incidence of transplant glomerulopathy did not differ between the two groups (ABO-C: 7%; ABO-I: 15%; p = 0.57). In the ABO-I transplants, risk factors for transplant glomerulopathy in univariate analysis were positive panel reactivity (relative risk, 45.0; p < 0.01) and a prior history of antibody-mediated rejection (relative risk, 17.9; p = 0.01). Furthermore, C4d deposition in the peritubular capillaries was detected in 94%, with diffuse staining in 66%. This deposition, however, was not linked to antibody-mediated rejection. We conclude that, in the ABO-I kidney transplantation setting, detection of C4d alone in protocol biopsies might not have any diagnostic or therapeutic relevance.

Evaluation of immunosuppressive regimens in ABO-incompatible living kidney transplantation--single center analysis.

Several protocols allow the successful ABO incompatible living-related kidney transplantation (ABO-ILKT), yet no single method has emerged as the best. We have made several substantial changes to our ABO-ILKT protocol over the past decade and a half and have attempted to determine whether the changes in immunosuppressive agents have resulted in a better outcome. We used methylprednisolone (MP), cyclosporine (CsA), azathioprine (AZ), antilymphocyte globulin (ALG) and deoxyspergualine (DSG) in the 105 cases of ABO-ILKT (group 1) between 1989 and 1999, and MP, tacrolimus (FK506), mycophenolate mofetil (MMF) in the 117 cases of ABO-ILKT (group 2) between 2000 and 2004. We compared the patient and graft survival rates as well as the incidence rate of acute rejection in these two eras, when different regimens were used. There were significant differences in the 1- and 5-year graft survival rates between groups 1 and 2 (1-year: 78% in group 1 vs. 94% in group 2; 5-year: 73% in group 1 vs. 90% in group 2, p = 0.008). Also, a higher incidence rate of acute rejection was significantly observed in group 1 (50/105, 48%) than in group 2 (18/117, 15%) (p < 0.001). We conclude that the FK/MMF combination regimen provides excellent graft survival results in ABO-ILKT.

Possible involvement of urokinase-type plasminogen activator release from human peripheral blood lymphocytes in the pathophysiology of chronic allograft nephropathy.

BACKGROUND: Little is known of the fibrinolytic host immune mechanisms responsible for induction of chronic allograft nephropathy (CAN), defined as a loss in glomerular filtration rate (GFR) caused by tubular atrophy and interstitial fibrosis, often with fibrous intimal thickening in the small arteries. However, chronic rejection has been reported to be associated with decreased activity of the fibrinolytic system. In our previous study, [Deamino-Cys1, D-Arg8]-vasopressin (dDAVP) induced urokinase-type plasminogen activator (uPA) release from human peripheral T lymphocytes via arginine vasopressin (AVP) V2-receptor-mediated reaction enhanced by an AVP V1-receptor antagonist. Therefore, we examined the level of uPA released from peripheral T lymphocytes by AVP in transplant patients with CAN in comparison with control groups. PATIENTS AND METHODS: In this study, we evaluated in vitro uPA releasing activity of lymphocytes obtained from renal allograft patients with well-functioning grafts (n = 9), CAN (n = 5), or acute rejection episodes (n = 5) compared with lymphocytes from healthy volunteers with normal renal function (n = 12) or patients with renal insufficiency (n = 5). RESULTS: Lymphocytes prepared from patients with chronic allograft nephropathy showed a significantly lower increase in uPA release induced by the combination of the V1-receptor antagonist and dDAVP compared with those from the other groups. CONCLUSION: This finding suggested that a decrease in uPA release from human peripheral blood lymphocytes by AVP-related peptides may be potentially involved in the pathophysiology of CAN.

Analysis of cause of death with a functioning graft: a single-center experience.

INTRODUCTION: After the introduction of new immunosuppressants, such as tacrolimus and mycophenolate mofetil, we have achieved excellent results for kidney transplantation with a low acute rejection rate. Currently, nonimmunological factors are considered to be the main cause of graft loss for long-term transplant patients. In this study, we analyzed the cause of death with a functioning graft. PATIENTS AND METHODS: We performed 1375 cases of living kidney transplantation (LKT) and 219 cases of cadaveric kidney transplantation (CKT) between January 1983 and December 2002. Of these patients, 86 LKT patients and 19 CKT patients died with a functioning graft. RESULTS: The mean duration of graft function was 4.8 +/- 4.5 years. The incidence of the causes of death were: infection, 24%; stroke, 17%; cardiovascular disease, 16%; malignant disease, 15%; hepatic failure, 11%; gastric ulcer, 4%; and accident/suicide 2%. Five- and 10-year graft survivals for LKT were 80.2 and 62.0%, respectively. The corresponding values for patients (with the exception of the patients who died with a functioning graft) was 83.0% and 66.1%, respectively. The 5- and 10-year graft survival rates for cadaveric kidney transplants were 70.8% and 48.9%, respectively. The corresponding values for patients (with the exception of the patients who died with a functioning graft) were 75.3% and 52.6%, respectively. CONCLUSION: To prevent death with a functioning graft, management of vascular disorders such as stroke and cardiovascular disease, malignant disease, and infectious disease is crucial for kidney transplant patients.

Microscopic examination of the urine helps to confirm the recovery of acute tubular necrosis after cadaveric renal transplantation: a case report.

INTRODUCTION: Delayed graft function due to acute tubular necrosis (ATN) is frequently seen in kidney transplants from non-heart-beating donors. However, only a biopsy can be used to assess the severity of ATN. Therefore, we studied the validity of microscopic findings in tubular epithelial cells (TECs) from urine as a means to monitor ATN. MATERIALS AND METHODS: The first voided urine in the morning was examined for the appearance and nuclear cytoplasmic (N/C) ratio of the TECs, using a murine staining with URO-3 monoclonal antibody to detect proximal tubular cells (PTCs). CASE: A 58-year-old man underwent cadaveric kidney transplantation in January, 2003 using tacrolimus, mycophenolate mofetil, and prednisone following basiliximab induction therapy. His graft did not function immediately; needle biopsy was performed on day 17. The pathological findings showed severe ATN without evidence of acute rejection. A large quantity of TECs was seen in his urine between days 7 and 14. After day 28, TECs with a large N/C ratio and that were URO-3 antibody-positive were detected. Urine volume increased gradually and hemodialysis was not necessary after day 36. CONCLUSION: The presence of URO-3-positive TECs with large N/C ratios suggests the reconstruction of PTCs. Therefore, it may be useful to monitor TEC findings to assess the severity ATN after cadaveric kidney transplantation.

Impact of fluvastatin on hyperlipidemia after renal transplantation.

BACKGROUND: Renal transplant recipients are at increased risk of atherosclerotic vascular disease with hyperlipidemia. Many recipients have preexisting cardiovascular disease at the time of transplantation, and immunosuppressive therapy may aggravate existing risk factors or promote development of new risk factors, notably hyperlipidemia and hypertension. Fluvastatin is one of the statins, an HMG-CoA reductase inhibitor, which has been shown to be effective in lowering cholesterol levels. We treated hyperlipidemia after renal transplantation with Fluvastatin for more than 6 months. We attempted to clarify the efficacy of fluvastatin on hyperlipidemia in renal transplant recipients. MATERIALS: Forty-five renal transplant recipients with hyperlipidemia were enrolled in this study. The mean age was 44.2 years, with 23 men and 22 women. Thirty-seven transplantations were from a living related donors and eight from cadaveric donors. Thirty-three recipients were ABO-compatible, seven recipients had minor mismatches, and five recipients were ABO-incompatible. The dose of fluvastatin was 20 mg per day. Levels of total cholesterol (TC), triglyceride (TG), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), serum creatinine (s-Cr), ALT, ALP, uric acid (UA), hematocrit (Ht), CPK, and blood pressure were examined in all recipients before treatment as well as 1, 3, and 6 months after Fluvastatin administration. RESULTS: The mean levels of TC and TG were significantly reduced from 256, to 224 and 215 mg/dL, and from 188 to 170 and 147 mg/dL at 1 and 6 months after treatment, respectively. The mean levels of HDL-C were 72 mg/dL before treatment, 81 mg/dL at 1 month, and 80 mg/dL at 6 months after treatment. The mean levels of LDL-C were 153 mg/dL before treatment, 145 mg/dL at 1 month, and 145 mg/dL at 6 months after treatment. Fluvastatin significantly produced a reduction rate in TC of 16%, TG of 22%, and LDL-C of 5% after 6 months of treatment, respectively. The mean levels of HDL-C of were increased 10% after 6 months of treatment. The serum creatinine and CPK were not significantly different. There were no clinically significant differences in other factors. No significant adverse effects were observed. CONCLUSIONS: Fluvastatin seemed to be safe and highly effective to control TC, TG, LDL-C, and HDL-C in renal transplant recipients.

Impact of HLA-identity on results of ABO-incompatible living kidney transplantation.

INTRODUCTION: Due to the continuing shortage of cadaveric donors in Japan, ABO-incompatible living kidney transplantation is being performed. Our previous studies showed that the long-term graft survival in ABO-incompatible living kidney transplantation was comparable to that in ABO-compatible living kidney transplantation. However, the impact on HLA-identity on the results of ABO-incompatible living donor kidney transplantation had not been investigated previously. MATERIALS AND METHODS: One hundred twenty-seven recipients underwent ABO-incompatible living kidney transplantation between January 1989 and December 2000. Five were grafted from HLA-identical sibling donors group (I). The remaining 122 recipients received grafts from an HLA-nonidentical donor (group N). Both groups were similar in terms of recipient age, donor age, warm ischemic time, and total ischemic time. Three or four sessions of plasmapheresis were performed prior to transplantation. Cyclosporine or tacrolimus, methylprednisolone, and azathioprine or mycophenolate mofetil were used for immunosuppression. Splenectomy was done at the time of kidney transplantation in all patients. RESULTS: Graft loss was seen in one of the five HLA-identical recipients due to chronic rejection. Five- and 10-year graft survival rates were 80.0% I vs 72.0% N, and 80.0% I vs 54.2% N, respectively. The incidence of acute rejection in the HLA-identical recipients was lower than that in the HLA-nonidentical recipients (20% I vs 67.2% N). In conclusion, long term graft survival among ABO-incompatible kidney transplants from HLA-identical sibling donors was much better than that from HLA-nonidentical sibling donors.

Impact of positive PRA on the results of ABO-incompatible kidney transplantation.

INTRODUCTION: Due to the continuing shortage of cadaveric donors in Japan, ABO-incompatible living kidney transplantation (LKT) is being performed. It is well known that highly sensitized patients with positive panel reactive antibodies (PRA) often present with acute rejection. Therefore, we examined the impact of a positive PRA on the results of ABO-incompatible LKT. MATERIALS AND METHODS: One hundred seventy-seven recipients underwent ABO-incompatible LKT between January 1989 and March 2003. Of these patients, 37 who had been examined for PRA before transplantation were included in this study. There were 25 men and 12 women of mean age 37.3 years. Plasmapheresis was performed to remove anti-ABO antibodies before transplantation. During the induction phase, methylprednisolone, azathioprine, or mycophenolate mofetil and cyclosporine or tacrolimus were used for immunosuppression. Splenectomy was performed at the time of kidney transplantation in all patients. PRA was measured using FlowPRA by flow cytometer. RESULTS: Eight of the 37 patients had a positive PRA before transplantation (class I, 5; class II, 1; class I and class II, 2). The incidence of acute rejection was 37.9% in the patients with a negative PRA and 37.5% in patients with a positive PRA. One patient with a negative PRA and one patient with a positive PRA lost grafts due to acute rejection. CONCLUSIONS: Positive PRA may not increase the incidence of acute rejection in ABO-incompatible LKT because plasmapheresis and splenectomy are performed to eliminate anti-ABO antibody.

Excellent outcome of ABO-incompatible living kidney transplantation under pretransplantation immunosuppression with tacrolimus, mycophenolate mofetil, and steroid.

INTRODUCTION: ABO-incompatible living kidney transplantation (LKT) has been performed to widen the indications for kidney transplantation. Since 2001, using a 7-day period of pretransplantation immunosuppression with tacrolimus (FK) plus mycophenolate mofetil (MMF) plus methylprednisolone (MP), we have observed a marked reduction in acute humoral/vascular rejection without any serious complications. PATIENTS AND METHODS: Forty-five adult patients underwent ABO-incompatible LKT at our institute between January 2000 and September 2002. There were 20 men and 25 women of mean age 33 years. Plasmapheresis was performed to remove anti-AB antibodies prior to kidney transplantation. In 2000, 13 patients were treated with FK plus MMF plus MP without 7-day pretransplantation immunosuppression (group 1). Since January 2001, we have administered FK (0.1 mg/kg/d) plus MMF (1-2 g/d) plus MP (125 mg/d) concomitantly with plasmapheresis starting from 7 days before transplantation in 32 patients (group 2). Splenectomy was performed at the time of kidney transplantation in all patients. RESULTS: Patient survival rate was 100% in both treatment groups. Graft survival rate was 92% and 97% in groups 1 and 2, respectively. One patient in group 1 lost the graft due to severe pancreatitis and 1 patient in group 2, due to severe humoral rejection. The incidence of acute rejection was 56% and 19% in group 1 and group 2, respectively. No patient experienced any lethal infectious complication. CONCLUSION: Pretransplantation immunosuppression for 7 days using FK, MMF, and MP in ABO-incompatible LKT provides an excellent outcome without severe infectious complications.

Efficacy of IgM anti-blood type antibody monitoring by enzyme-linked immunosorbent assay after renal transplantation across the blood barrier: high-dose immunoglobulin administration blocks IgM rather than IgG anti-blood type antibodies.

We used an enzyme linked immunosorbent assay (ELISA) to investigate the presence of subtypes of anti-blood-type antibodies in patients with biopsy-proven humoral rejection after ABO-incompatible renal transplantation. High agglutinin IgG and IgM anti-blood type antibodies from 12 ABO-incompatible recipients with vascular rejection were separately assessed using an ELISA. Patients who exhibited excellent renal function despite high agglutinin titers of anti-blood-type antibodies(n = 8) were also examined. All 12 rejection patients exhibited highly elevated titers of IgG and IgM, while the eight stable patients exhibited only slightly elevated IgG titers, but not IgM. IgG and IgM titers did not change after plasmapheresis and steroid pulse therapy, whereas IVIg treatment significantly blocked both IgG and IgM, with IgM being blocked to a larger extent than IgG. Blocking of IgM seems to play an important role in improving ABO-incompatible grafts.

Time-dependent risk factors influencing the long-term outcome in living renal allografts: donor age is a crucial risk factor for long-term graft survival more than 5 years after transplantation.

BACKGROUND: Most investigations have revealed that the improvement in early graft survival has not resulted in a corresponding improvement in long-term graft survival. The risk factors for long-term graft survival should be clarified. METHODS: A single-center experience of 1100 consecutive renal transplant recipients who received kidneys from living donors from 1983 to 1998 was reviewed to clarify the time dependency of risk factors for long-term graft survival. We examined various possible risk factors, including HLA-AB and -DR mismatches, ABO-blood group incompatibility, graft weight, donor age and sex, recipient age and sex, and the presence or absence of acute rejection by using the time-dependent, nonproportional Cox's hazards model. RESULTS: Acute rejection episode, donor age, HLA-AB 4-antigen mismatches, ABO-incompatible transplantation, smaller kidney weight compared with the patient's body weight (Kw/Bw ratio less than 2.67), and transplantation from an unrelated living donor were risk factors for long-term graft outcome. Multivariate analysis for time-dependent risk factors showed that donor age of more than 60 years was the most important risk factor for long-term graft failure after 5 years posttransplantation (hazard ratio: 2.57). In contrast, acute rejection, ABO incompatibility, and nonrelated donors were significant risk factors for short-term graft failure within 5 years after kidney transplantation (hazard ratios: 2.68, 1.57, and 1.69, respectively). CONCLUSIONS: Donor age of more than 60 years was a crucial risk factor affecting long-term graft survival. In contrast, acute rejection, ABO incompatibility, and nonrelated donors were significant risk factors for short-term graft failure.

A case of rapid progressive glomerulonephritis with IgA deposits after renal transplantation.

A 46-yr-old Japanese male who underwent a second cadaveric kidney transplantation on 31 October 1996 after suffering Type II diabetic mellitus for 25 yr was admitted to our institute on 23 January 1999, because of colicky abdominal pain and abdominal discomfort. Elevated levels of serum creatinine, severe proteinuria and microscopic haematuria were observed. The allograft biopsy specimen disclosed crescentic glomerulonephritis. Immunofluorescence showed granular deposits of mainly IgA and C3 along glomerular capillary walls and mesangial areas. Electron microscopy showed extensive subepithelial and mesangial electron dense deposits. Rapid and irreversible worsening of graft function led to resumption of haemodialysis on 31 May 1999. We speculated that this case was an atypical form of de novo Henoch-Schönlein purpura nephritis (HSPN) in transplanted kidney because of the histopathological findings of the allograft biopsy and clinical symptoms.

Removal of anti-A/B antibodies with plasmapheresis in ABO-incompatible kidney transplantation.

Because of a shortage of cadaver donors in Japan, ABO-incompatible living kidney transplantation has been carried out. Sixty-seven ABO-incompatible living kidney transplantations (LKT) were performed between January 1989 and December 1995 at our institution. In our previous report on the long-term results of ABO-incompatible LKT, graft survival of ABO-incompatible LKT up to 3 years was significantly lower than that of ABO-compatible LKT, but no significant difference was seen from 4 to 8 years. We removed anti-A/B antibodies by immunoadsorption and/or double filtration plasmapheresis before kidney transplantation. There was a significant difference between the anti-A/B antibody titers before and after plasmapheresis. The anti-A/B antibody titers also were well suppressed over the long term after transplantation.