T. Ito

Effect of stimulus intensity and voluntary contraction on corticospinal potentials following transcranial magnetic stimulation

Following magnetic transcranial stimulation, motor-evoked potentials (MEPs) from the abductor digiti minimi muscle, and evoked spinal cord potentials (ESCPs) from the cervical epidural space were recorded simultaneously in 9 subjects in the awake and anesthetized condition. In the awake condition, during voluntary contraction, one (n = 5) or two (n = 4) components of the ESCPs were elicited at the threshold stimulus intensity of the MEPs. As the stimulus intensity increased, an early response (n = 7) and multiple late components were recorded. The first component at high stimulus output (average 80%) preceded the small potentials elicited at threshold stimulus intensity. The latency of each component of the ESCPs during voluntary contraction was the same as that during the resting condition. In addition, the enhancement of amplitude of the ESCPs during voluntary contraction was not significant compared with that recorded at rest. During general anesthesia with volatile anesthetics, the first component of the ESCPs could be elicited at high stimulus intensity, but later components were markedly attenuated. In paired transcranial magnetic stimulation, the amplitude of this first potential following the test stimulus completely recovered within the 2 ms interstimulus interval. From these results, we hypothesized that the first component was generated non-synaptically (D-wave), but later components were generated transsynaptically (I-waves). Compound muscle action potentials (CMAPs) and F-waves also were recorded following supramaximal ulnar nerve stimulation at the wrist. Peripheral conduction time, which included synaptic delay in spinal motor neurons, was measured as follows (latency of CMAPs+ latency of F-wave + 1)/2 (ms). The central motor conduction time (CMCT) was measured by subtracting the peripheral conduction time from the onset latency of the MEP at high stimulus intensity in the awake state. During voluntary contraction, the calculated CMCT (4.9 +/- 1.0 ms) was the same as the onset latency of the second component of the ESCPs (I-wave, 4.3 +/- 0.2 ms) recorded from the C6-C6/7 epidural space. These results suggest that transcranial magnetic stimulation generates I-waves preferentially when the stimulus intensity was set at just the threshold level of the MEPs during voluntary contraction in the awake condition. At high stimulus intensity, transcranial magnetic stimulation can elicit both D- and I-waves, but most spinal cells require I-wave activation to fire. Facilitatory effects of voluntary contraction on the muscle response following transcranial magnetic stimulation mainly originates at a spinal level.

Evaluation of renal allograft fibrosis by transient elastography (Fibro Scan).

BACKGROUNDnChronic allograft injury (CAI) is one of the most important factors for graft failure after renal transplantation. Protocol biopsy is the most valuable tool for revealing subclinical renal allograft failure. Transient elastography (TE) is a noninvasive technique that has shown utility for the assessment of hepatic and renal fibrosis. This study sought to evaluate whether TE was a viable and effective method for the assessment of renal allograft failure.nnnPATIENTS AND METHODSnThirty-five patients underwent TE by Fibro Scan (Echosense, Paris, France). Biopsies were performed in 27 patients, allowing classification according to Banff chronic changes in the interstitium grade 0, grade 1 or grade 2.nnnRESULTSnMeasurement of parenchymal stiffness was successful in 31 of 35 patients (91%). Stiffness was significantly correlated with interstitial fibrosis (P < .05) and inversely related with estimated glomerular filtration rate (eGFR; P < .05). Stiffness values of patients with eGFR > 50 mL/min were lower than those of patients with eGFR < 50 mL/min (P < .05). Patients classed as CAI Banff grade 0 had significantly less parenchymal stiffness than patients with Banff grade 1 or grade 2 CAI (P < .05). Parenchymal stiffness measured by TE reflected interstitial fibrosis in renal allograft.nnnCONCLUSIONnAssessment of parenchymal renal allograft stiffness by TE was effective for identifying patients with CAI who may subsequently benefit from biopsy and modification of the immunosuppressive regimen. Assessment of parenchymal renal allograft stiffness can be effective for identifying patients with CAI. TE has the potential to reduce the number of renal allograft biopsies required for accurate assessment of CAI.

Advantages and Disadvantages of Pre-emptive Kidney Transplantation: Results From a Single Transplantation Center

BACKGROUNDnThere is a growing tendency to perform pre-emptive kidney transplantation (PKT). However, less research has been performed on outcomes of PKT and kidney transplantation (KT) after long-term dialysis (LD).nnnMETHODSnTo elucidate advantages of PKT to KTLD, 96 patients who underwent living-donor KT at our university from 2000 to 2011 were enrolled for this study: 64 patients in the PKT0 (0 months dialysis) group; 14 patients in the PKT-3 group (less than 3 months dialysis); 18 patients in the LD (dialysis > 120 months) group. All recipients were assessed for patients survival, graft survival, urinary tract infection, laboratory data, episodes of acute rejection, cytomegalovirus-related diseases, and other significant infectious diseases which required hospitalization.nnnRESULTSnAlthough there were no significant differences in 5-year graft survival (93.8% in PKT0, 85.7% in PKT-3, and 83.7% in control), 5-year patient survival is better in the PKT0 group (96.9%) and the PKT-3 group (92.9%) compared to 88.9% in the control group. Urinary tract infection is clearly correlated with the LD group (44.4% in the LD group vs 19.2% in the PKT group) primarily due to atrophic bladder and subsequent vesicoureteral reflux. Slightly higher rates of acute rejection were found in the PKT groups (30.8% vs 26.3%).nnnCONCLUSIONnThis study revealed that there are both advantages and disadvantages of PKT. It is clear, therefore, that PKT can be recommended for end-stage renal disease patients provided enough attention is paid to the onset of acute rejection.

Elderly Living Donor Liver Transplant Recipients Over 60 Years Old at a Japanese Single Center

BACKGROUNDnAmong living donor liver transplant (LDLT) recipients, the number of elderly individuals has been increasing because of longer survival due to the improvement of treatment for hepatic diseases such as hepatitis C (HCV). Here we report the outcomes of living donor recipients over the age of 60 years.nnnMATERIALS AND METHODSnIn 76 adult LDLT patients at our institution before September 2015, there were 21 recipients over 60 years old. We divided all of the recipients into 2xa0groups (elderly recipient group >60 years of age [nxa0= 21], and a nonelderly recipient groupxa0<60 years [nxa0= 55]), and we investigated outcomes in each group.nnnRESULTSnThe graft survival rates in the elderly group were 89.9% at 1 year, 89.9% at 3 years, 83.0% at 5 years, and 83.0% at 10 years. The graft survival rates in the nonelderly group was 91.1% at 1 year, 85.2% at 3 years, 82.8% at 5 years, and 82.9% at 10 year. There was no significant difference between the 2 age groups. In the elderly group, 3 patients died (2 patients had HCV recurrence and 1 patient had fungal infection in the brain, leading to a fatal subarachnoid hemorrhage). In the nonelderly group, 4 of 10 patients died of graft failure due to the graft size being too small.nnnCONCLUSIONnElderly patients, at the end stage of liver failure, are likely very frail and may have latent infections. Careful examination for latent infections before LDLT should be carefully performed in regard to indications for LDLT, which might reach satisfactory outcomes as in nonelderly LDLT recipients. Even if elderly patients are approved for transplantation, very careful management is needed.

Evaluation of rituximab dosage for ABO-incompatible living-donor kidney transplantation.

BACKGROUNDnThe introduction of rituximab has led to a growing tendency to perform ABO-incompatible living-donor kidney transplantation (LDKT) without splenectomy. However, the optimal dosage of rituximab is undefined.nnnMETHODnFifty-five LDKT recipients who had neither a history of hepatitis B infection nor positive crossmatch were enrolled between October 2005 and June 2014. Recipients were divided into three groups by year of transplantation: 2005 to 2008; 2009 to 2011; and 2012 to 2014. Percentages of CD20-positive B lymphocytes and blood-group antibody titers were monitored before renal transplantation. An initial rituximab dosage of 100 mg/body (for titers below 64) or 200 mg/body (for titers above 128) was administered 2 weeks before transplantation. If the percentage of peripheral B lymphocytes remained greater than 0.5%, additional rituximab (100 mg or 200 mg) was administered. Patient demographics, patient survival, graft survival, and complication rates were compared.nnnRESULTSnNine patients received rituximab 100 mg/body (low-dose rituximab [LDR] group). Overall survival and graft survival rates did not differ significantly between the LDR group and other cases. The incidences of myelosuppression and viral infection were lower in the LDR group than the other cases.nnnCONCLUSIONnA low dose of rituximab (100 mg/body) is adequate in ABO-incompatible LDKT, especially in cases with low blood-type antibody titer against ABO-antigens. Rituximab dosage reduction has been successful in our hospital without serious complications. Moreover, as over-dosage of rituximab may cause myelosuppression, it is reasonable to believe that LDR is a suitable option to safely perform ABO-incompatible LDKT without splenectomy.

Effectiveness of the Combination of Everolimus and Tacrolimus With High Dosage of Mizoribine for Living Donor–Related Kidney Transplantation

BACKGROUNDnEverolimus (EVR) has been used widely for the purpose of reducing the dosage of calcineurin inhibitor (CNI), leading to decreasing CNI nephrotoxicity. In Japan, high-dose mizoribine (MZR) (6xa0mg/kg/day) has been increasingly used because of incidences of virus infection and gastrointestinal disorder in kidney transplant recipients. However, the efficacy and safety of EVR and MZR combination therapy is still uncertain.nnnMETHODSnA total of 29 living kidney transplant recipients from October 2012 to June 2014 were analyzed. Tacrolimus (TAC), MZR, basiliximab, and prednisolone were administered to all recipients. EVR was added to the regimen for 10 recipients from postoperative day 10 to 14; TAC trough levels were minimized simultaneously (EVR group). The remaining 19 recipients were defined as the control group. We evaluated the outcomes between the 2 groups.nnnRESULTSnThe mean TAC trough level was 5.17xa0ng/mL at 1 month after transplantation in the EVR group, and 7.89xa0ng/mL in the control group (Pxa0= .007), respectively. The mean TAC trough level was 4.0xa0ng/mL at 18 months after transplantation in the EVR group, and 6.97xa0ng/mL in the control group (Pxa0= .003) respectively. There were no differences in the rate of acute rejection and serum creatinine level. There was no significant difference in the incidence of histological nephrotoxicity between the 2 groups in the 1-year biopsy results.nnnCONCLUSIONSnWe succeeded in reducing TAC trough level immediately after transplantation by adding EVR. Our study results suggest that this combination therapy is effective for kidney transplantation recipients.

Living-donor kidney transplantation with existing anti-donor specific antibodies at a Japanese single center.

Improving the short-term outcome of kidney transplantation, the rejection induced by anti-donor specific antibody (DSA) has been the large complication. We analyzed 324 living-donor kidney transplant recipients (procedures performed between April 2003 and August 2014) to investigate the outcome of kidney transplant recipients with DSA. We divided them into four groups (anti-blood type antibody alone, group A [n = 73]; anti-human lymphocyte antigen [HLA] antibody alone, group B [n = 11]; both antibodies, group C [n = 8]; and no DSA, group D [n = 232]) and investigated the incidence of rejection and those histologic findings. Each case with DSA underwent some desensitization therapy before transplantation. There was no significant difference in graft survival (all cases: 100% at 1 year, group A: 97.6%, B: 95.9%, C: 100%, and at 5 years, group D: 96.1%). There were some significant differences in incidence of acute antibody-mediated rejection (AAMR) and chronic active antibody-mediated rejection (CAAMR) among four groups (group A: 4.1% and 2.7%, B: 18.2% and 9.1%, C: 12.5% and 12.5%, D: 0% and 0.9%, respectively). Each AAMR case was improved by ordinary desensitization therapy, but half of the CAAMR cases, diagnosed early after transplantation, had no effect of any therapy to result in graft failure. Our results suggested that even the case with DSA could be transplanted safely by some desensitization therapy. However, we should be cautious regarding recipients with DSA for the long term even if there is no histologic change early after transplantation because graft loss may occur due to CAAMR.

Histopathologic impacts of everolimus introduction on kidney transplant recipients.

BACKGROUNDnIntroduction of everolimus (RAD) has been established as a new immunosuppressive medication for kidney transplant (KT) recipients. Administration of RAD is capable of reducing the dosage of coadministrated calcineurin inhibitors (CNI). However, histological investigations have rarely been performed.nnnMETHODSnTo clarify histopathologic effects of RAD, a total of 9 adult KT recipients were enrolled (RAD group, n = 5; Mycophenolate mofetil (MMF) group, n = 4). Renal graft biopsies had been performed at 3 weeks and 1 year following KT.nnnRESULTSnThere were no differences in 1-, 3-, and 5-year graft survival rates (RAD group: 100%, 100%, and 80%, respectively; MMF group: 100%, 100%, and 75%, respectively), and patient survival between the 2 groups (no deaths during the 5 years post-transplantation). Interestingly, although 2 patients in the RAD group had developed CNI nephrotoxicity clinically, renal biopsies had proven no CNI-related lesions 1 year later, which might be due to the reduction in CNI. On the other hand, 1 patient, in the MMF group, had been diagnosed histologically with new-onset CNI nephrotoxicity 1 year following KT. Importantly, the frequency and mean arteriolar hyalinosis (ah) scores, which reflect CNI nephrotoxicity, were significantly higher in the MMF group at 1-year biopsy (P < .05, P < .0001). Two patients in the RAD group improved their ah scores between 3 weeks and 1 year.nnnCONCLUSIONSnPathological findings revealed that reversible CNI nephrotoxicity can be improved by RAD with reduced CNI maintenance therapy. It is reasonable to believe, therefore, that introduction of RAD is useful for patients who have been diagnosed with CNI nephrotoxicity.

Usefulness and Safety of High-dose Mizoribine on ABO-incompatible Living Related Kidney Transplantation Using Anti-cd20 and Anti-cd25 Antibodies Without Splenectomy: 3-year Results

BACKGROUNDnMizoribine (MZR) has been developed as an immunosuppressive agent in Japan, but has a less potent immunosuppressive effect up to 3 mg/kg/d. We previously reported that high-dose MZR, at 6 mg/kg/d, would be effective and safe for ABO-incompatible(ABO-i) living donor kidney transplantation (LDKT) patients when combined with cyclosporine (CsA) or tacrolimus(FK), anti-CD20 and anti-CD25 monoclonal antibodies, and corticosteroid without splenectomy in a 1-year study. Therefore, we observed these patients for 3 years.nnnMETHODSnFrom 2007 to 2010, we encountered 24 cases of ABO-i LDKT using anti-CD20 and anti-CD25 monoclonal antibodies without splenectomy. The pretransplantation immunosuppressive regimen consisted of two doses of anti-CD20 antibody, mycophenolate mofetil (MMF, 25 mg/kg/d), prednisolone, calcineurin inhibitor (CNI; CsA 7 mg/kg or (FK 0.2 mg/kg) and two doses of anti-CD25 antibody. Antibody removal by plasmapheresis was performed before LDKT up to several times according to the antibody titer. The post-transplantation regimen consisted of high-dose MZR (6 mg/kg/d) instead of MMF (MZR group, N = 12) .nnnRESULTSnThe 3-year graft survival rates for the MZR and MMF groups were 91.7% and 100%, respectively. Serum creatinine levels for the MZR and MMF groups were 1.44 mg/dL and 1.31 mg/dL at 1 year, 1.55 mg/dL and 1.41 mg/dL at 2 years, and 1.51 mg/dL and 1.48 mg/dL at 3 years, respectively (not significant [NS]). The MZR group did not show a higher rate of elevated serum uric acid values. The percentage of patients who were administered anti-uric medication was 42.5% (5/12) in the MZR group and 50% (6/12) in the MMF group (P = NS) at the third year. Severe infection, such as cytomegalovirus, herpes zoster, was not observed at the second and third years in both groups.nnnCONCLUSIONnA high-dose MZR regimen including CNI (CsA or FK), steroid, and anti-CD20 and anti-CD25 antibodies without splenectomy was effective and safe in ABO-i renal transplantation.

Results of Kidney Transplantation for Diabetic Nephropathy: A Single-Center Experience

In Japan, diabetic nephropathy accounted for 16,225 (43.7%) of the 38,473 patients who began hemodialysis in 2010 and the number increases year by year. In 1991, we started a kidney transplantation program for patients with diabetic nephropathy in our institution, and the ratio of patients who underwent kidney transplantation for diabetic nephropathy traces the course of increase. Among the 516 patients who underwent primary kidney transplantation in our institution from January 1991 to February 2013, we divided them into 2 groups. One group was the diabetes mellitus (DM) group, which included patients with primary disease of diabetic nephropathy, and the other group was the non-DM group. The DM group included 50 patients, and in our institution the ratio traces the course to increase. There was no significant difference for the 1-year and 5-year patient survival rates and graft survival rates between the DM group and the non-DM group. Moreover, the rate of acute rejection in the 2 groups was not significantly different. Furthermore, when we investigated the causes of death in the 2 groups, there was no significant difference with the mortality of cases due to heart vascular disease in the DM group and the non-DM group. Also, no case in which the graft lost function due to recurrence of diabetic nephropathy was observed. Although the early outcome of kidney transplantation for diabetic nephropathy in our institution did not have inferiority in comparison with kidney transplantation for the other primary disease, we think that careful diabetic control after kidney transplantation is required for long-term outcome.