A case of cryopyrin-associated periodic syndrome with kidney transplant failure.

The cryopyrin-associated periodic syndrome (CAPS) is an autosomal dominant autoinflammatory disease characterized by fever, skin rash, and joint involvement with acute inflammatory response. The genetic defect involves the NLRP3 gene that encodes cryopyrin and leads to an abnormal production of interleukin-1 (IL-1). Therefore, anti-IL-1 treatment represents an effective therapy. One of the most severe manifestations of the disease is secondary amyloidosis that causes renal failure. We present a patient with CAPS who underwent renal transplantation for renal insufficiency caused by amyloidosis. The function of the transplanted kidney deteriorated because of the late administration of IL-1 receptor antagonist, anakinra. This case may indicate the importance of early initiation of anti-IL-1 treatment in CAPS patients who have undergone kidney transplantation.

Efficacy and safety of concentration-controlled everolimus with reduced-dose cyclosporine in Japanese de novo renal transplant patients: 12-month results.

BACKGROUND: No study to date has evaluated the efficacy and safety of everolimus with reduced-exposure cyclosporine in Japanese de-novo renal transplant (RTx) patients. METHODS: This 12-month, multicenter, open-label study randomized (1:1) 122 Japanese de-novo RTx patients to either an everolimus regimen (1.5 mg/day starting dose (target trough: 3 to 8 ng/ml) + reduced-dose cyclosporine) or a mycophenolate mofetil (MMF) regimen (2 g/day + standard dose cyclosporine). All patients received basiliximab and corticosteroids. Key endpoints at month 12 were composite efficacy failure (treated biopsy-proven acute rejection, graft loss, death, or loss to follow-up) and renal function (estimated glomerular filtration rate; Modification of Diet in Renal Disease-4). RESULTS: Clear cyclosporine exposure reduction was achieved in the everolimus group throughout the study (52% reduction at month 12). Month 12 efficacy failure rates showed everolimus 1.5 mg to be non-inferior to MMF (11.5% vs. 11.5%). The median estimated glomerular filtration rate at month 12 was 58.00 ml/minute/1.73 m2 in the everolimus group versus 55.25 ml/minute/1.73 m2 in the MMF group (P = 0.063). Overall, the incidence of adverse events was comparable between the groups with some differences in line with the known safety profile of the treatments. The everolimus group had a higher incidence of wound healing events and edema, whereas a higher rate of cytomegalovirus infections was reported in the MMF group. CONCLUSIONS: This study confirmed the efficacy of everolimus 1.5 mg/day (target trough: 3 to 8 ng/ml) in Japanese RTx patients for preventing acute rejection, while allowing for substantial cyclosporine sparing. Renal function and safety findings were comparable with previous reports from other RTx populations. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT00658320.

Early histologic lesions and risk factors for recurrence of diabetic kidney disease after kidney transplantation.

BACKGROUND: Recurrence of diabetic kidney disease (DKD) after diabetic kidney transplantation has been reported. The aim of this study was to determine the early histologic lesions, focusing especially on abnormal glomerular angiogenesis, and clinical risk factors of recurrent DKD after kidney transplantation. METHODS: The authors studied 34 renal transplant recipients with diabetes and 30 without diabetes. All patients had undergone both baseline and posttransplant follow-up biopsies. Glomerular morphometric analyses of the mesangial area, the capillary number, and the capillary area were performed with a computer-assisted image analyzer, and glomerular basement membrane (GBM) thickness was evaluated by electron microscopy. The incidence of polar vasculosis as an angiogenic phenomenon was also evaluated. Clinical data including hemoglobin (Hb)A1c, blood pressure, urinary albumin excretion, and serum lipid profiles were compared with histologic parameters. RESULTS: Together with the increased glomerular mesangial area and GBM thickness, the glomerular capillary number and area and the incidence of polar vasculosis were significantly higher in patients with diabetes. Most of these alterations were significantly associated with the mean posttransplant HbA1c levels but not with blood pressure or lipid profiles. In the multiple regression analysis, HbA1c level remained significantly associated with these histologic parameters. CONCLUSIONS: Similar to mesangial expansion and GBM thickening, glomerular neovascularization represented by increased capillary number and area and glomerular polar vasculosis can occur as an early diabetic lesion in recurrent DKD. Posttransplant hyperglycemia is a significant risk factor predictive of the progression of recurrent DKD in kidney allografts.

Kidney transplantation restored uncoupled bone turnover in end-stage renal disease.

BACKGROUND: While kidney transplantation (KTx) reverses many disorders associated with end-stage renal disease (ESRD), patients who have received KTx often have chronic kidney disease and bone and mineral disorder (CKD-MBD). However, it is unknown how bone metabolism changes by KTx. PATIENTS AND METHODS: Living donor-KTx recipients (n = 34) at Tokyo Women's Medical University were prospectively recruited and the levels of bone-specific alkaline phosphatase (BAP) and serum cross-linked N-telopeptides of Type 1 collagen (NTX) were measured before, 6 and 12 months after transplantation. RESULTS: Before KTx, serum BAP was within the reference range in more than half of patients while NTX was high in most patients. Serum NTX was higher in patients with longer dialysis durations compared to that with shorter durations before KTx. However, there was no difference in serum BAP between these patients. After KTx, BAP increased while NTX decreased along with the decline of PTH. In addition, the numbers of patients who showed high BAP and NTX were comparable after KTx. CONCLUSION: These results suggest that bone formation is suppressed and uncoupled with bone resorption in patients with ESRD and this uncoupling is restored by KTx. Further studies are necessary to clarify the mechanism of bone uncoupling in patients with ESRD.

Nine-yr experience of 700 hand-assisted laparoscopic donor nephrectomies in Japan.

OBJECTIVE: We reviewed the introduction of a new, minimally invasive, live kidney donation program in our department. METHODS: The operating times of 700 consecutive hand-assisted laparoscopic donor nephrectomies (HALDN) conducted from February 2001 to April 2010 were examined. The risk factors for prolonging operating times were analyzed and major surgical barriers in HALDN investigated. RESULTS: All procedures were successfully performed without the requirement for conversion to open surgery or blood transfusion. The overall prevalence of perioperative complications was 3.0%, with no mortality, in this non-obese donor population with mean body mass index (BMI) as low as 23.2 ± 3.2 kg/m(2) . After the initial learning curve, a second learning plateau was detected until around case 300. Multivariate analyses showed that the significant risk factors were male sex, graft weight, number of renal arteries, right nephrectomy, and previous epigastric surgery (p < 0.05). HALDN provided direct handling of the surgical field, secure vascular control, safe manipulation of adhesive tissues, and served to maintain surgical safety. Mean values of the BMI of donors had a significant positive correlation with the prevalence of complications between large studies (p = 0.042). CONCLUSIONS: Laparoscopic donor nephrectomy was safely introduced and established in a single institution with the help of the hand-assistance method.

De novo membranous nephropathy and antibody-mediated rejection in transplanted kidney.

BACKGROUND: The etiology of de novo membranous nephropathy (MN) after kidney transplantation is still uncertain. Immunological response to various allograft antigens is speculated to be a candidate for the etiology. METHODS: Seventeen patients with post-transplant de novo MN were studied clinically and pathologically in comparison with control post-transplant patients without MN. Double immunofluorescent staining was performed to identify the presence of donor-specific human leukocyte antigen (HLA) combined with IgG in the deposits on glomerular capillary walls. RESULTS: De novo MN occurs in relatively late period after transplantation (102.1 ± 68.3 months), presenting various degree of proteinuria. Histological findings associated with antibody-mediated rejection (AMR), such as peritubular capillaritis and C4d deposition in peritubular capillary, were more frequently observed in the patients with de novo MN than the non-MN control patients. Donor-specific antibody (DSA) was detected in five patients at the time of biopsy. In one case of de novo MN with DSA, a donor-derived HLA was identified in the subepithelial deposits on the glomerular capillary walls combined with IgG deposition. CONCLUSIONS: DSA and AMR might play some roles for the pathogenesis in some patients with de novo MN after kidney transplantation.

Renoprotective effect of erythropoietin against ischaemia-reperfusion injury in a non-human primate model.

BACKGROUND: The renoprotective effect of erythropoietin (Epo) against ischaemia-reperfusion injury (IR/I) was evaluated in a non-human primate model. METHODS: Crab-eating macaques were divided into two groups: Control (n = 10), treated with saline, and EPO (n = 10), treated with Epo. Epo was injected intravenously at a dose of 12,000 units, 5 min before clamping the renal pedicle and 5 min before declamping. Renal IR/I was created by clamping the left renal artery for 90 min following right nephrectomy. Haemoglobin (Hb), haematocrit (Ht), creatinine (Cr), blood urea nitrogen (BUN), cystatin C and interleukin-6 (IL-6) were measured before (Pre) and after (Day 0) the operation, and on post-operative days: Day 1, Day 3, Day 5 and Day 7. Apoptotic cells were counted on Day 1. RESULTS: There were no differences in Hb and Ht between the two groups. Cr, BUN, cystatin C and IL-6 levels in the EPO group were lower than those in the Control group at most of the observation points. The number of apoptotic cells in the Control was significantly higher than that of and EPO group. CONCLUSIONS: Epo significantly ameliorates renal IR/I in this non-human primate model. Our findings justify the clinical application of Epo, not only for acute renal failure, but also in transplantation.

Medullary ray injury in renal allografts.

Non-immune injury leading to interstitial fibrosis and tubular atrophy (IF/TA) in renal allografts has various etiologies, but pathological means of verification have yet to be developed. Medullary ray injury (MRI) is a pathological feature of many non-immune injuries inducing IF/TA and pathological determination of calcineurin inhibitor (CNI) toxicity proceeding to striped fibrosis. We investigated the contribution of CNI toxicity to MRI and other non-immune etiologies related to IF/TA. In this study MRI is defined as fibrosis and inflammation localized exclusively to the medullary ray. Thirty-six protocol biopsies showing MRI were analyzed and classified histopathologically as following: MRI related to CNI toxicity; chronic obstruction or reflux nephropathy; and acute or chronic pyelonephritis. The etiology of MRI was CNI toxicity (n= 16, 44.4%), chronic obstruction (n= 13, 36.1%), acute or chronic pyelonephritis (n= 2, 5.6%), and other (n= 5, 13.9%). We performed cystography in seven cases of MRI related to chronic obstruction or reflux nephropathy and six cases showing vesicoureteral reflux. The ci+ct score showed significant progression after one year in 30 of the 36 cases (1.53 ± 1.04 vs. 3.03 ± 1.13, P < 0.01). MRI has various etiologies and may also predict changes in urological complications. The classification of MRI may be useful to determine the non-immune etiology leading to IF/TA.

Islet transplantation using donors after cardiac death: report of the Japan Islet Transplantation Registry.

BACKGROUND: This report summarizes outcomes of islet transplantation employing donors after cardiac death (DCD) between 2004 and 2007 as reported to the Japan Islet Transplantation Registry. METHOD: Sixty-five islet isolations were performed for 34 transplantations in 18 patients with insulin-dependent diabetes mellitus, including two patients who had prior kidney transplantation. All but one donor (64/65) was DCD at the time of harvesting. RESULTS: Factors influencing criteria for islet release included duration of low blood pressure of the donor, cold ischemic time, and usage of Kyoto solution for preservation. Multivariate analysis selected usage of Kyoto solution as most important. Of the 18 recipients, 8, 4, and 6 recipients received 1, 2, and 3 islet infusions, respectively. Overall graft survival defined as C-peptide level more than or equal to 0.3 ng/mL was 76.5%, 47.1%, and 33.6% at 1, 2, and 3 years, respectively, whereas corresponding graft survival after multiple transplantations was 100%, 80.0%, and 57.1%, respectively. All recipients remained free of severe hypoglycemia while three achieved insulin independence for 14, 79, and 215 days. HbA1c levels and requirement of exogenous insulin were significantly improved in all patients. CONCLUSION: Islet transplantation employing DCD can ameliorate severe hypoglycemic episodes, significantly improve HbA1c levels, sustain significant levels of C-peptide, and achieve insulin independence after multiple transplantations. Thus, DCD can be an important resource for islet transplantation if used under strict releasing criteria and in multiple transplantations, particularly in countries where heart-beating donors are not readily available.

Activation of the transcription factor c-Jun in acute cellular and antibody-mediated rejection after kidney transplantation.

c-Jun is a transcription factor that belongs to the activator protein-1 family of proteins. In human kidney disease, c-Jun is activated in glomerular and tubular cells and plays a major role in renal pathophysiology. However, the contribution of this pathway to renal allograft rejection has not been determined. We investigated whether c-Jun is activated in acute allograft rejection. c-Jun activation was assessed with immunohistochemistry using phospho-specific c-Jun antibodies in control human renal tissue and renal tissue from patients with acute cellular rejection, acute antibody-mediated rejection, and no rejection in the month after transplantation. In patients with acute cellular rejection, c-Jun activation was observed primarily in infiltrated T cells associated with tubulitis, interstitial cell infiltration, and endarteritis. The number of infiltrated phosphorylated c-Jun-positive cells in the tubules and interstitium was correlated with the Banff classification "t" and "i" scores. In patients with acute antibody-mediated rejection, c-Jun activation was observed in injured endothelial cells as well as in infiltrated cells, including macrophages, in the glomerular and peritubular capillaries. Furthermore, the serum creatinine levels and changes in serum creatinine from the previous year were significantly correlated with the total tubulointerstitial phosphorylated c-Jun-positive score (representing the number of positive nuclei in the tubules, interstitium, and peritubular capillaries). In conclusion, c-Jun was activated in acute antibody-mediated rejection and acute cellular rejection and was associated with reduced graft function. These findings suggest that c-Jun plays a key role in pathological events and may represent a novel therapeutic target in acute renal allograft rejection.

Two cases of ANCA-associated vasculitis in post-transplant kidney: relapse and de novo.

Two cases of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (ANCA-V) occurred in the transplanted kidney were reported. Case 1 was a 57 yr-old female whose original disease was MPO-ANCA-V. A relapse of necrotizing crescentic glomerulonephritis occurred one year after transplantation with positive serum reaction for MPO-ANCA. In spite of several immunosuppressive treatments, the disease progressed and she returned to hemodialysis treatment three yr and seven months after transplantation. Case 2 was a 34 yr-old female whose original disease was IgA nephropathy. She had a stable clinical condition during 13 yr after transplantation; however, de novo onset of necrotizing crescentic glomerulonephritis occurred at 14 yr 10 months after transplantation with positive serum reaction for MPO-ANCA. She returned to hemodialysis treatment five yr after the onset of ANCA-V. Urinary abnormities such as microhematuria and proteinuria were useful diagnostic findings but the titers of serum MPO-ANCA were relatively low in both patients. Concerning the treatment, steroid pulse therapy was effective in some extents but the disease progressed to graft failure in both cases. ANCA-V is a severe glomerulonephritis which can occur in kidney allograft in the manner of relapse and de novo. Detection of urinary abnormalities and positive serum ANCA combined with histological confirmation of necrotizing crescentic glomerulonephritis and/or vasculitis is required for early diagnosis and effective treatment of ANCA-V in renal transplant patients.

A long-term prevention of diabetic nephropathy in a patient with type 1 diabetes after simultaneous pancreas and kidney transplantation.

We report a case of type 1 diabetes mellitus who was successfully treated with simultaneous pancreas and kidney (SPK) transplantation and both grafts survived for 16 yr. A 30-yr-old woman underwent SPK transplantation from a non-heart-beating donor in January 1992. She was treated with combined immunosuppressive therapy consisting of cyclosporine, azathioprine, methylprednisolone, and anti-lymphocyte globulin. Allograft kidney biopsy was performed 10 yr after transplantation to determine the cause of proteinuria, which revealed no recurrence of diabetic nephropathy, suggesting that long-term normalization of glycemic control achieved by successful pancreas transplantation can prevent recurrence of diabetic nephropathy in the kidney allograft.

Peritubular capillaritis in early renal allograft is associated with the development of chronic rejection and chronic allograft nephropathy.

Peritubular capillaritis (PTCitis) has been recognized as one form of acute/active allograft rejection, and its relation to humoral immunity has been suggested. However, its mechanisms remain to be fully clarified, and there are no criteria for evaluating the extent of PTCitis in a biopsied allograft. In this study, we first evaluated the extent of PTCitis in early allografts in patients presenting with acute cellular rejection (ACR) and antibody-mediated rejection (AbAR). We also included patients who showed no evidence of ACR and/or AbAR. Next, we investigated whether or not PTCitis persisted and if peritubular capillary basement membrane (PTCBM) thickening was present in their follow-up biopsy specimens. We adopted the scoring system of PTCitis, which was presented at the Seventh Banff Conference on Allograft Pathology in 2003. In total, 53 patients were included in this study. At first biopsy, 17 showed ACR, eight showed AbAR, 16 showed mild PTCitis only, and 14 were without significant pathologic changes. The PTC score was the highest in the AbAR group, and in some patients the score gradually increased during the follow-up period. Similar changes were also observed in the group with mild PTCitis only. In late allografts, half of the patients with AbAR developed chronic rejection (CR), and the PTCBM score was the highest in that group. Surprisingly, CR was present in more than 30% of patients without ACR and/or AbAR but mild PTCitis only. In the control group, only a few showed CR and/or chronic allograft nephropathy (CAN). In conclusion, it became clear that we should carefully monitor for mild PTCitis in early allografts. In addition, our data also proved the usefulness of the PTC score and PTCBM score.

Lobular damage caused by cellular and humoral immunity in liver allograft rejection.

BACKGROUND: Diagnosis of acute liver allograft rejection (ALAR) is usually performed by the estimation of changes in portal areas. In this study, changes in the hepatic lobules were investigated retrospectively by immunohistochemistry, and compared with changes in the portal areas. Humoral immunity in ALAR was also studied by C4d-staining. MATERIALS AND METHODS: In total, 35 biopsy specimens from 20 patients who had undergone living-related liver transplantation were included. Specimens had been graded as mild, moderate-to-severe acute rejection based on the Banff Schema. Changes in hepatic lobules were investigated by hematoxylin-eosin (H & E) staining, an immunohistochemical study using anti-CD3 (T cells), anti-GMP-17 (cytotoxic cells), anti-CD68 (macrophages) and C4d, and the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end-labeling (TUNEL) method. RESULTS: Changes in hepatic lobules consisted of the infiltration of mononuclear cells, swelling and necrosis of hepatocytes, and hemorrhages. The degree of these changes increased with the severity of ALAR. Immunohistochemical analysis revealed that infiltrating cells included CD3+ T cells, GMP-17+ cytotoxic cells and CD68+ macrophages. The number of infiltrating cells increased with the severity of the ALAR. The TUNEL assay demonstrated apoptotic cells in ALAR and the number of apoptotic cells increased with the severity of the ALAR. In moderate-to-severe rejection, C4d depositions were observed in the hepatic sinusoids as well as the portal veins and hepatic arteries. CONCLUSIONS: Changes in the hepatic lobules were observed in ALAR and the severity increased with the severity of ALAR. Apoptosis was involved in the mechanism of cell death and humoral immunity plays a role in the mechanism of ALAR.

Injury and progressive loss of peritubular capillaries in the development of chronic allograft nephropathy.

BACKGROUND: Chronic allograft nephropathy (CAN) remains the most important cause of late renal graft loss. However, the mechanism for graft dysfunction and the process of the development of CAN are not well understood. This study examined the role of microvascular injury in the development of CAN. METHODS: We studied renal biopsies obtained from grafts with CAN (N= 79) and pretransplant control kidneys (N= 20). Microvascular injury was examined morphologically, and was correlated with interstitial fibrosis, glomerular sclerosis, graft function, and the severity of CAN. The humoral and cellular immunity involved in CAN were examined by C4d, CD3, and TIA-1 staining. RESULTS: In all the cases of CAN, microvascular injury was evident with or without CD3-positive T cells, TIA-1-positive cytotoxic cells, and/or C4d+ complement deposition. Irrespective of chronic rejection (N= 14), C4d+ chronic humoral rejection (N= 6), or other CAN, the development process of CAN was characterized by injury and progressive loss of identifiable peritubular capillaries (PTCs) accompanied with the development of interstitial fibrosis. Injured PTCs were characterized morphologically by the process of angioregression with the presence of apoptotic cells, lamination of the basement membrane, and loss of PTCs. The low number of PTCs correlated significantly with the severity of CAN (r=-0.74, P < 0.001), the development of interstitial fibrosis (r=-0.75, P < 0.001), graft dysfunction (r=-0.69, P < 0.001), and also correlated weakly with proteinuria (r=-0.45, P < 0.05). In the glomeruli, capillary loss significantly correlated with the degree of glomerular sclerosis (r=-0.66, P < 0.001) and proteinuria (r=-0.65, P < 0.001), but did not correlate with the severity of CAN (r=-0.24, P > 0.05) or graft dysfunction (r=-0.32, P > 0.05). CONCLUSION: CAN was characterized by progressive injury to the renal microvasculature and the development of renal scarring. In particular, injury, angioregression and progressive loss of the PTC network strongly contributed to the development of interstitial fibrosis and graft dysfunction in CAN, and might play a crucial role in the development of CAN.

beta6 integrin is up-regulated in chronic renal allograft dysfunction.

Up-regulation of beta6 integrin, which is indispensable to the activation of transforming growth factor-beta1 (TGF-beta1), was investigated in chronic renal allograft dysfunction (CAD). A total of 103 renal biopsy samples (normal, 10; acute rejection, 30; CAD, 63) were immunohistochemically evaluated for expression of TGF-beta1 and beta6 integrin. No TGF-beta1 or -beta6 integrin was detected in normal kidney, but both TGF-beta1 and -beta6 integrin reactivity were observed in the distal tubules in acute rejection, and even greater reactivity was observed in the distal tubules in the CAD samples. Semiquantitative analysis revealed that the reactivity of TGF-beta1 and -beta6 integrin was significantly greater in the CAD kidney than in the normal kidney and the kidney in acute rejection. The results suggest that beta6 integrin as well as TGF-beta1 is up-regulated in CAD and that it may serve as an alternative target for the treatment for CAD.

Polymyxin B-immobilized fiber hemoperfusion after emergency surgery in patients with chronic renal failure.

The purpose of this study was to evaluate the effect of direct hemoperfusion using a Polymyxin B (PMX) immobilized fiber column in septic patients with chronic renal failure after emergency surgery. Twenty-four renal failure patients, including 19 dialysis patients, with sepsis or septic shock were treated with direct hemoperfusion after emergency surgery. The 24 consecutive patients included nine with necrotic enterocolitis, six with colonic perforation due to diverticulitis, three with ruptured suture after colectomy, one with duodenal perforation, four with blood access infection, and one with an infected abdominal aortic aneurysm. The acute physiology and chronic health evaluation II score ranged from 13 to 26 (19 +/- 3). After completion of the first and the second hemoperfusion, mean blood pressure was significantly elevated from 69 +/- 12 mm Hg to 89 +/- 15 mm Hg and from 78 +/- 14 mm Hg to 95 +/- 13 mm Hg, respectively (P < 0.01). In addition, the catecholamine dosage needed to maintain the circulation could be decreased markedly after the treatment. The blood concentration of endotoxin in patients with Gram-negative sepsis, before and after the treatment, significantly decreased from 36 +/- 19 pg/mL to 19 +/- 19 pg/mL (P < 0.05). PMX was effective in patients with Gram-positive sepsis as well as Gram-negative sepsis. The 28-day mortality rate in patients who had emergency abdominal surgery was 10% (2/20), whereas that in patients with dialysis access infection was 50% (2/4). There was a significant difference in the Sequential Organ Failure Assessment (SOFA) score of all patients before and after treatment using PMX (9.2 +/- 3.3 vs. 7.5 +/- 3.5, P < 0.05). Furthermore, the SOFA score of survivors decreased significantly after PMX treatment (8.4 +/- 3.5 vs. 6.7 +/- 2.6, P < 0.01). Our results suggest that the early application of PMX may prevent multiple organ failure and improve survival in patients with chronic renal failure and sepsis/septic shock after emergency abdominal surgery, regardless of the type of pathogenic bacteria involved.

Preconditioning regimen consisting of anti-CD20 monoclonal antibody infusions, splenectomy and DFPP-enabled non-responders to undergo ABO-incompatible kidney transplantation.

Patients undergoing ABO-incompatible kidney transplantation must have their anti-donor blood-type antibody titer (ADBT) reduced to below 1:16 by using either plasma-exchange (PEX) or double filtration plasma exchange (DFPP) before they can safely undergo a transplantation. The ADBT can be reduced to under 1:16 in most cases; however, some cases (non-responders) do not respond to PEX or DFPP treatment. To enable kidney transplantations to be performed in non-responders, we developed a new preconditioning regimen consisting of anti-CD20 monoclonal antibody (rituximab) infusions, a splenectomy, and DFPP. Four non-responders were infused with rituximab at a dose of 375 mg/m(2) weekly for 3-4 wk and splenectomized 1 or 2 wk before transplantation. Four to five DFPP-sessions were then performed after the splenectomy. Using this preconditioning regimen, the ADBT was reduced to below 1:16, enabling kidney transplantations to be successfully performed in all patients. After the kidney transplantation, no episodes of humoral rejection were observed, and only one episode of cellular rejection was encountered. The cellular rejection was associated with a reduction in immunosuppressant administration because of CMV infection that occurred 80 d after the kidney transplantation. The renal allografts were functioning well in all patients after a mean follow-up period of 390 d. No serious complications or side effects were encountered. We have developed a new preconditioning regimen that enables PEX and DFPP non-responders to undergo ABO-incompatible kidney transplantations.

C4d deposition in peritubular capillary and alloantibody in the allografted kidney suffering severe acute rejection.

BACKGROUND: Alloantibodies and C4d deposition in peritubular capillaries (PTCs) are thought to be related to antibody-mediated acute rejection. The purpose of this study was to evaluate the relationship between C4d deposition in PTCs and alloantibodies at various days after allograft dysfunction due to severe acute rejection. METHOD: There were 620 renal transplantations (Tx) performed. Forty patients diagnosed with acute humoral and/or vascular rejection showed graft dysfunction with anuria or dysuria. The patients were divided into four groups by ABO compatibility and clinical course after graft dysfunction: compatible recipients with graft loss (c-GL; n = 6); compatible recipients with recovery from graft dysfunction (c-RE; n = 10); incompatible recipients with graft loss (i-GL; n = 9); and incompatible recipients with recovery from graft dysfunction (i-RE; n = 15). RESULTS: C4d depositions in 4/6 c-GL recipients increased, and those in 8/10 c-RE recipients decreased after graft dysfunction. These changes in C4d deposition between the c-GL and the c-RE groups were significantly different (P < 0.01). These titres of anti-A/B IgG antibody in 7/9 i-GL recipients increased and those in 8/15 i-RE recipients decreased after graft dysfunction. These changes in titre between the i-GL and the i-RE groups were significantly different (P < 0.01). All c-GL recipients and 4/10 c-RE recipients had anti-HLA antibody at the last biopsy. There was a significant difference in the number of recipients who had anti-HLA antibody between the c-GL and the c-RE groups (P < 0.05). CONCLUSIONS: These results indicate that changes in C4d deposition in PTCs in the c-ABO group and titre of anti-A/B IgG antibody in the ABO-incompatible groups exert a strong impact on graft survival after dysfunction in the early period after Tx.