Emergence of SARS-CoV-2 with Dual-Drug Resistant Mutations During a Long-Term Infection in a Kidney Transplant Recipient.

Introduction: Various therapeutic agents are being developed for the treatment of coronavirus disease 2019 (COVID-19). Therefore, it is crucial to accumulate information regarding the features of drug-resistant viruses to these antiviral drugs. Methods: We investigated the emergence of dual-drug resistance in a kidney transplant recipient who received sotrovimab (from day 0) and remdesivir (RDV) (from day 8 to day 17). We sequenced the whole viral genomes from nasopharyngeal swabs taken on day 0 and seven points after starting treatment (on days 12, 19, 23, 37, 43, 48, and 58). The genetic traits of the wild-type (day 0) and descendant viruses (after day 12) were determined by comparing the genomes with those of a Wuhan strain and the day 0 wild-type strain, respectively. Three viral isolates (from samples collected on days 0, 23, and 37) were investigated for their escape ability and growth kinetics in vitro. Results: The sotrovimab resistant mutation (S:E340K) and the RDV resistant mutation RdRp:V792I (nt: G15814A) emerged within 12 days (day 12) and 11 days (day 19) after the treatment, respectively. The day 23 isolate harboring S:E340K/RdRp:V791I was resistant to both sotrovimab and RDV, showing 364- and 2.73-fold higher resistance respectively, compared with the wild-type. Moreover, compared with the day 23 isolate, the day 37 isolate accumulated multiple additional mutations and had a higher level of resistance to both drugs. Conclusion: Drug-resistant variants with double mutations (S:E340K/RdRp:V791I) became dominant within 23 days after starting treatment, suggesting that even a combination therapy involving sotrovimab and RDV, dual-drug resistant viruses may emerge rapidly in immunocompromised patients. The dual-resistant variants had lower virus yields than those of the wild-type virus in vitro, suggesting that they paid a fitness cost.

Single vs Multiple Arterial Reconstructions in Living Donor Liver Transplant.

BACKGROUND: It is true that multiple arterial reconstructions are sometimes required in living donor liver transplant (LDLT). However, the best procedure is still controversial regarding arterial reconstruction in liver grafts with multiple arteries. METHODS: A total of 93 patients, 55 right lobe grafts and 38 left lobe grafts, who underwent LDLT at our university from 2003 to 2017 were enrolled for this study. Regarding arterial reconstruction in grafts with multiple hepatic arteries, the dominant artery was reconstructed first. Subsequently, when both the pulsating arterial flow from the remaining artery stumps and the intra-graft arterial flow by Doppler ultrasonography were confirmed, the remaining arteries were not reconstructed. The patients were divided into the following 3 groups: (1) single artery/single reconstruction (n = 81), (2) selective arterial reconstruction of multiple arterial grafts (n = 7), and (3) multiple arterial reconstructions (n = 5). RESULTS: A total of 12.9% (12/93; right lobe: 2/55; left lobe 10/38) of grafts had multiple arteries. The incidence of multiple arteries was significantly higher in the left lobe grafts (P = .0029). The arterial diameters (SD) of multiple arterial grafts were narrower (2.43 [0.84] mm) than single arterial grafts (3.70 [1.30] mm) (P = .0135). Extra-anatomic arterial reconstruction were frequently required in multiple arterial reconstructions (group 1 and 2 vs 3) (P = .0007). The strategy of selective arterial reconstruction with the above criteria did not negatively affect the rates of biliary complications or the overall patient survival (P = .52). CONCLUSIONS: It can be argued that selective arterial reconstructions demonstrated acceptable outcomes in LDLT, provided that the above criteria were satisfied.

Impact of Donor and Recipient Age on Outcomes After Living Donor Liver Transplant.

BACKGROUND: Living donor liver transplant between elderly donors and recipients has gained popularity, but the effects of their age remain unknown. Our aim is to evaluate the effects of matching by donor and recipient age with special insights into their recovery periods. METHODS: Ninety-five living donor liver transplant pairs, excluding the left lateral segment graft cases, who underwent surgery were enrolled. Median follow-up was 97 months (range, 1-212 months). Elderly recipients were classified as being 51 years or older. Donor-recipient pairs were divided into (1) nonelderly donor/nonelderly recipient (YY) (n = 26), (2) elderly donor/nonelderly recipient (n = 8), (3) nonelderly donor/elderly recipient (n = 38), and (4) elderly donor/elderly recipient (EE) (n = 23). RESULTS: The 1-, 3-, and 5-year survival rates were 92.7%, 92.7%, and 88.9% (YY); 75.0%, 62.5%, and 62.5% (EY); 80.5%, 76.3%, and 67.9% (EY); and 86.9%, 82.6%, and 78.1% (EE) (P = .30), respectively. Perioperative parameters were comparable between the 4 groups. Liver grafts from the elderly population exhibited higher peaks of transaminases post-transplant regardless of recipient age (P ≤ .05). Postoperative recovery of total bilirubin in the EE group was relatively slower (P = .27). Required rates of plasma exchange postoperatively were relatively higher in the EE group (34.8% vs 15.4% in the YY group). CONCLUSIONS: These findings suggest a modest and not statistically significant effect that elderly liver grafts exhibit slower recovery trajectories in the acute phase but finally achieve acceptable outcomes.

Intra-Liver Allograft C3d-Binding Donor-Specific Anti-HLA Antibodies Predict Rejection After Liver Transplantation.

BACKGROUND: There is no doubt that antibody-mediated rejection (AMR) due to donor-specific anti-HLA antibodies (DSA) brings a poor outcome for liver transplant recipients. However, the relationship between intragraft DSA (g-DSA), complement-binding abilities, and AMR remains unknown. MATERIALS AND METHODS: We enrolled a total of 20 liver transplant recipients who underwent protocol or episode graft biopsies in the mid to long term after liver transplant (median 48.5, range 6-198 months), and their status of g-DSA and complement 3d (C3d)-binding abilities was assessed with the graft immunocomplex capture fluorescence analysis (ICFA) technique. RESULTS: The prevalence of g-DSA was 15.0 % in liver transplant recipients (3/20), and serum DSA (s-DSA) also existed in 15.0% of recipients. The number of g-DSA+/s-DSA+, g-DSA+/s-DSA-, g-DSA-/s-DSA+, and g-DSA-/s-DSA- cases are 1, 2, 2, and 15, respectively. The g-DSA+ group demonstrated a significant high rejection activity index: 3.67 ± 1.53, compared with the g-DSA- group: 1.24 ± 1.15 (P = .0045). Moreover, C3d-binding reaction was notably higher in the g-DSA+ group (C3d index: 1.87 ± 0.38 vs 0.76 ± 0.35) (P < .0001). Overall, the g-DSA+ group was more associated with liver allograft rejection-not only AMR, but also T cell-mediated rejection (P = .031). CONCLUSIONS: These results suggest that the existence of g-DSA and intragraft C3d-binding reaction had a negative impact on the liver allografts, but in contrast s-DSA did not have any significant impact.

Hand-Assisted Laparoscopic Subtotal Colectomy for Ogilvie Syndrome Associated With Idiopathic Fibrosis of Colon After Simultaneous Pancreas Kidney Transplant.

Ogilvie syndrome (acute colonic pseudo-obstruction) is a rare, acquired, life-threatening disorder for which treatment plans vary from simple observation to surgical intervention. Ogilvie syndrome has been reported in patients after renal or liver transplant, but its occurrence after simultaneous pancreas-kidney transplant is rare. Herein, we present the case of a 45-year-old female recipient of a deceased donor simultaneous pancreas-kidney transplant who developed Ogilvie syndrome 10 days after a previous fecal ileus that had resolved at posttransplant week 3. She demonstrated Ogilvie syndrome with obstructive colitis features (severe abdominal pain and high-grade fever), which we immediately treated with colonic decompensation by placement of a transanal ileus tube. After several screening examinations and discontinuation of unnecessary medicines, we were not able to confirm the cause of Ogilvie syndrome in our patient. After 2 weeks, the patient remained unresponsive to the conservative treatment, and so hand-assisted laparoscopic subtotal colectomy was performed to remove the dilated colon. Her symptoms gradually resolved after surgery. Histologically, we confirmed submucosal fibrotic changes, especially at the distal end of the resected colon, without evidence of amyloidosis, and the number of Auerbach plexus ganglia had decreased. Nevertheless, we observed no degenerated appearance of ganglion cells in the Auerbach plexus or the Meissner plexus. After exclusion of several collagen diseases, including systemic sclerosis, we determined that idiopathic colonic fibrosis was the likely cause of Ogilvie syndrome in our patient. When surgery is indicated in transplant patients with Ogilvie syndrome with obstructive colitis features, colectomy should be considered.

A Case of Small Intestinal Ileus Due to Wandering Spleen with a Large Cyst.

BACKGROUND Splenic cysts are rare. Most are due to previous trauma, infection, or infarction. They are generally handled by laparoscopic surgical removal if they are larger than 5 cm. However, very large cysts may require splenectomy. Another factor in the choice of therapy is the patient's underlying condition. We present the case of a giant splenic cyst in a woman 1 year after a renal transplant. CASE REPORT A 28-year-old woman presented with acute abdominal pain and nausea. One year before, she had received an ABO-identical living donor renal transplantation from her father, and was maintained on oral tacrolimus and prednisolone. A CT scan with contrast showed enteric ileus and an abnormal position of the spleen, which was involved by a cyst measuring 12×12.5×9 cm. A nasogastric tube, and later a small bowel tube, were inserted to decompress the ileus. The patient underwent laparotomy 11 days after admission. We confirmed an internal hernia with volvulus due to migration of the spleen; however, there was no evidence of necrosis. The patient was treated with splenectomy and reduction of the hernia. There were no complications. CONCLUSIONS This was a very unusual emergency following renal transplantation. Splenectomy has been performed in the past for immunosuppression in cases of donor ABO-incompatibility. We therefore considered that it would be more expedient to remove the spleen than to remove the cyst and perform splenopexy.

Detection of Intragraft Anti-Blood Group A and B Antibodies Following Renal Transplantation.

BACKGROUND: Graft immunocomplex capture fluorescence analysis is an attractive method to detect intragraft donor-specific anti-HLA antibodies. In ABO-incompatible transplantation, anti-A and B antibodies are also considered to be important donor specific antibodies (ABO-DSA). Therefore, it is useful to monitor intragraft ABO-DSAs to assess antibody-mediated rejection. METHODS: To capture A and B antigens, anti-Band III, von Willebrand factor (VW), and plasmalemma vesicle-associated protein (PLVAP) beads were produced. The allograft specimen was homogenized in a lysis buffer. Subsequently, A and B antigens were captured by anti-Band III, VW, or PLVAP beads. The immune complexes were then detected by phycoerythrin-conjugated anti-human IgG antibodies and analyzed using a Luminex system. RESULTS: Although Band III and VW beads yielded false positives and false negatives, PLVAP beads captured A and B antigens with high sensitivity (91.7%) and specificity (100%) when an index > 1.5 was considered positive. The proximity in A and B antigens and PLVAP expression was confirmed using immunohistochemical evaluation. Furthermore, sodium dodecyl sulfate polyacrylamide gel electrophoresis supported that PLVAP is an A and B antigen carrier protein. CASE REPORT: Biopsies were conducted following an ABO-incompatible renal transplant (type A to O) and evaluated for ABO-DSA. Graft immunocomplex capture fluorescence analysis was demonstrated as follows: 3.19 (1 h, serum creatinine [s-Cr] 3.95 mg/dL, titer IgG 1:512, glomerulitis [g] 0, peritubular capillaritis [ptc] 0, complement 4d [C4d] 1); 1.8 (4 d, s-Cr 2.29 mg/dL, titer 1:256, g 0, ptc 0, C4d 3); 1.2 (22 d, s-Cr 1.58 mg/dL, titer 1:128, g 0, ptc 2, C4d 3). This result indicated that the remnant ABO-DSA were adsorbed and subsequently removed from the allograft successfully. CONCLUSIONS: This novel application could be used to detect intragraft ABO-DSAs, which could lead to a correct diagnosis and shed light on the ABO-DSA kinetics following ABO-incompatible transplantation.

Clearance of Intra-graft Donor Specific Anti-HLA Antibodies in the Early Stage of Antibody-Mediated Rejection Following Rituximab and Apheresis Therapy in Renal Transplantation.

BACKGROUND: The management of acute or, in particular, chronic antibody-mediated rejection (AMR) resulting from donor-specific HLA antibodies (DSA) is a critical barrier to obtaining better long-term graft survival. To ascertain the efficacy of anti-AMR therapies, the transition of intra-graft DSA (g-DSA) was assessed. METHODS: Allograft biopsy specimens were analyzed by graft immunocomplex capture fluorescence analysis, as previously described. One hundred recipients who underwent graft biopsies between April 2016 and December 2017 were enrolled for this study. Fifteen recipients diagnosed with g-DSA positive (+) received anti-humoral treatments and underwent follow-up biopsies. g-DSA levels were assessed again by a follow-up biopsy at 6-12 months following the treatments. RESULTS: With anti-humoral treatments, 9 out of 15 recipients comprised a g-DSA negative (-) (3.59 ± 2.82-.58 ± .25): g-DSA6-12- group, while the remaining 6 recipients comprised a g-DSA +(20.6 ± 17.0-14.9 ± 14.1): g-DSA6-12+ group. The initial g-DSA scores were significantly higher in the g-DSA6-12+ group (P = .01). All samples were diagnosed as chronic AMR in the g-DSA+ groups, whereas there were 3 chronic AMR, 4 acute AMR, and 2 incomplete AMR samples in the g-DSA- group. Interestingly, the frequency of responsible DSA belonging to class II tended to be higher in the g-DSA6-12+ group (4/6) compared to the g-DSA6-12- group (2/9) (P = .14). CONCLUSION: These results imply that chronic exposure to DSA causes significant and irreversible damage to the allograft. Timely and adequate anti-humoral intervention might reverse the early phase of AMR with complete clearance of g-DSA.

Upper extremity distal dual bypass enables arteriovenous fistula construction in a critical limb ischemia.

BACKGROUND: Arteriovenous fistula (AVF) trouble in a dialysis patient sometimes results in severe forearm ischemia. CASE PRESENTATION: We present the case of 27-year-old man with severe steal syndrome complained of AVF malfunction. There was a condition where an upstream artery of AVF is occluded and AVF is maintained by regurgitation from the palmar arch with ischemic digits. The patient underwent distal dual bypass: proximal to peripheral artery arterioarterial and arteriovenous bypasses and brachial arterioplasty. His skin perfusion pressure improved from 17 to 90 mmHg with enough quantity of blood: 250 ml/min for hemodialysis. CONCLUSIONS: In severe steal syndrome cases, it is often observed that proximal artery is occluded and AVF inflow was supplied from palmar circulation and collateral vessels. Distal dual bypass is effective to re-establish digital circulation and repair AVF malfunction simultaneously in PAD patients.

Distal Bypass to the Palmar Arch to Rescue Digital Ischemia Due to Peripheral Artery Disease.

Digital ischemia is a serious problem in peripheral artery diseases (PAD) patients. Case 1: A 60-year-old woman with large arteriovenous fistula (AVF) complained of digital ischemia symptoms. The patient underwent dissection of AVF and distal bypass to the palmar arch with successful repair. Case 2: A 47-year-old female, diagnosed with renal failure, and scleroderma, complained of a digital gangrene. A bypass was performed from the left brachial artery to the superficial palmar arch. The digital gangrene showed a complete recovery within 2 months after surgery. Distal bypass to the palmar arch thus appears to be a useful procedure to re-establish digital circulation in PAD patients.

Clinicopathological and immunohistochemical analysis of plasma cell-rich rejection in renal transplantation: Involvement of intratubular Th1/Th2 balance in plasma cell enrichment.

AIM: Plasma cell-rich rejection (PCRR) has been considered a subtype of acute T-cell-mediated rejection (ATCR). However, PCRR is recognized as refractory rejection and different from ATCR in various ways. In order to elucidate the pathogenesis of PCRR, we analysed PCRR clinicopathologically and immunohistochemically by comparing it with ATCR. METHODS: Twelve cases of PCRR (PCRRs) and 22 cases of usual ATCR (ATCRs) diagnosed at our hospital between January 2008 and March 2017 were included. Between PCRRs and ATCRs, we compared clinical data, Banff classification, graft outcome and the total sum number of T-bet- and GATA3-positive lymphocytes infiltrating in tubular epithelium using immunohistochemistry. RESULTS: Plasma cell-rich rejections occurred later than ATCRs (median time after transplantation 1340.5 days vs. 52.5 days). Serum creatinine levels at discharge after treatment were significantly higher in PCRRs than in ATCRs (median 2.38 vs. 1.65 mg/dL). Cumulative rate of graft loss was significantly higher in PCRRs than in ATCRs (1-, 2- and 5-year: 26.7%, 51.1% and 51.1% vs. 0%, 0% and 17.5%). For profiles of Th1 and Th2, we found significantly lower ratio of T-bet/GATA3-positive lymphocytes in PCRRs compared with ATCRs. CONCLUSION: This study suggests that PCRR is more refractory than ATCR and there are significant differences in populations of helper T-cell subsets between them. We consider helper T-cell subset analysis valuable for developing new treatment strategies for PCRR.

Risk Factors and Management for Biliary Complications Following Adult Living-Donor Liver Transplantation.

BACKGROUND Biliary complications (BCs) following liver transplantation are very serious. Nevertheless, it is still uncertain which components influence the incidence of BCs the most. MATERIAL AND METHODS A consecutive sample of 74 adult recipients who underwent living-donor liver transplantation were enrolled in this study. BCs that were Clavien-Dindo classification grade II or higher were determined as BCs. RESULTS There were 11 out of the 74 recipients who experienced BCs. There were no differences in preoperative background factors between the BCs+ and BCs- group. Unexpectedly, the number of bile duct orifices did not contribute to the BCs (p=0.722). In comparison with the BCs- group, the frequency of post-operative bleeding requiring re-operation was relatively higher (27.3% vs. 7.9%, p=0.0913) and this complication was the only independent risk factor (p=0.0238) for the onset of BCs. Many of the BCs+ recipients were completely treated by endoscopic or radiological intervention (81.8%). However, surgical revision was required for 2 recipients (18.2%). CONCLUSIONS Given these results, it is reasonable to believe that definite hemostasis is required to prevent future BCs. In addition, bile duct multiplicity was not associated with BCs.

New Alert Message Settings for the XN-series Automated Hematology Analyzer Are Useful for Avoiding Falsely High WBC Counts and to Detect Specimens with Giant Platelets.

We encountered blood specimens from a patient with MYH9 related diseases, which gave falsely high white blood cell (WBC) counts during laboratory analysis using Sysmex XN-series automated hematology analyzers. This overcount was revealed to be caused by the overlapping of platelet (PLT) distribution with the WBC area in the WNR channel, which was used for routine WBC count with the XN-series. On the other hand, the WBC count obtained through the WDF channel of the XN-series seemed more accurate in such a case. We then created and introduced alert message settings for such rare but critical specimens, which gives a warning when the discrepancy in WBC counts between the WNR and WDF channels is higher than 1.0×109/L. By using the alert message setting, we were able to detect some specimens which gave falsely high WBC counts with the routine WNR channel from three other cases of giant PLTs. In conclusion, our alert message setting seems useful in avoiding false reporting of WBC count due to abnormal cells, including giant PLTs.

Significance of Proper Graft Selection in Adult Living-Donor Liver Transplant Recipients with Preoperative Deteriorated Condition.

BACKGROUND The outcome of living-donor liver transplantation (LDLT) is poor for recipients with severely deteriorated preoperative condition. This study therefore evaluated the proper graft selection according to the recipients' preoperative condition. MATERIAL AND METHODS We evaluated the clinical outcomes in 66 patients who underwent adult LDLT from October 2003 to June 2016 in our institution, excluding fulminant liver failure and ABO-incompatible cases. Preoperative risk factors included MELD score >20, preoperative hospitalization for over 2 weeks or intensive care unit admission and bacterial infection within 1 month before LDLT. Patients were classified into those with 0-1 risk factors (Group LR, n=44) and those with 2-3 risk factors (Group HR, n=22). RESULTS The overall survival (OS) rate after LDLT was significantly lower in Group HR than in Group LR (1-year: HR 83.9% vs. LR 93%, 3-year: HR 70.8% vs. LR 90.5%, 5-year: HR 62% vs. LR 87.6%; p=0.029). In Group LR, OS rates did not differ significantly by graft type or donor age. In Group HR, OS rates at 1 (93.8% vs. 66.7%), 3 (85.2% vs. 50%), and 5 (75.8% vs. 25%) years were significantly higher using right (n=16) vs. left (n=6) lobe grafts (p=0.046). CONCLUSIONS Proper graft selection is very important to improve the outcome of LDLT recipients in deteriorated preoperative condition. LDLT using right-lobe grafts may be recommended for high-risk severely deteriorated patients.

Graft Immunocomplex Capture Fluorescence Analysis to Detect Donor-Specific Antibodies and HLA Antigen Complexes in the Allograft.

BACKGROUND: Immunocomplex capture fluorescence analysis (ICFA) is an attractive method to detect donor-specific anti-HLA antibodies (DSA) and HLA antigen complexes. Currently, antibody-mediated rejection (AMR) due to DSA is usually diagnosed by C4d deposition and serological DSA detection. Conversely, there is a discrepancy between these findings frequently. Thereupon, our graft ICFA technique may contribute to establish the diagnosis of AMR. METHODS: Graft samples were obtained by a percutaneous needle biopsy. Then, the specimen was dissolved in PBS by the lysis buffer. Subsequently, HLA antigens were captured by anti-HLA beads. Then, DSA-HLA complexes were detected by PE-conjugated anti-human IgG antibodies, where DSA had already reacted with the allograft in vivo, analyzed by a Luminex system. RESULTS: A ratio (sample MFI/blank beads MFI) was calculated: ≥ 1.0 was determined as positive. We found that DSA-HLA complexes in the graft were successfully detected from only slight positive 1.03 to 79.27 in a chronic active AMR patient by graft ICFA. Next, positive graft ICFA had predicted the early phase of AMR (MFI ratio: 1.38) even in patients with no serum DSA. Finally, appropriate therapies for AMR deleted DSA deposition (MFI ratio from 0.3 to 0.7) from allografts. CONCLUSIONS: This novel application would detect early phase or incomplete pathological cases of AMR, which could lead to a correct diagnosis and initiation of appropriate therapies. Moreover, graft ICFA might address a variety of long-standing questions in terms of DSA. ABBREVIATIONS: AMR: Antibody-mediated rejection; DSA: Donor-specific antibodies; ICFA: Immunocomplex capture fluorescence analysis.

Histological reversibility of diabetic nephropathy after kidney transplantation from diabetic donor to non-diabetic recipient.

AIM: Given the recent increase in the prevalence of diabetes mellitus, it is not uncommon for kidney transplantation donors to have diabetes. We perform kidney transplantation in our hospital if the diabetic donors are receiving oral hypoglycaemic agents, but not insulin, and their haemoglobin A1C (HbA1C) is below 6.5%. There are few reports about histological changes to diabetic nephropathy after transplantation of kidney grafts from donors with diabetes mellitus to non-diabetic recipients. Therefore, we studied the histological diabetic changes in grafts from diabetic donors at protocol biopsies (1 hour, 1 month, 1 year), and evaluated whether they improved under the recipient's good glycaemic control. METHODS: Three cases of kidney transplantation from donors with diabetes mellitus to non-diabetic recipients were selected. We used a pathological classification established by the Renal Pathology Society for evaluating histological improvements in diabetic nephropathy. RESULTS: The results revealed that early diabetic changes found at the 1-hour and 1-month protocol biopsies were reversed and improved at the 1-year biopsy. CONCLUSION: We concluded that early diabetic changes in grafts from diabetic donors may improve if the graft recipient has good glycaemic control after kidney transplantation.

Overlapped glomerular lesions of chronic rejection and recurrent lupus nephritis in transplanted kidney: a case report.

We describe a renal transplant recipient with systemic lupus erythematosus (SLE) who showed continuous proteinuria and low complement levels without clinical evidence of active SLE. Her first renal allograft biopsy, performed nine yr and eight months after transplantation, revealed unusual histological change of glomeruli, and it initially led us to make a contradictory diagnosis based on light and electron microscopic examinations. Diffuse global double- or multi-contour glomerular basement membrane was caused by chronic endothelial injury owing to chronic rejection, and mesangial proliferation associated with mesangial electron-dense deposit was a histological change characteristic of recurrent lupus nephritis (RLN). Immunofluorescence study displayed weak mesangial staining of IgM and C1q. We concluded that this case presented overlapped chronic rejection and RLN. Because both transplant nephropathy and lupus nephritis present constellations of various histologies, it is difficult to diagnose their overlap. Complete morphologic studies with both immunofluorescence and electron microscopic evaluations in addition to microscopic examination should be performed to elucidate complex histological findings.

A case of recurrent focal segmental glomerulosclerosis (FSGS) involving massive proteinuria (>50 g/day) immediately after renal transplantation.

A 15-yr-old girl with end-stage kidney disease caused by primary focal segmental glomerulosclerosis (FSGS) underwent a living-related donor kidney transplantation. The allograft functioned well immediately after reperfusion, but massive proteinuria exceeding 50 g/d appeared on day 3. Treatment with rituximab and plasma exchange (PE) successfully decreased the proteinuria to 10 g/d. A biopsy specimen on day 30 showed no segmental glomerulosclerosis but partial interstitial infiltration of inflammatory cells. An increased number of podocytes showed intracytoplasmic vacuolization, and an electron micrograph showed diffuse mild subendothelial edema and foot process effacement. The podocytes were hypertrophied but were not detached from the basement membrane. As the therapies used to reduce the patient's proteinuria were having a limited effect, intravenous steroid pulse therapy followed by low-density lipoprotein apheresis was performed. A biopsy specimen taken on day 120 showed no segmental glomerulosclerosis. Thrombus formation in one glomerulus and packed lymphocytes in the capillary loop of another glomerulus were detected. The patient's clinical course was compatible with FSGS recurrence. Although the early pathological changes were not typical of FSGS, they might be indicative of the primary lesion that subsequently progresses to typical FSGS.

Reversal of age-related thymic involution by an LHRH agonist in miniature swine.

UNLABELLED: BACKGROUND AND AIMS OF STUDY: We have previously demonstrated a requirement for the presence of a juvenile thymus for the induction of transplantation tolerance to renal allografts by a short-course of calcineurin inhibition in miniature swine. We have also shown that aged, involuted thymi can be rejuvenated when transplanted as vascularized thymic lobes into juvenile swine recipients. The present studies were aimed at elucidating the extrinsic factors facilitating this restoration of function in the aged thymus. In particular, we tested the impact of sex steroid blockade by Luteinizing Hormone-Releasing Hormone (LHRH). MATERIALS AND METHODS: 30 naive animals (25 males and 5 females) were used for measurement of serum testosterone levels. 3 mature male pigs (aged at 22, 22 and 29 months old) were used to test the effects of Lupron (LHRH analog) injection at 45 mg (per 70-80 kg body weight) as a 3-month depot on testosterone levels and thymic rejuvenation. Thymic rejuvenation was assessed by histology, flow cytometric analysis, morphometric analysis and TREC assays. RESULTS: Hormonal alterations were induced by Lupron and resulted in macroscopic and histologic regeneration of the thymus of aged animals within 2 months, as evidenced by restoration of juvenile thymus architecture and increased cellularity. Two animals that were evaluated for TREC both showed increased levels in the periphery following Lupron treatment. CONCLUSION: Treatment of aged animals with Lupron leads to thymic rejuventaion in adult miniature swine. This result could expand the applicability of thymus-dependent tolerance-inducing regimens to adult recipients.