Renal Allograft Transplantation Research Articles

Proteasome inhibition by bortezomib: Effect on HLA-antibody levels and specificity in sensitized patients awaiting renal allograft transplantation

BackgroundSensitization to human leukocyte antigen (HLA) prolongs waiting list time and reduces allograft survival in solid organ transplantation. Current strategies for pretransplant desensitization are based on B-cell depletion and extracorporeal treatment. The proteasome inhibitor bortezomib allows direct targeting of the antibody-producing plasma cell and has been used in antibody-mediated rejection (AMR) and recipient desensitization with varying results. Here, we report the effect of bortezomib preconditioning on HLA antibody titers and specificity in highly sensitized patients awaiting renal allograft transplantation. Patients and methodsTwo highly sensitized patients awaiting third kidney transplantation were given one cycle of bortezomib (1.3mg/m², days 1, 4, 8, 11), as part of recipient desensitization. Time-course and levels of anti-HLA antibodies, as well as specificity to previous transplant antigens were monitored by luminex technology. In addition, measles and tetanus toxoid immunoglobulin G (IgG) was measured. ResultsFollowing bortezomib, overall changes in IgG levels were small and no sustained reduction in anti-HLA class I or II antibody levels was observed over more than 100days of follow-up to both, donor specific and non-donor specific antigens. Moreover, anti-measles and -tetanus toxoid IgG levels remained unchanged. ConclusionsBortezomib preconditioning alone does not result in sustained reduction of HLA antibody levels or alter protective immunity in sensitized patients. This supports the notion, that bortezomib requires activation of plasma cells, as in AMR, to effectively reduce HLA antibody production. Hence, in a pretransplant setting, combination strategies may be required to derive benefit from proteasome inhibition.

Modifications to Facilitate Extraperitoneal Robot-Assisted Radical Prostatectomy Post Kidney Transplant

Renal transplantation is the treatment of choice for patients with end-stage renal failure. With advances in immunosuppression, the short-term and long-term outcome has improved significantly. Subsequently, urologists are encountering more transplant recipients with genitourinary malignancies, and therefore urologists are becoming increasingly compelled to offer curative treatment options. We present modifications to facilitate E-RARP in these patients that include modified trocar arrangement, delayed bladder neck transection, utilizing the robotic Hem-o-lok applier, and posterior reconstruction of the anastomosis using a barbed V-loc suture. A 68-year-old male with a history of polycystic kidney disease, end-stage renal failure, and an allograft renal transplantation in the right iliac fossa, presented with T1c, Gleason 3+4 prostate cancer. He had a preoperative PSA of 6.93ng/mL, ASA score of 3, and a BMI of 26kg/m2. Follow-up for metastasis (MRI and bone scan) was negative. E-RARP was performed via the extraperitoneal approach using a 5-port 2-arm approach at an insufflation pressure of 10 mm Hg. The radical prostatectomy was successfully performed. Ureterovesical anastomosis was completed, and total console time was 130 minutes, with an estimated blood loss of 125mL. Final pathology was T2bNx, Gleason 3+4 with negative surgical margins. The patient was discharged with no change in serum creatinine or GFR. The catheter was removed on POD 10 with no intraoperative or immediate postoperative complications. E-RARP in the carefully selected renal allograft recipient is feasible and accomplished safely with technical modifications to avoid injuring the renal allograft, transplanted ureter, and ureteroneocystostomy.

Light chain deposition disease in a postrenal transplant patient

The morphological spectrum of light chain deposition disease (LCDD) may range from normal glomerular morphology to mesangio-proliferative to mesangio-capillary to nodular sclerosing patterns. Due to the inconsistencies regarding treatment and the universally poor graft outcome of post-transplant LCDD, it is imperative to maintain a high index of suspicion and perform relevant investigations for clinching this diagnosis. A 40-year-old lady was diagnosed as a case of membrano-proliferative glomerulonephritis 3 years back, for which she underwent a live unrelated renal allograft transplant. Postoperative period was complicated by an acute rise in serum creatinine on the 21st postoperative day. Biopsy showed patchy acute cortical necrosis, which responded to conservative management. The present admission was for renal failure and subnephrotic proteinuria. A kidney biopsy was performed, and all the 14 glomeruli examined showed a mesangiocapillary pattern of glomerular injury with cellular nodule formation in some. The nodules were PAS and Congo red negative. Immunofluorescence showed glomerular and tubular basement staining for Kappa light chains only. Electron microscopy showed the characteristic granular deposits in subendothelial location in the glomerulus, and in tubular basement membranes, thus confirming the diagnosis of LCDD. Membranoproliferative pattern of glomerular injury in the pre- and posttransplant setting has a wide range of differential diagnoses; LCDD being one of them.

Abstract 16874: Predictors of Major Adverse Cardiac Events in Renal Transplant Recipients

Background: Renal transplantation has become the treatment of choice in end stage renal disease patients. Though the incidence of acute myocardial infarction is reduced after kidney transplant as compared to patients awaiting kidney transplant, major adverse cardiac events (MACE) are still common after renal transplant, especially in early post operative period. Methods: We reviewed medical records of 321 consecutive adult patients from our institution who received renal allograft transplantation between1995 and 2003. Details on cardiac risk factors, medications, stress test results, coronary angiogram and coronary intervention were collected and related to MACE. Results: The characteristics of 321 patients were as follows: age at transplant 49±13 years, 40% male, 37% diabetics, 87% with hypertension, LV ejection fraction 58±17%. MACE occurrd in 21 patients with cumulative MACE rate of 6.5% over the 3 years after renal transplant, most of them (57%) occurring within 30 days, 67% within 90 days and 84% within 180 days. MACE was not predicted by any of the clinical or pharmacological variables including age, gender, hypertension, diabetes, prior myocardial infarction, smoking, duration of dialysis, LV ejection fraction, or therapy with beta blockers, angiotensin converting enzyme inhibitors or calcium channel blockers. However, a clinical decision to perform a stress test or a coronary angiogram was predictive of a higher MACE rate. The MACE rate was 12.3% in the group with positive stress tests (n=65), 6.1 % in those with negative stress tests (n=134), and 4.1% in the those not referred for a stress test (n=122) (p=0.03). Patients who underwent pre-transplant coronary angiography (n=91), regardless of coronary anatomy, had a higher MACE rate (11 vs 4.8%, p=0.04) than those who did not undergo coronary angiography (n=230). Conclusions: (1) The MACE rate following renal transplantation decreases exponentially over time, most occurring in the first 90 days and is not predicted by any of the traditional risk factors or drug therapies. (2) However, a clinical decision leading to a stress test or coronary angiography and stress test positivity are highly predictive of a higher MACE rate.

86-P Inflammatory cytokine release signals through TLR-2 and TLR-4 in renal allograft transplantation

86-P Inflammatory cytokine release signals through TLR-2 and TLR-4 in renal allograft transplantation

Nocardia infection in kidney transplant recipients: case report and analysis of 66 published cases

Nocardiosis is a rare but life-threatening opportunistic infection, especially in immune compromised patients, including kidney transplant recipients. Primary pulmonary infection is the most common clinical pattern, and can easily result in disseminated Nocardia infection if treatment therapy is not adequate at the beginning. In this article, we report a new case of disseminated nocardiosis (lungs, skin, and pericardium) after renal allograft transplantation. We also review the English literature published from 1980 to 2010 and analyze the clinical characteristics of nocardiosis in kidney transplant recipients.

One case report of patient with hyperkalemia resulting from tacrolimus after renal allograft transplantation

One case report of patient with hyperkalemia resulting from tacrolimus after renal allograft transplantation

Linezolid combined with trimethoprim–sulfamethoxazole therapy for the treatment of disseminated nocardiosis

We describe a case of disseminated nocardiosis in a 45-year-old male with a history of chronic glomerular nephritis and allograft renal transplantation both treated with immunosuppressive drugs. Clinical symptoms included fever, chest distress, breathlessness, subcutaneous nodules and pustules. Pulmonary computed tomography scans revealed areas of consolidation in both lung fields, pleural effusion and massive pericardial effusion. Bacterial culture of the pus in the subcutaneous abscesses and pericardial effusion showed growth of Nocardia asteroides sensitive to linezolid and trimethoprim-sulfamethoxazole (TMP-SMZ) for both. Treatment with linezolid combined with TMP-SMZ resulted in a clear clinical improvement and bacterial clearance.

Nonrejection pathology of renal allograft biopsies: 10 years experience from a tertiary care center in north India

Renal dysfunction in allograft transplant is common and its assessment is done using Revised Banff '97 working classification, which is the accepted formulation for the evaluation of histological appearance of renal allograft biopsies. The nonrejection category under the Banff working classification of renal allograft pathology forms a large group resulting in allograft dysfunction. To evaluate the spectrum of histopathological changes seen in renal allograft dysfunction. A total of 119 renal biopsies were studied over 10 years presenting with renal allograft dysfunction from a tertiary center in North India. Majority of the biopsies were in the nonrejection category (47.1%), which included few cases of acute tubular necrosis (25.2%), cyclosporine nephrotoxicity (16%), infections (10.9%), and thrombotic microangiopathy (3.4%). The second largest category in our study was acute/active cellular rejection group (31.9%), which displayed moderate to severe tubulitis, mononuclear cell infiltrate in the interstitium, and vasculitis. Antibody-mediated rejection cases were seen in 28.6% of the renal biopsies followed by chronic allograft nephropathy cases (12.6%) showing features of tubular atrophy and interstitial fibrosis. Borderline changes with features of mild tubulitis contributed to 7.6% of the biopsies. The smallest group comprised of only 4.2%, which were within normal histological limits. Timely accurate diagnosis of renal allograft dysfunction is essential for prompt, effective management of renal transplant patients. Thus, nonrejection pathology forms a significant cause of renal dysfunction in patients with renal allograft transplantation.

Size Matters in Renal Allograft Survival

The clinical importance of nephron mass is a widely recognized determinant of renal fate and function.1 Those who are born with adequate numbers of nephrons get through life with less risk for cardiovascular and chronic kidney disease. Size also matters when it comes to selecting a donor for renal allograft transplantation. In their interesting and provocative article in this issue of JASN , Giral et al. 2 describe a new clinical marker of allograft success: The ratio of the weight of the renal allograft before implantation to the recipient weight, or Kw/Rw. Recipients of …

Inhibition of chemokine-glycosaminoglycan interactions in donor tissue reduces mouse allograft vasculopathy and transplant rejection.

BackgroundBinding of chemokines to glycosaminoglycans (GAGs) is classically described as initiating inflammatory cell migration and creating tissue chemokine gradients that direct local leukocyte chemotaxis into damaged or transplanted tissues. While chemokine-receptor binding has been extensively studied during allograft transplantation, effects of glycosaminoglycan (GAG) interactions with chemokines on transplant longevity are less well known. Here we examine the impact of interrupting chemokine-GAG interactions and chemokine-receptor interactions, both locally and systemically, on vascular disease in allografts.Methodology/Principal FindingsAnalysis of GAG or CC chemokine receptor 2 (CCR2) deficiency were coupled with the infusion of viral chemokine modulating proteins (CMPs) in mouse aortic allograft transplants (n = 239 mice). Inflammatory cell invasion and neointimal hyperplasia were significantly reduced in N-deacetylase-N-sulfotransferase-1 (Ndst1 f/f TekCre +) heparan sulfate (GAG)-deficient (Ndst1−/−, p<0.044) and CCR2-deficient (Ccr2−/−, p<0.04) donor transplants. Donor tissue GAG or CCR2 deficiency markedly reduced inflammation and vasculopathy, whereas recipient deficiencies did not. Treatment with three CMPs was also investigated; Poxviral M-T1 blocks CC chemokine receptor binding, M-T7 blocks C, CC, and CXC GAG binding, and herpesviral M3 binds receptor and GAG binding for all classes. M-T7 reduced intimal hyperplasia in wild type (WT) (Ccr2+/+, p≤0.003 and Ccr2−/−, p≤0.027) aortic allografts, but not in Ndst1−/− aortic allografts (p = 0.933). M-T1 and M3 inhibited WT (Ccr2+/+ and Ndst1 +/+, p≤0.006) allograft vasculopathy, but did not block vasculopathy in Ccr2−/− (p = 0.61). M-T7 treatment alone, even without immunosuppressive drugs, also significantly prolonged survival of renal allograft transplants (p≤0.001).Conclusions/SignificanceInterruption of chemokine-GAG interactions, even in the absence of chemokine-receptor blockade, is a highly effective approach to reduction of allograft rejection, reducing vascular inflammation and prolonging allograft survival. Although chemokines direct both local and systemic cell migration, interruption of inherent chemokine responses in the donor tissue unexpectedly had a greater therapeutic impact on allograft vasculopathy.

Explantation of the recipient internal iliac artery for bench-surgery during live donor renal transplants with multiple renal arteries

Transplantation of renal allografts with multiple arteries is challenging. We describe a simple technique to facilitate multiple anastomoses. The internal iliac artery and suitable branches are dissected and then explanted from the recipient by dividing the main trunk of the vessel. Multiple renal arteries can then be anastomosed end-to-end to suitable branches of the internal iliac graft over silastic catheters, on the back table, under cold storage conditions (Fig. 1). The kidney is then implanted by re-anastomosis of the internal iliac trunk to its parent main stem. This quicker and simpler arterial anastomosis optimises perfusion, reduces anastomosis time and warm ischaemic injury. Figure 1 Explanted internal iliac artery graft in position prior to anastomosis to the renal allograft.

Recurrence of focal segmental glomerulosclerosis in renal allograft: An in-depth review

Focal segmental glomerulosclerosis is a major cause of chronic kidney disease requiring transplantation in children. Recurrence rate in the renal allograft transplantation is as high as 50%. Recurrence of FSGS is associated with renal dysfunction and early graft loss. To date, there is no established therapy for recurrent FSGS after renal transplant. We have reviewed the current English literature in order to summarize current practices with emphasis on graft outcome. We conclude that despite multiple approaches to the post transplant management of recurrent FSGS, none have been shown to be consistently beneficial. Currently, pheresis combined with high dose anti-calcineurin with or without rituximab seems to be the most promising. Further controlled studies are needed to define the optimal therapeutic regimens to treat recurrent of FSGS.

Gene expression profiling of the donor kidney at the time of transplantation predicts clinical outcomes 2 years after transplantation

We have previously demonstrated that biomarkers of inflammation and immune activity detected within intraoperative renal transplant allograft biopsies are linked to adverse short-term post-transplantation clinical outcomes. Now we provide a post hoc analysis of our earlier data in the light of longer clinical follow-up. A total of 75 consecutively performed renal allografts were analyzed for gene expression of proinflammatory molecules, inflammation-induced adhesion molecules, and antiapoptotic genes expressed 15 minutes after vascular reperfusion to determine whether this analysis can aid in predicting long-term quality of renal function, proteinuria, graft loss, and death-censored graft. We have built predictive models for proteinuria (area under the curve = 0.859, p = 0.0001) and graft loss (area under the curve = 0.724, p = 0.027) 2 years post-transplantation using clinical variables in combination with intragraft gene expression data of tumor necrosis factor–α, interleukin-6, CD40, CD3, and tumor necrosis factor–α, Bcl-2, and interferon-γ, respectively. This post hoc analysis demonstrates that hypothesis-driven, targeted polymerase chain reaction profiling of gene expression in the donor kidney at the time of engraftment can predict 2-year post-transplantation clinical outcomes.

Synchronous hepatic, mesenteric and pulmonary Epstein–Barr virus‐associated smooth muscle tumors in a renal transplant recipient

Epstein-Barr virus-associated smooth muscle tumors (EBV-SMT) are distinct lesions that occur in immunocompromised patients. EBV-SMT following solid organ transplantation are rare and generally have an indolent biological behavior. Post-transplant EBV-SMT have been reported in various anatomical locations. This report describes a synchronous and multicentric development of EBV-SMT in liver, mesentery, and lung of a 33-yr-old male patient, 10 yr after a deceased allograft renal transplantation. The hepatic and mesenteric tumors were available for study. These tumors were composed of bland looking, desmin-positive, spindle-shaped cells which showed a strong nuclear staining for EBV with in situ hybridization technique. A literature review of post solid organ transplant EBV-SMT in the liver and lung, particularly regarding their pathogenesis, synchronicity and biological behavior would be provided.

Diagnosis of C4d+ Renal Allograft Acute Humoral Rejection by Urine Protein Fingerprint Analysis

This study aimed to develop urine protein fingerprint models for the diagnosis of acute rejection (AR) and complement split product positive (C4d+) acute humoral rejection (AHR) following renal allograft transplantation. Urine samples from 101 renal transplant recipients were analysed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry combined with bioinformatics. The patients comprised 36 with stable allograft function (stable group), 10 with acute tubular necrosis (ATN) and 55 with AR (20 with C4d- acute cellular rejection [ACR] and 15 with C4d+ AHR). The ATN group was differentiated from the stable group with a sensitivity and specificity of 100% (pattern 1). The stable group was differentiated from the AR group with a specificity of 86.4% and a sensitivity of 85.4% (pattern 2). The C4d- ACR subgroup was differentiated from the C4d+ AHR subgroup with a specificity and sensitivity of 95% and 80%, respectively (pattern 3). It is concluded that urine protein fingerprint analysis can provide a non-invasive tool to diagnose AR and C4d+ AHR.

Outcomes of kidney transplant tourism in children: a single center experience

Transplant tourism is a necessity for children with end-stage renal disease living in regions without established local transplantation programs. The use of kidneys from living unrelated donors (LURDs) was common practice in Asia prior to the recent global condemnation of commercial organ transplantation. Objective information on the outcomes of pediatric transplant tourism is scarce. Here, we report the Dubai experience with 45 renal allograft transplantations performed outside the United Arab Emirates (UAE) between 1993 and 2009. Transplantation from 33 LURDs, ten living related donors (LRDs) and two deceased donors was performed in 14 different countries. The mean number of human leukocyte antigen (HLA) A/B/DR allele matches was 1.4 +/- 0.8 in the LURD graft recipients and 3.9 +/- 0.7 in the LRD recipients. Outcomes were compared with those of a matched group of 3,150 pediatric LRD transplantations from the Collaborative Transplant Study (CTS). Ten-year patient survival was 100% in the LRD patients, 91.2% in the LURD patients, and 92% in the CTS patients. The three deaths in the LURD group occurred within the first 4 months after transplantation and were related to acute rejection. One-year and 10-year graft survival was 100% in the LRD group and 94.8% and 66.7% in the CTS-LRD groups, vs 87.8% and 43.4% in the LURD group. Major viral infections [Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella zoster (VZV)] were four-times more common in patients that had received LURD grafts than in those that had received LRD grafts. In conclusion, whereas LRD kidney transplantation performed abroad yields excellent long-term results, transplantation of LURD kidneys is fraught with a high complication rate affecting graft and even early patient survival.

Decreased abundance of urinary exosomal aquaporin-1 in renal ischemia-reperfusion injury

Urinary exosomes, secreted into urine from renal epithelial cells, are known to contain many types of renal functional membrane proteins. Here, we studied whether renal ischemia-reperfusion (I/R) affects urinary exosomal aquaporin-1 (AQP1) excretion in rats subjected to renal I/R and patients who underwent renal transplantation. Immunoblotting studies demonstrated reduction of the urinary exosomal AQP1 level even at 6 h after renal I/R, and the level continued to be low over 96 h after I/R. Renal AQP1 mRNA and protein analyses revealed that the decreased excretion of urinary exosomal AQP1 is associated with renal AQP1 protein retention in the early phase and with a decreased expression level of renal AQP1 in the later phase of renal I/R injury. Decreased abundance of urinary exosomal AQP1 in a recipient patient was also observed at 48 h after renal allograft transplantation. No significant decrease in urinary exosomal AQP1 was observed in a rat model of nephropathy or in patients with proteinuria. Our studies suggest that the renal AQP1 expression level is possibly controlled by its urinary exosomal excretion and indicate that urinary exosomal AQP1 is a novel urinary biomarker for renal I/R injury.

Planned renal allograft transplantation after tumor excision: Increasing the availability of living-donor kidneys

Planned renal allograft transplantation after tumor excision: Increasing the availability of living-donor kidneys

Spironolactone ameliorates transplant vasculopathy in renal chronic transplant dysfunction in rats

Chronic transplant dysfunction (CTD) is the leading cause of long-term renal allograft loss and is characterized by specific histological lesions including transplant vasculopathy, interstitial fibrosis, and focal glomerulosclerosis. Increasing evidence indicates that aldosterone is a direct mediator of renal damage via the mineralocorticoid receptor (MR). The MR antagonist spironolactone is renoprotective in native chronic kidney disease, but its effects on CTD are unknown. We studied the effects of spironolactone treatment on CTD development in the Dark Agouti-to-Wistar-Furth renal allograft transplant model, by treatment with 20 mg/kg spironolactone or vehicle daily by oral gavage from 2 days before transplantation (donors and recipients) throughout the experiment (12 wk, recipients). Dark Agouti-to-Dark Agouti isografts served as negative controls. Spironolactone significantly ameliorated the development of transplant vasculopathy in allografts by reducing the number of affected intrarenal arteries. In addition, spironolactone treatment showed a trend toward reduced proteinuria and focal glomerulosclerosis, and significantly reduced glomerular macrophage influx. However, spironolactone treatment did not affect interstitial fibrosis, interstitial macrophage influx, creatinine clearance, and systolic blood pressure. We conclude that spironolactone selectively ameliorates transplant vasculopathy and glomerular lesions in renal CTD in rats. These results suggest that spironolactone may have renoprotective potential as an adjunct treatment in renal transplantation to ameliorate CTD.