Incidentally found focal xanthogranulomatous pyelonephritis with extensive venous thrombus.

A 71-year-old woman with history of asthma presented with 2 months history of shortness of breath; on imaging an incidental left renal mass was noted. Subsequent renal protocol CT was obtained that showed a 4.5 cm left upper pole exophytic mass with renal vein thrombus extending into the inferior vena cava to the level of the caudate lobe concerning for renal cell carcinoma. She underwent an open left radical nephrectomy and IVC thrombectomy with subsequent postoperative pathology demonstrating xanthogranulomatous pyelonephritis without renal cell carcinoma.

Ureteral stent duration and the risk of BK polyomavirus viremia or bacteriuria after kidney transplantation.

OBJECTIVES: Ureteral stents are used in kidney transplantation (KTX) to decrease post-operative complications, but they are associated with BK polyomavirus viremia (BKV). Our primary outcome was to determine the association between ureteral stent duration and BKV. Secondary outcome measures were the association between bacteriuria and stent duration or use of ureteral stent strings. METHODS: Between January 2010 and January 2015, 403 patients underwent KTX at the Virginia Mason Medical Center and met inclusion criteria. Stent duration was classified as short (<3 weeks) or long (>3 weeks). Multivariate logistic regression models were created to assess for factors associated with BKV. The covariates in the BKV model were chosen a priori based on stent duration and risk factors previously described in the literature. RESULTS: Ureteral stents were placed in 304 (75.4%) transplants. Stent strings were left attached in 166 (54.6%) patients. On multivariate analyses, long stent duration was significantly associated with increased risk of BKV compared with no stent (odds ratio [OR] 1.92, P=.044, 95% confidence interval [CI] 1.04-3.74). Short stent duration was not associated with BKV. Sixty-two (15.4%) patients had bacteriuria. Bacteriuria was associated with female gender (OR 2.77, P<.001, 95% CI 1.58-4.95), and there was a dose-dependent effect with stent duration compared with no stent-short duration (OR 2.46, P=.049, 95% CI 1.05-6.49) and long duration (OR 3.58, P=.004, 95% CI 1.58-9.25). Stent strings were not associated with either complication. CONCLUSIONS: The association between ureteral stents and BKV may be dose dependent.

Ultrasound-targeted microbubble destruction-mediated gene delivery into canine livers.

Ultrasound (US) was applied to a targeted canine liver lobe simultaneously with injection of plasmid DNA (pDNA)/microbubble (MB) complexes into a portal vein (PV) segmental branch and occlusion of the inferior vena cava (IVC) to facilitate DNA uptake. By using a 1.1 MHz, 13 mm diameter transducer, a fivefold increase in luciferase activity was obtained at 3.3 MPa peak negative pressure (PNP) in the treated lobe. For more effective treatment of large tissue volumes in canines, a planar unfocused transducer with a large effective beam diameter (52 mm) was specifically constructed. Its apodized dual element configuration greatly reduced the near-field transaxial pressure variations, resulting in a remarkably uniform field of US exposure for the treated tissues. Together with a 15 kW capacity US amplifier, a 692-fold increase of gene expression was achieved at 2.7 MPa. Transaminase and histology analysis indicated minimal tissue damage. These experiments represent an important developmental step toward US-mediated gene delivery in large animals and clinics.

Opioid-Limiting Pain Control After Transurethral Resection of the Prostate: A Randomized Controlled Trial.

OBJECTIVE: To assess whether a multimodal opioid-limiting protocol and patient education intervention can reduce postoperative opioid use following transurethral resection of the prostate. METHODS: This prospective, non-blinded, single-institution, randomized controlled trial (NCT04102566) assigned 50 patients undergoing a transurethral resection of the prostate to either a standard of care control (SOC) or multimodal experimental group (MMG). The intervention included adding ibuprofen to the postoperative pain regimen, promoting appropriate opioid use while hospitalized, an educational intervention, and discharging without opioid prescription. Data regarding demographics, operative data, opioid use, pain scores, and patient satisfaction were compared. RESULTS: A total of 47 patients were included, n = 23 (MMG) and n = 24 (SOC). Demographic and operative findings were similar. Statistical analysis for noninferiority demonstrated non-inferior inpatient pain control (mean pain score 2.5 MMG vs 2.4 SOC, P = 0.0003). The multimodal group used significantly fewer morphine milligram equivalents after discharge (0 vs 4.1, P = 0.04). Inpatient use was reduced but did not reach statistical significance (6.0 vs 9.8, P = 0.2). Mean satisfaction scores with pain control were similar (9.6 MMG vs 9.2 SOC, P = 0.32). No opioid prescriptions were requested after discharge. Adverse events and medication side effects were infrequent and largely similar between groups. CONCLUSION: Implementation of an opioid-limiting postoperative pain protocol and patient education resulted in no outpatient opioid use while maintaining patient satisfaction with pain control. Eliminating opioids following a common urologic procedure will decrease risk of opioid-related adverse events and have a positive downstream impact.

Comparison of continuous intravenous lidocaine versus transversus abdominis plane block for kidney transplant surgery: a randomized, non-inferiority trial.

BACKGROUND AND OBJECTIVES: Transversus abdominis plane (TAP) blocks are associated with an improvement in postoperative analgesia following kidney transplant surgery. However, these blocks carry inherent risk and require a degree of expertise to perform successfully. Continuous intravenous lidocaine may be an effective alternative. In this randomized, non-inferiority study, we hypothesized that a continuous lidocaine infusion provides similar postoperative analgesia to a TAP block. METHODS: Subjects presenting for kidney transplant surgery were randomized in a 1:1 ratio to either an ultrasound-guided unilateral, single-injection TAP block (TAP group) or a continuous infusion of lidocaine (Lido group). The primary outcome of this non-inferiority study was opioid consumption within the first 24 hours following surgery. Secondary outcomes included pain scores, patient satisfaction, opioid-related adverse events, time to regular diet, and persistent opioid use. RESULTS: One hundred and twenty subjects, 59 from the TAP group and 61 from the Lido group, completed the study per protocol. Analysis of the primary outcome showed a cumulative geometric mean intravenous morphine equivalent difference between the TAP (14.6±3.2 mg) and Lido (15.9±2.4 mg) groups of 1.27 mg (95% CI -4.25 to 6.79; p<0.001), demonstrating non-inferiority of the continuous lidocaine infusion. No secondary outcomes showed clinically meaningful differences between groups. CONCLUSIONS: This study demonstrates that a continuous infusion of lidocaine offers non-inferior postoperative analgesia compared with an ultrasound-guided unilateral, single-injection TAP block in the first 24 hours following kidney transplant surgery. TRIAL REGISTRATION NUMBER: NCT03843879.

Omental roll-up: a technique for islet engraftment in a large animal model.

BACKGROUND: Attrition of transplanted islets is significant after hepatic embolization. This study was designed to investigate a novel surgical technique for islet transplantation into the omentum. This site allows placement of the islets in a three-dimensional (3D) matrix, with growth factors, to temporarily culture the islets in vivo while revascularization progresses. MATERIALS AND METHODS: Five female dogs (three partial and two total pancreatectomies) received an autologous islet transplant in the omentum. Islets were suspended in 1 mL of PBS containing 10 ug of vascular endothelial growth factor (VEGF). Fresh autologous plasma (10 mL) was mixed with the islet/VEGF suspension. The coagulum containing the islets and VEGF was then placed on the greater omentum. The leading edge of omentum was rolled up to secure the islet/VEGF/coagulum in position and to present the thin islet layer with two omental surfaces for implantation. Omentum was recovered at 2, 13, 21, 42, and 180 d. RESULTS: Immunohistochemical staining for synaptophysin, glucagon, and insulin confirmed the presence of transplanted islets in all omenta. Insulin and C peptide production from the omental islets was confirmed in portal venous samples, and normalization of morning glucose levels beginning on day 7 was seen in the total pancreatectomy experiment. CONCLUSIONS: Autologous islets implant in rolled-up omentum when placed as a VEGF/autologous plasma coagulum. This technique has potential benefits, including the opportunity to accelerate revascularization and to investigate local strategies for modulating the immune response.

Evaluation of vascular delivery methodologies to enhance rAAV6-mediated gene transfer to canine striated musculature.

A growing body of research supports the development of recombinant adeno-associated viral (rAAV) vectors for delivery of gene expression cassettes to striated musculature as a method of treating severe neuromuscular conditions. However, it is unclear whether delivery protocols that achieve extensive gene transfer in mice can be adapted to produce similarly extensive gene transfer in larger mammals and ultimately patients. Consequently, we sought to investigate methodological modifications that would facilitate rAAV-mediated gene transfer to the striated musculature of canines. A simple procedure incorporating acute (i) occlusion of limb blood flow, (ii) exsanguination via compression bandage, and (iii) vector "dwell" time of <20 minutes, markedly enhanced the transduction of limb muscles, compared with a simple bolus limb infusion of vector. A complementary method whereby vector was infused into the jugular vein led to efficient transduction of cardiomyocytes and to a lesser degree the diaphragm. Together these methods can be used to achieve transgene expression in heart, diaphragm, and limb muscles of juvenile dogs using rAAV6 vectors. These results establish that rAAV-mediated gene delivery is a viable approach to achieving systemic transduction of striated musculature in mammals approaching the dimensions of newborn humans.

Delaying DLA-haploidentical hematopoietic cell transplantation after total body irradiation.

Exposure to accidental or deliberate radiation poses a threat to public health, proving lethal at higher doses in large part because of deleterious effects on marrow. In those cases, allogeneic hematopoietic cell transplantation (HCT) might be required to restore marrow function. Most radiation accident victims will have HLA-haploidentical relatives who could serve as HCT donors. Here, we assessed in a canine HCT model the total body irradiation (TBI) doses after which transplants might be required and successful engraftment would be possible. In an attempt at mimicking the logistical problems likely to exist after radiation accidents, 4-, 8- or 10-day intervals were placed between TBI and HCT. To keep the experimental readout simple, no graft-versus-host disease (GVHD) prevention was administered. All dogs transplanted after a 4-day delay following 700 or 920 cGy TBI successfully engrafted, whereas virtually all those given 450 or 600 cGy rejected their grafts. Transplant delays of 8 and 10 days following 920 cGy TBI also resulted in successful engraftment in most dogs, whereas a delay of 8 days after 700 cGy resulted in virtually uniform graft failure. The time courses of acute GVHD (aGVHD) and rates of granulocyte recovery in engrafting dogs were comparable among dogs regardless of the lengths of delay. In other studies, we showed that most dogs not given HCT survived 700 cGy TBI with intensive supportive care, whereas those given 800 cGy TBI and higher died with marrow aplasia. Thus, DLA-haploidentical HCT was successful even when carried out 4, 8, or 10 days after TBI at or above radiation exposures where dogs survived with intensive care alone.

The Benefit of an Enhanced Recovery Program for Living Kidney Donors.

In our efforts to continue to evolve the care of living kidney donors, the application of enhanced recovery after surgery guidelines appears to offer expedited recovery and decrease the incidence of readmission.

Complete Chain of the First Global Kidney Exchange Transplant and 3-yr Follow-up.

BACKGROUND: Global Kidney Exchange (GKE) offers an opportunity to expand living renal transplantation internationally to patients without financial means. These international pairs are entered into a US kidney exchange program that provides long-term financial support in an effort to identify opportunities for suitable exchanges for both these international pairs and US citizens. OBJECTIVE: While the promise of GKE is significant, it has been met with ethical criticism since its inception in 2015. This paper aims to demonstrate the selection process and provide >3 yr of follow-up on the first GKE donor and recipient from the Philippines. DESIGN, SETTING, AND PARTICIPANTS: The first GKE transplant occurred with a young Filipino husband and wife who were immunologically compatible, but lacked the financial means to continue hemodialysis or undergo a kidney transplant in their home country. The pair was enrolled in the Alliance for Paired Donation matching system, several alternative kidney exchanges were identified, and the pair subsequently underwent renal transplantation and donation in the USA financed by philanthropy. The resulting nonsimultaneous extended altruistic chain provided transplantation for the Filipino husband and 11 US patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The Filipino donor and recipient were followed by transplant professionals in both the Philippines and the USA. Follow-up data were maintained as required by the Organ Procurement and Transplantation Network in the USA. RESULTS AND LIMITATIONS: The Filipino donor has normal blood pressure and renal function, and the Filipino recipient is doing well 3.5 yr after their donation and transplantation. CONCLUSIONS: While criticisms of GKE highlight concerns for possible exploitation of financially disadvantaged groups, these results demonstrate that these concerns did not come to fruition, and the outcome experienced by the GKE donor and recipient (and other US participants) was successful. PATIENT SUMMARY: The first Filipino Global Kidney Exchange (GKE) donor-recipient pair continues to be followed by both US and Filipino transplant centers. Both are in good health, support the GKE program, and advocate for its expansion.

Immunity to adeno-associated virus-mediated gene transfer in a random-bred canine model of Duchenne muscular dystrophy.

Recombinant adeno-associated virus (rAAV)-mediated gene transfer has shown promise for treating diseases in various animal models including the mdx mouse model of Duchenne muscular dystrophy (DMD). In many cases, however, preclinical studies in inbred mice have not successfully predicted human clinical responses. To assess the potential clinical utility of treating human DMD patients by AAV-mediated gene delivery, we performed a series of direct intramuscular injections in random-bred wild-type dogs. AAV serotypes 2 and 6 carrying different promoter-transgene cassettes were produced as previously described for murine studies and administered intramuscularly. The injection sites were biopsied at various time points and analyzed for transgene expression and immunohistochemical analysis. In contrast to the generally nonimmunogenic nature of these vectors in murine studies, both AAV2 and AAV6 vectors elicited robust cellular immune responses regardless of the transgene expressed, the cellular specificity of the promoter, and the muscle type injected. Viral purification by various methods did not diminish T cell-mediated infiltration. Our data indicate that AAV2 and AAV6 capsid proteins can elicit primary cellular immune responses when injected into the skeletal muscle of random-bred dogs, and suggest the possibility of cellular immunity to AAV vectors in humans.

Long-term tolerance to kidney allografts in a preclinical canine model.

Durable immune tolerance supporting vascularized allotransplantation offers the possibility of extending graft survival and avoiding harmful complications of chronic immunosuppression. Immune tolerance to renal allografts was induced in a preclinical canine model through engraftment of donor hematopoietic cells using a combination of low-dose total body irradiation and a short course of immunosuppression. Subsequently, donor renal allografts were transplanted accompanied by bilateral native nephrectomies. With 5-year follow up, we found normal renal function in all recipients and no histological evidence of acute or chronic rejection. This tolerance does not extend universally to donor skin grafts, however, with two of four animals rejecting delayed donor skin grafts. Hematopoietic chimerism produces durable and robust immune tolerance to kidney allografts, although incomplete tolerance to donor skin grafting.

Intussusception in canine recipients of hematopoietic cell grafts and surgical correction.

Intussusception is a common complication after canine hematopoietic cell transplantation (HCT). The present study was undertaken to evaluate predisposing factors of intussusception and to test whether intussusception can be managed surgically during the period immediately after HCT. We determined the incidence of intussusception after HCT was performed in 325 canine recipients (autologous, n = 43; allogeneic, n = 282) during the interval from January 2002 to May 2005. Intussusception was diagnosed in 16 of 325 dogs (4.9%). Intussusception was not significantly associated with the dose of irradiation, source of hematopoietic graft, use of immunosuppressive agents, gender, or age at transplant. A group of 9 of the affected dogs underwent small-bowel resection after diagnosis, and 7 were managed without surgical intervention. Despite complicating factors such as gastrointestinal toxicity and low neutrophil and platelet counts induced by the marrow conditioning regimen and the use of immunosuppressive agents, successful surgical management of intussusception was achieved in 6 of 9 dogs, as compared with successful management of 0 of 7 without surgery. Intussusception did not recur after surgical intervention in any dog. Recent HCT and post-transplant immunosuppressive therapy are not absolute contraindications to surgical intervention for intussusception in canine recipients of HCT.

RDP58 does not prevent graft-versus-host disease after dog leukocyte antigen-nonidentical canine hematopoietic cell transplantation.

Graft-versus-host disease (GVHD) remains a cause of substantial morbidity for patients undergoing allogeneic hematopoietic cell transplantation (HCT). The present study was undertaken to investigate the effectiveness of RDP58, a peptide derived from the human leukocyte antigen class I heavy chain, in preventing GVHD in the established dog leukocyte antigen (DLA)-nonidentical canine model. Dogs underwent HCT from unrelated DLA-nonidentical donors after conditioning with 920 cGy total body irradiation. Engraftment and achievement of full donor chimerism was seen in five of six dogs, whereas one dog showed rejection and died of marrow aplasia. All five dogs with engraftment developed acute GVHD and were euthanized at an average of 20.6 days after HCT. Compared with historical controls, the Suse of RDP58 neither prevented acute GVHD nor significantly prolonged survival of DLA-nonidentical HCT recipients.

Impact of cytomegalovirus in organ transplant recipients in the era of antiviral prophylaxis.

BACKGROUND: Antiviral prophylaxis has been shown to decrease the incidence of cytomegalovirus (CMV) disease in organ transplant recipients, but whether CMV disease that occurs despite prophylaxis is associated with mortality remains unknown. METHODS: The clinical features and risk factors for CMV disease in a cohort of liver transplant recipients who received antiviral prophylaxis were assessed retrospectively. Cox proportional hazard regression was used to assess the relationship of CMV to mortality during the first posttransplant year. RESULTS: CMV disease developed in 37 of 437 (8.5%) recipients at a median of 4.5 (range, 2.5 to 12) months posttransplant and was associated only with donor-seropositive/recipient-seronegative serostatus in multivariate analysis (P<0.0001). Mortality at 1 year was 12% (51 of 437) and was infection-associated in 49% of cases. In multivariate analysis, CMV disease was independently associated with overall mortality at 1 year (HR, 5.1, P=0.002) and even more strongly with infection-associated mortality (HR 11, P=0.002). There was no association of CMV with noninfection-associated mortality (P>0.05). CONCLUSIONS: Late CMV disease is an important clinical problem in liver transplant recipients who receive antiviral prophylaxis, and is strongly and independently associated with mortality. Strategies to prevent late CMV disease are warranted.

Partial donor-specific tolerance to delayed skin grafts after rejection of hematopoietic cell graft.

BACKGROUND: Donor-specific tolerance (DST) is induced after allogeneic hematopoietic cell transplantation (HCT) and is a potential strategy for prolonging survival of solid organ grafts. DST may persist in recipients with transient mixed hematopoietic chimerism (MC) when solid organ transplantation and HCT are done concomitantly. METHODS: In a canine model of allogeneic HCT after nonmyeloablative conditioning, DST to skin grafts was evaluated in dog leukocyte antigen (DLA)-identical recipients with stable MC (n=11), or after rejection of the hematopoietic cell (HC) graft (n=19). RESULTS: There was significant improvement in the survival of DLA-identical HC donor-derived skin grafts in recipients with MC compared to normal recipients (n=7; P<0.0001). However, HC donor-derived skin grafts in four recipients with MC developed an inflammatory reaction without skin graft loss. This may represent partial DST. Survival of DLA-identical HC donor-derived skin grafts was also significantly prolonged compared to normal recipients even when skin grafting was delayed until after rejection of the HC graft (P=0.002). An inflammatory reaction developed in all nine of the surviving HC donor-derived skin grafts in this group, but there was no graft loss at last follow-up (median, 30 [range, 9-84] weeks). An increased time to rejection of the hematopoietic graft was associated with prolonged survival of the subsequent skin graft (P=0.02). CONCLUSION: In a model of stable MC, DST to skin grafts may be complete or partial. Partial DST can persist after HC graft rejection even if solid organ transplantation is delayed. Further investigations are required to understand the mechanisms responsible for DST after allogeneic HCT.

Late-onset cytomegalovirus disease in liver transplant recipients despite antiviral prophylaxis.

BACKGROUND: The incidence and impact of cytomegalovirus (CMV) disease that occurs despite CMV prophylaxis among liver transplant recipients have been incompletely defined. METHODS: The incidence and risk factors for CMV disease during the first posttransplant year in a cohort of liver transplant recipients who received antiviral prophylaxis with oral ganciclovir were retrospectively analyzed using Cox proportional-hazard regression models. RESULTS: CMV disease developed in 19 of 259 recipients (7% [95% confidence interval 0.04-0.11]) at a median of 4.5 months posttransplant, included syndrome (63%) or tissue-invasive disease (37%), and was independently associated with an increased risk of mortality during the first posttransplant year (hazard ratio 14 [95% confidence interval 3.8-54], P=0.0007). The incidence was higher (10/38 [26%] vs. 8/180 [4.5%], P<0.0001) in seronegative recipients (R-) of an organ from a seropositive donor (D+) compared with seropositive (R+) patients, respectively. D+R- status was the only variable significantly associated with CMV disease in multivariate analysis. CONCLUSIONS: Late CMV disease develops in a substantial proportion of D+R- recipients after prophylaxis is discontinued, is not accurately predicted by patient factors, and is associated with increased mortality. New strategies to identify D+R- patients at risk and to reduce the incidence and impact of late CMV disease in this group are warranted.

FTY720 does not abrogate acute graft-versus-host disease in the dog leukocyte antigen-nonidentical unrelated canine model.

BACKGROUND: Acute graft-versus-host disease (GVHD) remains a significant impediment to successful hematopoietic stem-cell transplantation (HSCT). Here, we examined the effectiveness of 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol hydrochloride (FTY720), an immunosuppressant that retraffics activated lymphocytes to secondary lymphoid organs, for the treatment of acute GVHD in an established dog leukocyte antigen-nonidentical unrelated canine HSCT model. METHODS: Dogs were given HSCT after conditioning with 920 cGy total body irradiation. The dogs received methotrexate 0.4 mg/kg/day on days 1, 3, 6, and 11 and FTY720 (5 mg/kg/day orally) after developing GVHD. RESULTS: Five of six dogs achieved engraftment, developed acute GVHD, and were treated with FTY720. FTY720 resulted in a profound decrease in lymphocytes and a temporary mitigation of clinical GVHD; however, GVHD recurred in all dogs. Four of five dogs were euthanized because of severe GVHD and the fifth because of severe inanition associated with moderate GVHD. CONCLUSIONS: Compared with controls, treatment of GVHD with FTY720 did not control this complication or significantly increase survival.