Inhibitors of the mammalian target of rapamycin (MTOR) belong to a family of drugs with potent immunosuppressive, antiangiogenic, and antiproliferative properties. De novo or worsening proteinuria can occur during treatment with these agents, but the mechanism by which this occurs is unknown. We generated and characterized mice carrying a podocyte-selective knockout of the Mtor gene. Although Mtor was dispensable in developing podocytes, these mice developed proteinuria at 3 weeks and end stage renal failure by 5 weeks after birth. Podocytes from these mice exhibited an accumulation of the autophagosome marker LC3 (rat microtubuleassociated protein 1 light chain 3), autophagosomes, autophagolysosomal vesicles, and damaged mitochondria. Similarly, human podocytes treated with the MTOR inhibitor rapamycin accumulated autophagosomes and autophagolysosomes. Taken together, these results suggest that disruption of the autophagic pathway may play a role in the pathogenesis of proteinuria in patients treated with MTOR inhibitors.

We report detailed histological and molecular characteristics of four post transplant lymphoproliferative disorders (PTLD) presenting in the skin of renal transplant patients, and their clinical outcome. Three had B-cell lymphomas (cases 1-3), and one had a T-cell lymphoma (case 4). All B-cell lymphomas showed Epstein-Barr virus (EBV) by immunohistochemistry (IHC) or in situ hybridization (ISH). Cases 1 and 2 were large cell lymphomas, and case 3 a plasmacytoma. Case 1 showed light chain restriction and heavy chain gene rearrangement by polymerase chain reaction (PCR). The patient was then diagnosed with an abdominal lymphoma and died of sepsis. Case 2 had no recoverable DNA. Case 3 had a plasmacytoma that showed monoclonal light chain restriction on IHC and an oligoclonal heavy chain rearrangement by PCR. In cases 2 and 3, the lesions regressed following reduction of immunosuppression, and died 1.5 and 8 years later from unrelated medical causes. Case 4 was a CD 30+ anaplastic large T-cell lymphoma with no EBV detected by IHC, ISH and PCR, and died of heart failure 2 years later. Cutaneous manifestations of PTLD are rare, show wide array of clinical and pathological features, and generally have a favorable prognosis. EBV appears to be associated only with B-cell cutaneous lymphomas.

Excellent outcomes can be achieved using a 2-stage approach with replacement or augmentation of the urethral plate in adults with failed hypospadias repair. In our experience buccal mucosa appears to be associated with fewer complications and less stricture recurrence than skin grafts.

The hybrid SGSs performed as well as or better than the non-hybrid systems, and should be considered for clinical testing in patients whose unique anatomy warrants the flexibility that the use of hybrids provides.

Clear-cell renal cell carcinoma (ccRCC) is a common therapy resistant disease with aberrant angiogenic and immunosuppressive features. Patients with metastatic disease are treated with targeted therapies based on clinical features: low-risk patients are usually treated with anti-angiogenic drugs and intermediate/high-risk patients with immune therapy. However, there are no biomarkers available to guide treatment choice for these patients. A recently published phase II clinical trial observed a correlation between ccRCC patients' clustering and their response to targeted therapy. However, the clustering of these groups was not distinct. Here, we analyzed the gene expression profile of 469 ccRCC patients, using featured selection technique, and have developed a refined 66-gene signature for improved sub-classification of patients. Moreover, we have identified a novel comprehensive expression profile to distinguish between migratory stromal and immune cells. Furthermore, the proposed 66-gene signature was validated using a different cohort of 64 ccRCC patients. These findings are foundational for the development of reliable biomarkers that may guide treatment decision-making and improve therapy response in ccRCC patients. Clear-cell renal cell carcinoma (ccRCC) tumors have been reported to be highly angiogenic and with immunosuppressive features 1,2. Recent publications show increased expression of the immune inhibitory ligand and receptors (PD-L1/CTLA4) on tumor cells and/or tumor-infiltrating immune cells 3,4. Currently, tumor mutation burden is considered a predictive biomarker for response to immune checkpoint inhibitors (ICIs). However, research studies have shown that ccRCC has low mutational burden but highest immune infiltration score compared to other cancer types 5,6. In a different study, a pan-cancer analysis found renal cell carcinomas (RCC) to have the highest proportion of indel mutations, which can increase tumor neoantigen abundance 7. These anomalies in ccRCC make it the perfect platform to study dynamic biomarkers. ccRCC patients with clinically localised tumor undergo partial or radical nephrectomy, but ~30% of the patients present with de novo metastatic disease 8. Metastatic patients are usually treated with systemic therapies based on the clinical features 9. The prognostic value of different risk stratification tools is limited to clinical and pathological features of the patients 10. In Canada, International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk model is applied with six clinical and laboratory factors: Karnofsky performance status, time of first-line targeted therapy from diagnosis, haemoglobin concentration, serum calcium concentration, neutrophil and platelet counts 9. According to the IMDC risk stratification, low-risk metastatic RCC patients are usually treated with anti-angiogenic tyrosine kinase inhibitors (TKIs) and intermediate/high-risk patients with ICIs 11. Risk stratification models based on gene expression pattern (both messenger and long non-coding RN...

PDGF-B induced angiogenesis without fibrosis in the peritoneum. The lack of significant ultrafiltration dysfunction and epithelial mesenchymal transition, as observed in patients on PD, suggests that PDGF-B may play a role, but is not the integral component, in response to peritoneal injury.

DISCLOSURESIn the past year, TP has received honoraria and consultancy fees from Baxter healthcare and Covidien. JhC has received speaking honoraria and consultancy fees from Baxter healthcare;

Sirolimus (rapamycin), an inhibitor of the mechanistic target of rapamycin (MTOR), was originally proposed as an immunosuppressant to prevent rejection of solid organ transplants. There were expectations that MTOR inhibitors would replace nephrotoxic calcineurin inhibitors (CNIs). Despite its potential advantages, evidence that sirolimus causes de novo or worsening proteinuria is unequivocal. Given the well-recognized proteinuric effect of MTOR inhibitors, we were interested in understanding its role in maintaining the glomerular filtration barrier. To investigate this in vivo, we developed a mouse model with a podocyte selective deletion of the Mtor gene (Mtor pod-KO).