Catherine Horsfield

Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution

Papillary renal cell carcinoma (pRCC) is an important subtype of kidney cancer with a problematic pathological classification and highly variable clinical behaviour. Here we sequence the genomes or exomes of 31 pRCCs, and in four tumours, multi-region sequencing is undertaken. We identify BAP1, SETD2, ARID2 and Nrf2 pathway genes (KEAP1, NHE2L2 and CUL3) as probable drivers, together with at least eight other possible drivers. However, only ~10% of tumours harbour detectable pathogenic changes in any one driver gene, and where present, the mutations are often predicted to be present within cancer sub-clones. We specifically detect parallel evolution of multiple SETD2 mutations within different sub-regions of the same tumour. By contrast, large copy number gains of chromosomes 7, 12, 16 and 17 are usually early, monoclonal changes in pRCC evolution. The predominance of large copy number variants as the major drivers for pRCC highlights an unusual mode of tumorigenesis that may challenge precision medicine approaches.

Arteriovenous fistula in the rat tail: a new model of hemodialysis access dysfunction

Problems with vascular access are an important cause of morbidity and mortality in hemodialysis patients. We established a rodent model of arteriovenous fistula by anastomosing the end of a lateral vein to the side of the ventral artery of the rat tail. All operations were technically successful and in all animals the fistula was patent with a dilated fistula vein clearly visible after 28 days. Neointimal hyperplasia was found in 4 out of 5 fistulae with varied pathology from immature to more mature lesions seen both proximal and distal to the anastomosis. There was no particular pattern to the presence of or type of lesion found at any particular site of the fistulae. This fistula promises to be useful in analyzing pathologic processes that occur in native arteriovenous fistulae since the vein is accessible to functional studies and to test new subcutaneous or intravascular treatments.

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal

Summary The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance.

Low-grade phyllodes tumor of the seminal vesicle treated with laparoscopic excision.

Background A 43-year-old man presented with a 2-year history of hematospermia and dull ache in the left testis. On physical examination he had left epididymal tenderness and a normal digital rectal examination.Investigations Transrectal ultrasonography and MRI.Diagnosis Low-grade phyllodes tumor of the left seminal vesicle.Management Laparoscopic excision of the left seminal vesicle.

Toll-Like Receptor 2 or Toll-Like Receptor 4 Deficiency Does Not Modify Lupus in MRLlpr Mice

Systemic lupus erythematosus is an autoimmune disease with a high morbidity and nephritis is a common manifestation. Previous studies in murine lupus models have suggest a role for Toll-like receptor 2 and 4. We examined the role of these molecules in MRL lpr mice which is one of the most established and robust murine models. We compared disease parameters in Toll-like receptor 2 or Toll-like receptor 4 deficient mice with their littermate controls. We found no difference in the severity of glomerulonephritis as assessed by histology, serum creatinine and albuminuria when Toll-like receptor 2 or Toll-like receptor 4 deficient MRLlpr mice were compared with Toll-like receptor sufficient controls. We also found similar levels of anti-dsDNA and anti-ssDNA antibodies. These results show that Toll-like receptor 2 and Toll-like receptor 4 do not play a significant role in MRLlpr mice, and therefore they may not be important in human lupus.

Drug-induced lupus and antiphospholipid syndrome associated with cysteamine therapy

Serological evidence of drug-induced lupus (DIL) and antiphospholipid syndrome (APS) were detected in a paediatric patient with nephropathic cystinosis during work-up for live related renal transplantation. Cysteamine was considered the most likely cause. Antinuclear (ANA) and antihistone antibodies disappeared after stopping cysteamine. ANA became positive after reintroduction of cysteamine. The patients post-transplant course was complicated by severe thrombosis, with histological findings in her native nephrectomy consistent with APS. This is the first reported case of DIL and APS secondary to cysteamine therapy. Clinicians should exclude autoimmune abnormalities in patients with cystinosis, especially if patients report non-specific, unusual or unexplained symptoms.

Congenital disorders of glycosylation: a rare cause of nephrotic syndrome

Congenital disorders of glycosylation (CDG) are inborn errors of metabolism presenting with multi-system organ involvement due to defective glycosylation of glycoproteins. We report here a case of microcephaly, hypotonia, seizure disorder and severe developmental delay since infancy in whom screening for CDG with transferring isoelectric focussing (TIEF) revealed a type I pattern. Following investigation, the specific defect in glycosylation remains to be identified; hence, a diagnosis of CDG Ix (type unknown) was made. At the age of 15-months the patient developed nephrotic syndrome and renal biopsy indicated a histopathological diagnosis of diffuse mesangial sclerosis on histopathology. Since cases of CDG Ix may often develop hypoalbuminaemia secondary to malabsorption or liver disease, this case highlights the need for additional regular monitoring for glomerular proteinuria, and indicates that a diagnosis of nephrotic syndrome should be considered in all types of CDG. Furthermore, we propose that early treatment with anti-proteinuric agents may be necessary to limit proteinuria and slow disease progression.

A lot of questions (and a few answers …) in retroperitoneal fibrosis

A lot of questions (and a few answers...) in retroperitoneal fibrosis1 Archie Fernando1, James Pattison2, Catherine Horsfield3, Matthew Bultitude1, David D’Cruz4 and Tim O’Brien1 Departments of Urology1, Nephrology2, Histopathology3 and Immunology4 at Guy’s and St Thomas’ NHS Foundation Trust Corresponding author: Tim O’Brien, Department of Urology, Guy’s and St Thomas’ NHS Trust, Great Maze Pond, London SE1 9RT, United Kingdom. Email: tim.obrien@gstt.nhs.uk

IMPROVING THE INTERPRETATION OF URETEROSCOPIC BIOPSIES: USE OF BOUIN'S FIXATIVE

Introduction: The aim of this study was to compare the metabolic profiles of diabetic and non-diabetic patients with uric acid stones to understand whether preventive strategies should be tailored to reflect different causative factors. Methods: The results of the metabolic evaluation of patients with uric acid stones identified prospectively from the Metabolic Stone Clinic at St. Joseph’s Hospital, London, Canada were reviewed. Information included patients’ clinical histories, 24 hour urine collections, blood chemistry and stone analysis. Results: Complete data were obtained from 68 patients with uric acid stones. Twenty-two patients had diabetes. There were no statistically significant differences in mean age, body mass index, or history of gout. Among diabetics, pure uric acid stones were identified in 14 patients (63%) and mixed uric acid in 8 (36%). Pure uric acid stones were more common in the diabetic cohort (63% vs. 46%, p 0.16). Urine pH, serum and urine uric acid levels and 24-hour urine volumes were similar in both groups. The diabetic group had an increased average oxalate excretion (424 mol/d vs. 324 mol/d, p 0.003). Conclusion: The exact etiological basis for the higher oxalate excretion in diabetic uric acid stone formers is unclear. Whether this is a metabolic feature of diabetes, due to dietary indiscretion or the iatrogenic consequence of dietary advice requires further investigation.

Improved long-term graft function in pediatric transplant renal recipients with chronic allograft nephropathy.

Abstract:  CAN is the leading cause of graft loss in pediatric renal transplant recipients. A retrospective single centre analysis of pediatric transplant patients with CAN treated with MMF in conjunction with CNI minimisation/withdrawal is reported. 35 children were successfully started on MMF. The mean age at transplant was 7.9 ± 0.1 years. MMF was introduced 3.5 ± 0.1 years after transplantation and patients were followed up for a mean of 32.2 ± 0.5 months. CAN was confirmed on biopsy in 31 patients. CNI was stopped in 23 patients at a mean time of 16.5 ± 0.6 months after MMF introduction and minimised in the remaining patients. Prior to MMF introduction, GFR was deteriorating by 21.6 ± 0.07 ml/min/1.73 m2/yr. After MMF, there was an overall improvement in GFR of 4.0 ± 0.03 ml/min/1.73 m2/yr. This was most marked in the first six months when the GFR improved by 20.8 ± 0.06 ml/min/1.73 m2/day. Mean acute rejection episode rate prior to MMF was significantly reduced after MMF introduction. MMF was discontinued in a total of 4 patients due to adverse effects. CNI minimisation/withdrawal with MMF introduction is safe and leads to significant initial improvement with subsequent stabilisation of GFR and improved long term graft survival in pediatric renal transplant recipients with CAN.