The Pace of Prostatic Intraepithelial Neoplasia Development Is Determined by the Timing of Pten Tumor Suppressor Gene Excision

Loss of the PTEN tumor suppressor is a common occurrence in human prostate cancer, particularly in advanced disease. In keeping with its role as a pivotal upstream regulator of the phosphatidylinositol 3-kinase signaling pathway, experimentally-induced deletion of Pten in the murine prostate invariably results in neoplasia. However, and unlike humans where prostate tumorigenesis likely evolves over decades, disease progression in the constitutively Pten deficient mouse prostate is relatively rapid, culminating in invasive cancer within several weeks post-puberty. Given that the prostate undergoes rapid androgen-dependent growth at puberty, and that Pten excisions during this time might be especially tumorigenic, we hypothesized that delaying prostate-specific Pten deletions until immediately after puberty might alter the pace of tumorigenesis. To this end we generated mice with a tamoxifen-inducible Cre recombinase transgene enabling temporal control over prostate-specific gene alterations. This line was then interbred with mice carrying floxed Pten alleles. Despite evidence of increased Akt/mTOR/S6K axis activity at early time points in Pten-deficient epithelial cells, excisions induced in the post-pubertal (6 wk-old) prostate yielded gradual acquisition of a range of lesions. These progressed from pre-malignant changes (nuclear atypia, focal hyperplasia) and low grade prostatic intraepithelial neoplasia (PIN) at 16–20 wks post-tamoxifen exposure, to overtly malignant lesions by ∼1 yr of age, characterized by high-grade PIN and microinvasive carcinoma. In contrast, when Pten excisions were triggered in the pre-pubertal (2 week-old) prostate, neoplasia evolved over a more abbreviated time-frame, with a spectrum of premalignant lesions, as well as overt PIN and microinvasive carcinoma by 10–12 wks post-tamoxifen exposure. These results indicate that the developmental stage at which Pten deletions are induced dictates the pace of PIN development

Sociodemographic associations with abnormal estimated glomerular filtration rate (eGFR) in a large Canadian city: a cross-sectional observation study

Abstract Background Chronic kidney disease (CKD) is often asymptomatic in its early stages but is indicated and is diagnosed with an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2. Certain sociodemographic groups are known to be at risk for CKD, but it is unclear if there are strong associations between these at risk groups with abnormal eGFR test results in Canada. Using only secondary laboratory and Census data, geospatial variation and sociodemographic associations with abnormal eGFR result rate were investigated in Calgary, Alberta. Methods Secondary laboratory data from all adult community patients who received an eGFR test result were collected from Calgary Laboratory Service’s Laboratory Information System, which is the sole supplier of laboratory services for the large metropolitan city. Group-level sociodemographic variables were inferred by combining laboratory data with the 2011 Canadian Census data. Poisson regression and relative risk (RR) were used to calculate associations between sociodemographic variables with abnormal eGFR. Geographical distribution of abnormal eGFR result rates were analyzed by geospatial analysis using ArcGIS. Results Of the 346,663 adult community patients who received an eGFR test result, 28,091 were abnormal (8.1%; eGFR < 60 ml/min/1.73m2). Geospatial analysis revealed distinct geographical variation in abnormal eGFR result rates in Calgary. Women (RR = 1.11, P < 0.0001), and the elderly (age ≥ 70 years; P < 0.0001) were significantly associated with an increased risk for CKD, while visible minority Chinese (RR = 0.73, P = 0.0011), South Asians (RR = 0.67, P < 0.0001) and those with a high median household income (RR = 0.88, P < 0.0001) had a significantly reduced risk for CKD. Conclusions Presented here are significant sociodemographic risk associations, and geospatial clustering of abnormal eGFR result rates in a large metropolitan Canadian city. Using solely publically available secondary laboratory and Census data, the results from this study aligns with known sociodemographic risk factors for CKD, as certain sociodemographic variables were at a higher risk for having an abnormal eGFR test result, while others were protective in this analysis

Anticoagulant Related Nephropathy Induced by Dabigatran

We describe a case of biopsy-proven dabigatran related nephropathy in a patient without underlying IgA nephropathy. To date, dabigatran related nephropathy was only reported in patients with concurrent or undiagnosed IgA nephropathy, suggesting that it may predispose patients to dabigatran associated injury. The patient is an 81-year-old woman with multiple medical comorbidities, including nonvalvular atrial fibrillation, who was anticoagulated with dabigatran. She presented to hospital with acute kidney injury in the setting of volume overload. Her estimated glomerular filtration rate decreased from a baseline of 57 mL/min/1.73 m2 to 4 mL/min/1.73 m2, necessitating hemodialysis. Renal ultrasound findings, fractional excretion of sodium, and urinalysis suggested acute kidney injury. Renal biopsy showed acute tubular injury, tubular red blood cell casts, and an absence of active glomerulonephritis, similar to the pathological findings of warfarin related nephropathy. A diagnosis of anticoagulant related nephropathy secondary to dabigatran was therefore established. This case demonstrates that dabigatran, like warfarin, may increase tubular bleeding risk in patients, irrespective of underlying kidney or glomerular disease.Peer Reviewe

Trends in Biopsy-Based Diagnosis of Kidney Disease: A Population Study

Background: Kidney biopsy is considered the gold standard for diagnosis of renal disease. It is increasingly performed in cases of diagnostic uncertainty, including in patients with coexistent diabetes and hypertension, for which a presumptive clinical diagnosis can be made. Little is known about the incidence and distribution of biopsy-proven kidney diseases. Changes in the distribution of biopsy diagnoses over time may have significant implications for resource allocation and future research. Objective: We studied the relative frequency of kidney diseases in Southern Alberta over the past 30 years, to determine whether the population-standardized annual biopsy rate and incidence of selected diagnostic categories have changed. We hypothesized an increasing incidence of renal biopsies and a growing proportion of nonglomerular diseases (eg, tubulointerstitial disorders) likely due to evolving indications for biopsy. Given the rise in obesity, diabetes, and aging population with chronic kidney disease (CKD), we anticipated a rise in nephroangiosclerosis and diabetic nephropathy over time. Design: Retrospective population-based cohort study using the Biobank for the Molecular Classification of Kidney Disease (BMCKD). Setting: Southern Alberta, Canada. Patients: All patients who underwent renal biopsy between 1985 and 2015 in our database. Measurements: We used descriptive and quantitative analysis to characterize demographics and biopsy-based diagnoses. Methods: We conducted a retrospective population-based cohort study to analyze all consecutive patients who underwent at least one kidney biopsy over a 30-year period in Southern Alberta (1985-2015). We considered the first adequate biopsy. We described the annual standardized incidence of biopsy-proven kidney diseases over time and summarized associated patient characteristics. We assumed a Poisson distribution for biopsy counts and used provincial demographic information to standardize rates. Results: During the study period, 6434 people (58% male; mean age: 47.9 years) underwent a kidney biopsy. The population-standardized annual biopsy rate increased from 10.8 biopsies per 100 000 person-years in the first 5 years of the study (1985-1989) to 18.2 biopsies per 100 000 person-years in the last 5 years (2010-2014). The mean age at the time of biopsy increased from 42.5 years (1985-1989) to 51.4 years (2010-2014). Glomerular diseases remained the most prevalent histopathological group, with a growing representation of diabetic kidney disease from 3.69% to 16.18%, and a relative decrease in the proportion of other glomerular diseases from 72.32% to 62.92% of glomerular diagnoses. Tubulointerstitial diseases increased from 5.87% to 7.36% of total diagnoses. Limitations: Classification schemes have changed over time, so recently recognized conditions may have been misclassified in earlier data. There was a changing group of pathologists and nephrologists over this period. Variations in interpretation and application of biopsy indications by physician may influence recorded prevalence of certain diagnoses. We do not yet have complete information on indications or patient outcomes linked to the database. Conclusions: In Southern Alberta, kidney biopsy is being utilized more frequently and in older people. Diabetic nephropathy is increasingly diagnosed, which may reflect either or both changes in the prevalence of causative factors and local biopsy practices

Proteinase-Activated Receptor-1 and Immunomodulatory Effects of a PAR1-Activating Peptide in a Mouse Model of Prostatitis

Background. Nonbacterial prostatitis has no established etiology. We hypothesized that proteinase-activated receptor-1 (PAR1) can play a role in prostatitis. We therefore investigated the effects of PAR1 stimulation in the context of a new model of murine nonbacterial prostatitis. Methods. Using a hapten (ethanol-dinitrobenzene sulfonic acid- (DNBS-)) induced prostatitis model with both wild-type and PAR1-null mice, we examined (1) the location of PAR1 in the mouse prostate and (2) the impact of a PAR1-activating peptide (TFLLR-NH2: PAR1-TF) on ethanol-DNBS-induced inflammation. Results. Ethanol-DNBS-induced inflammation was maximal at 2 days. In the tissue, PAR1 was expressed predominantly along the apical acini of prostatic epithelium. Although PAR1-TF on its own did not cause inflammation, its coadministration with ethanol-DNBS reduced all indices of acute prostatitis. Further, PAR1-TF administration doubled the prostatic production of interleukin-10 (IL-10) compared with ethanol-DNBS treatment alone. This enhanced IL-10 was not observed in PAR1-null mice and was not caused by the reverse-sequence receptor-inactive peptide, RLLFT-NH2. Surprisingly, PAR1-TF, also diminished ethanol-DNBS-induced inflammation in PAR1-null mice. Conclusions. PAR1 is expressed in the mouse prostate and its activation by PAR1-TF elicits immunomodulatory effects during ethanol-DNBS-induced prostatitis. However, PAR1-TF also diminishes ethanol-DNBS-induced inflammation via a non-PAR1 mechanism by activating an as-yet unknown receptor

Proteinase-Activated Receptor-1 and Immunomodulatory Effects of a PAR1-Activating Peptide in a Mouse Model of Prostatitis

Background. Nonbacterial prostatitis has no established etiology. We hypothesized that proteinase-activated receptor-1 (PAR1) can play a role in prostatitis. We therefore investigated the effects of PAR1 stimulation in the context of a new model of murine nonbacterial prostatitis. Methods. Using a hapten (ethanol-dinitrobenzene sulfonic acid- (DNBS-)) induced prostatitis model with both wild-type and PAR1-null mice, we examined (1) the location of PAR1 in the mouse prostate and (2) the impact of a PAR1-activating peptide (TFLLR-NH2: PAR1-TF) on ethanol-DNBS-induced inflammation. Results. Ethanol-DNBS-induced inflammation was maximal at 2 days. In the tissue, PAR1 was expressed predominantly along the apical acini of prostatic epithelium. Although PAR1-TF on its own did not cause inflammation, its coadministration with ethanol-DNBS reduced all indices of acute prostatitis. Further, PAR1-TF administration doubled the prostatic production of interleukin-10 (IL-10) compared with ethanol-DNBS treatment alone. This enhanced IL-10 was not observed in PAR1-null mice and was not caused by the reverse-sequence receptor-inactive peptide, RLLFT-NH2. Surprisingly, PAR1-TF, also diminished ethanol-DNBS-induced inflammation in PAR1-null mice. Conclusions. PAR1 is expressed in the mouse prostate and its activation by PAR1-TF elicits immunomodulatory effects during ethanol-DNBS-induced prostatitis. However, PAR1-TF also diminishes ethanol-DNBS-induced inflammation via a non-PAR1 mechanism by activating an as-yet unknown receptor.Peer Reviewe

The biobank for the molecular classification of kidney disease: research translation and precision medicine in nephrology

Abstract Background Advances in technology and the ability to interrogate disease pathogenesis using systems biology approaches are exploding. As exemplified by the substantial progress in the personalized diagnosis and treatment of cancer, the application of systems biology to enable precision medicine in other disciplines such as Nephrology is well underway. Infrastructure that permits the integration of clinical data, patient biospecimens and advanced technologies is required for institutions to contribute to, and benefit from research in molecular disease classification and to devise specific and patient-oriented treatments. Methods and results We describe the establishment of the Biobank for the Molecular Classification of Kidney Disease (BMCKD) at the University of Calgary, Alberta, Canada. The BMCKD consists of a fully equipped wet laboratory, an information technology infrastructure, and a formal operational, ethical and legal framework for banking human biospecimens and storing clinical data. The BMCKD first consolidated a large retrospective cohort of kidney biopsy specimens to create a population-based renal pathology database and tissue inventory of glomerular and other kidney diseases. The BMCKD will continue to prospectively bank all kidney biopsies performed in Southern Alberta. The BMCKD is equipped to perform molecular, clinical and epidemiologic studies in renal pathology. The BMCKD also developed formal biobanking procedures for human specimens such as blood, urine and nucleic acids collected for basic and clinical research studies or for advanced diagnostic technologies in clinical care. The BMCKD is guided by standard operating procedures, an ethics framework and legal agreements with stakeholders that include researchers, data custodians and patients. The design and structure of the BMCKD permits its inclusion in a wide variety of research and clinical activities. Conclusion The BMCKD is a core multidisciplinary facility that will bridge basic and clinical research and integrate precision medicine into renal pathology and nephrology