2-Step-Scores with optional nephropathology for the prediction of adverse outcomes for brain-dead donor kidneys in Eurotransplant.

BACKGROUND AND HYPOTHESIS: The decision for acceptance or discard of the increasingly rare and marginal brain-dead donor kidneys in Eurotransplant (ET) countries has to be made without solid evidence. Thus, we developed and validated flexible clinicopathological scores called 2-Step Scores for the prognosis of delayed graft function (DGF) and one-year death-censored transplant loss (1y-tl) reflecting the current practice of six ET countries including Croatia and Belgium. METHODS: The training set was n=620 for DGF and n=711 for 1y-tl, with validation sets n=158 and n=162. In step 1, stepwise logistic regression models including only clinical predictors were used to estimate the risks. In step 2, risk estimates were updated for statistically relevant intermediate risk percentiles with nephropathology. RESULTS: Step 1 revealed an increased risk of DGF with increased cold ischaemia time, donor and recipient BMI, dialysis vintage, number of HLA-DR mismatches or recipient CMV IgG positivity. On the training and validation set, c-statistics were 0.672 and 0.704, respectively. At a range between 18% and 36%, accuracy of DGF-prognostication improved with nephropathology including number of glomeruli and Banff cv (updated overall c statistics of 0.696 and 0.701, respectively).Risk of 1y-tl increased in recipients with cold ischaemia time, sum of HLA-A. -B, -DR mismatches and donor age. On training and validation sets, c-statistics were 0.700 and 0.769, respectively. Accuracy of 1y-tl prediction improved (c-statistics = 0.706 and 0.765) with Banff ct. Overall, calibration was good on the training, but moderate on the validation set; discrimination was at least as good as established scores when applied to the validation set. CONCLUSION: Our flexible 2-Step Scores with optional inclusion of time-consuming and often unavailable nephropathology should yield good results for clinical practice in ET, and may be superior to established scores. Our scores are adaptable to donation after cardiac death and perfusion pump use.

UT-A1/A3 knockout mice show reduced fibrosis following unilateral ureteral obstruction.

Renal fibrosis is a major contributor to the development and progression of chronic kidney disease. A low-protein diet can reduce the progression of chronic kidney disease and reduce the development of renal fibrosis, although the mechanism is not well understood. Urea reabsorption into the inner medulla is regulated by inner medullary urea transporter (UT)-A1 and UT-A3. Inhibition or knockout of UT-A1/A3 will reduce interstitial urea accumulation, which may be beneficial in reducing renal fibrosis. To test this hypothesis, the effect of unilateral ureteral obstruction (UUO) was compared in wild-type (WT) and UT-A1/A3 knockout mice. UUO causes increased extracellular matrix associated with increases in transforming growth factor-ß, vimentin, and α-smooth muscle actin (α-SMA). In WT mice, UUO increased the abundance of three markers of fibrosis: transforming growth factor-ß, vimentin, and α-SMA. In contrast, in UT-A1/A3 knockout mice, the increase following UUO was significantly reduced. Consistent with the Western blot results, immunohistochemical staining showed that the levels of vimentin and α-SMA were increased in WT mice with UUO and that the increase was reduced in UT-A1/A3 knockout mice with UUO. Masson's trichrome staining showed increased collagen in WT mice with UUO, which was reduced in UT-A1/A3 knockout mice with UUO. We conclude that reduced UT activity reduces the severity of renal fibrosis following UUO.

Zinc deficiency induces hypertension by promoting renal Na+ reabsorption.

Zn2+ deficiency (ZnD) is a common comorbidity of many chronic diseases. In these settings, ZnD exacerbates hypertension. Whether ZnD alone is sufficient to alter blood pressure (BP) is unknown. To explore the role of Zn2+ in BP regulation, adult mice were fed a Zn2+-adequate (ZnA) or a Zn2+-deficient (ZnD) diet. A subset of ZnD mice were either returned to the ZnA diet or treated with hydrochlorothiazide (HCTZ), a Na+-Cl- cotransporter (NCC) inhibitor. To reduce intracellular Zn2+ in vitro, mouse distal convoluted tubule cells were cultured in N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN, a Zn2+ chelator)- or vehicle (DMSO)-containing medium. To replete intracellular Zn2+, TPEN-exposed cells were then cultured in Zn2+-supplemented medium. ZnD promoted a biphasic BP response, characterized by episodes of high BP. BP increases were accompanied by reduced renal Na+ excretion and NCC upregulation. These effects were reversed in Zn2+-replete mice. Likewise, HCTZ stimulated natriuresis and reversed BP increases. In vitro, Zn2+ depletion increased NCC expression. Furthermore, TPEN promoted NCC surface localization and Na+ uptake activity. Zn2+ repletion reversed TPEN effects on NCC. These data indicate that 1) Zn2+ contributes to BP regulation via modulation of renal Na+ transport, 2) renal NCC mediates ZnD-induced hypertension, and 3) NCC is a Zn2+-regulated transporter that is upregulated with ZnD. This study links dysregulated renal Na+ handling to ZnD-induced hypertension. Furthermore, NCC is identified as a novel mechanism by which Zn2+ regulates BP. Understanding the mechanisms of ZnD-induced BP dysregulation may have an important therapeutic impact on hypertension.

Questionable specificity of histologic findings in calcific uremic arteriolopathy.

A variety of criteria exist for histopathologic diagnosis of calciphylaxis, also known as calcific uremic arteriolopathy but data on their specificity are limited. To assess this, histologic findings of 38 skin biopsies performed for a suspicion of calcific uremic arteriolopathy were compared with histologic findings in skin obtained from healthy margins of 43 amputations in patients with end-stage renal disease (ESRD) without evidence of calcific uremic arteriolopathy. Abnormalities in small arteries or arterioles were present in 35% of amputation specimens and 55% of skin biopsies, and among these only thrombosis but not calcification was significantly more prevalent in skin biopsies. The prevalence of extravascular calcification did not differ. Vascular lesions were more common in skin biopsies from patients with high clinical suspicion of calcific uremic arteriolopathy (81%), significantly driven by increases in both calcification and thrombosis, compared to amputations (35%). The combination of medial calcification and thrombosis was six-fold more prevalent in high-suspicion skin biopsies than in amputation specimens. The location of affected vessels did not differ. In two autopsy cases, some but not all findings of involved skin were also present in uninvolved skin. Thus, histopathologic findings historically associated with calcific uremic arteriolopathy can also occur in viable tissue from unaffected patients with ESRD, calling into question the specificity of individual histologic findings for calcific uremic arteriolopathy. However, the combination of medial calcification and thrombosis was rare in unaffected patients and may provide a higher degree of specificity.

NADPH oxidase-2 mediates zinc deficiency-induced oxidative stress and kidney damage.

Zn2+ deficiency (ZnD) is comorbid with chronic kidney disease and worsens kidney complications. Oxidative stress is implicated in the detrimental effects of ZnD. However, the sources of oxidative stress continue to be identified. Since NADPH oxidases (Nox) are the primary enzymes that contribute to renal reactive oxygen species generation, this study's objective was to determine the role of these enzymes in ZnD-induced oxidative stress. We hypothesized that ZnD promotes NADPH oxidase upregulation, resulting in oxidative stress and kidney damage. To test this hypothesis, wild-type mice were pair-fed a ZnD or Zn2+-adequate diet. To further investigate the effects of Zn2+ bioavailability on NADPH oxidase regulation, mouse tubular epithelial cells were exposed to the Zn2+ chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) or vehicle followed by Zn2+ supplementation. We found that ZnD diet-fed mice develop microalbuminuria, electrolyte imbalance, and whole kidney hypertrophy. These markers of kidney damage are accompanied by elevated Nox2 expression and H2O2 levels. In mouse tubular epithelial cells, TPEN-induced ZnD stimulates H2O2 generation. In this in vitro model of ZnD, enhanced H2O2 generation is prevented by NADPH oxidase inhibition with diphenyleneiodonium. Specifically, TPEN promotes Nox2 expression and activation, which are reversed when intracellular Zn2+ levels are restored following Zn2+ supplementation. Finally, Nox2 knockdown by siRNA prevents TPEN-induced H2O2 generation and cellular hypertrophy in vitro. Together, these findings reveal that Nox2 is a Zn2+-regulated enzyme that mediates ZnD-induced oxidative stress and kidney hypertrophy. Understanding the specific mechanisms by which ZnD contributes to kidney damage may have an important impact on the treatment of chronic kidney disease.

HIV associated kidney diseases: Clarifying concordance between renal failure in HIV infection and histopathologic manifestations at kidney biopsy.

Patients with HIV infection have a wide spectrum of renal diseases. Some are known to be the direct effect of the viral infection while others are renal diseases that also occur in uninfected populations. HIV associated nephropathy (HIVAN) is considered to be a subtype of primary focal and segmental glomerulosclerosis that is distinct in HIV infected patients. It is more frequent in the African-American population and associated with mutations of the apolipoprotein L1 (APOL1) gene. HIV associated immune complex kidney disease (HIVICD) encompasses a spectrum of HIV associated renal diseases characterized by the presence of immune complex deposition within glomeruli. Thrombotic microangiopathy (TMA) is a complication of HIV infection that presents with hemolytic anemia, thrombocytopenia, and renal failure. TMA in HIV patients is associated with very high mortality. Lastly, the multitude of antiretroviral drugs used for treatment of HIV infections can result in nephrotoxicity. Although a kidney biopsy may not be the first line study for renal disease, knowledge of the different histopathologic features of HIV-associated and unassociated diseases is of paramount importance in the treatment and subsequent outcome of renal function in HIV infected patients. In this review we will describe the histopathologic features and discuss the pathophysiology of the entities previously named.

Pendrin localizes to the adrenal medulla and modulates catecholamine release.

Pendrin (Slc26a4) is a Cl(-)/HCO3 (-) exchanger expressed in renal intercalated cells and mediates renal Cl(-) absorption. With pendrin gene ablation, blood pressure and vascular volume fall, which increases plasma renin concentration. However, serum aldosterone does not significantly increase in pendrin-null mice, suggesting that pendrin regulates adrenal zona glomerulosa aldosterone production. Therefore, we examined pendrin expression in the adrenal gland using PCR, immunoblots, and immunohistochemistry. Pendrin protein was detected in adrenal lysates from wild-type but not pendrin-null mice. However, immunohistochemistry and qPCR of microdissected adrenal zones showed that pendrin was expressed in the adrenal medulla, rather than in cortex. Within the adrenal medulla, pendrin localizes to both epinephrine- and norepinephrine-producing chromaffin cells. Therefore, we examined plasma catecholamine concentration and blood pressure in wild-type and pendrin-null mice under basal conditions and then after 5 and 20 min of immobilization stress. Under basal conditions, blood pressure was lower in the mutant than in the wild-type mice, although epinephrine and norepinephrine concentrations were similar. Catecholamine concentration and blood pressure increased markedly in both groups with stress. With 20 min of immobilization stress, epinephrine and norepinephrine concentrations increased more in pendrin-null than in wild-type mice, although stress produced a similar increase in blood pressure in both groups. We conclude that pendrin is expressed in the adrenal medulla, where it blunts stress-induced catecholamine release.

Clinical heterogeneity of Xp11 translocation renal cell carcinoma: impact of fusion subtype, age, and stage.

Xp11 translocation renal cell carcinomas harbor chromosome translocations involving the Xp11 breakpoint, resulting in gene fusions involving the TFE3 gene. The most common subtypes are the ASPSCR1-TFE3 renal cell carcinomas resulting from t(X;17)(p11;q25) translocation, and the PRCC-TFE3 renal cell carcinomas, resulting from t(X;1)(p11;q21) translocation. A formal clinical comparison of these two subtypes of Xp11 translocation renal cell carcinomas has not been performed. We report one new genetically confirmed Xp11 translocation renal cell carcinoma of each type. We also reviewed the literature for all published cases of ASPSCR1-TFE3 and PRCC-TFE3 renal cell carcinomas and contacted all corresponding authors to obtain or update the published follow-up information. Study of two new, unpublished cases, and review of the literature revealed that 8/8 patients who presented with distant metastasis had ASPSCR1-TFE3 renal cell carcinomas, and all but one of these patients either died of disease or had progressive disease. Regional lymph nodes were involved by metastasis in 24 of the 32 ASPSCR1-TFE3 cases in which nodes were resected, compared with 5 of 14 PRCC-TFE3 cases (P=0.02).; however, 11 of 13 evaluable patients with ASPSCR1-TFE3 renal cell carcinomas who presented with N1M0 disease remained disease free. Two PRCC-TFE3 renal cell carcinomas recurred late (at 20 and 30 years, respectively). In multivariate analysis, only older age or advanced stage at presentation (not fusion subtype) predicted death. In conclusion, ASPSCR1-TFE3 renal cell carcinomas are more likely to present at advanced stage (particularly node-positive disease) than are PRCC-TFE3 renal cell carcinomas. Although systemic metastases portend a grim prognosis, regional lymph node involvement does not, at least in short-term follow-up. The tendency for PRCC-TFE3 renal cell carcinomas to recur late warrants long-term follow-up.

Sacrococcygeal teratomas: clinico-pathological characteristics and isochromosome 12p status.

The biological behavior of teratomas is highly variable, and morphologic features alone are insufficient to predict their clinical course. Prognostic factors that influence behavior include the following: patient sex, age, anatomic site, coincident neoplasm, and cytogenetic abnormalities. Gonadal teratomas have been well-characterized; postpubertal testicular teratomas are commonly associated with isochromosome 12p (i12p) and considered to nearly always carry a potential for malignant behavior, whereas ovarian and prepubertal testicular teratomas are i12p negative and predominantly benign in behavior. For extragonadal sites, such as sacrum and coccyx, clinical characteristics and i12p status are yet to be adequately characterized. As part of this study, we identified 19 sacrococcygeal teratomas in our surgical pathology archives from 1990 to 2012. Clinical records and slides were reviewed to confirm the original diagnosis. Gains in chromosome 12p, including i12p status were assessed in representative paraffin sections by fluorescence in situ hybridization. Our cases included 16 mature sacrococcygeal teratomas (11 prepubertal and 5 postpubertal) and three immature saccrococygeal teratomas (all prepubertal). Among mature teratomas, the average tumor size was larger in adults compared with prepubertal patients. A higher number of adult cases were recurrences (80% vs 21%), but only pediatric recurrences were managed with postoperative chemotherapy. All examined tumors were negative for i12p. 100% survival was documented in our cohort with a median follow-up of 6 years. We present a large series of sacrococcygeal teratomas and the first series to examine postpubertal adults at this anatomic site. All tumors lacked chromosome 12p gains, including i12p. Both pre- and postpubertal sacrococcygeal teratomas had a favorable outcome regardless of age or sex.

No tumor-free waiting period after treatment of multilocular cystic renal cell carcinoma: a new case and review of the literature.

Most pretransplant malignancies require a tumor-free waiting period before transplantation. End-stage renal disease (ESRD) patients have an increased risk of renal cell carcinoma (RCC), which is mostly detected from routine screening during pre-kidney transplant evaluation. RCC must be quiescent prior to kidney transplantation. However, the tumor-free waiting period for RCC varies depending on the types of RCC. Multilocular cystic RCC (MCRCC), one subtype of clear cell RCC, has low malignant potential and may not require a tumor-free waiting period. We report a case of an ESRD patient with a newly diagnosed MCRCC that was found during routine pre-kidney transplant evaluation. A plan for kidney transplantation within 6 months of successful tumor removal by nephrectomy was made. The literature regarding MCRCC in kidney transplantation is reviewed.

An International Survey of Genitourinary and Renal Pathologists Regarding Evaluation of the Non-Neoplastic Parenchyma in Kidney Cancer Specimens.

Increasing survivorship in kidney cancer patients has shifted treatment strategies to optimize renal function preservation. In 2010, the College of American Pathologists (CAP) updated their synoptic reporting guidelines for tumor nephrectomies to require evaluation of the nonneoplastic kidney parenchyma. We conducted this study to understand current practice behaviors regarding the evaluation of the nonneoplastic kidney parenchyma in tumor nephrectomy specimens. We emailed a 14-item multiple-choice survey to members of the Renal Pathology Society and Genitourinary Pathology Society. We also emailed a 12-item survey to program and associate program directors of American pathology residencies to assess the current state of renal pathology education. Ninety-eight genitourinary and 104 renal pathologists responded to the survey on the nonneoplastic kidney parenchyma. Ninety-five percent of respondents who examine tumor nephrectomies reported evaluating the nonneoplastic kidney parenchyma. Seventy-five percent of genitourinary pathologists and 67% of renal pathologists use synoptic reporting, and 81% use the CAP protocol. Thirty-nine percent of respondents report always contacting the clinician when they find evidence of medical renal disease. Forty-two program leaders responded to our renal pathology education survey, and 64% of them have a mandatory renal pathology rotation that on average lasts about 2 to 4 weeks. The majority of pathologists examine the nonneoplastic kidney parenchyma of tumor nephrectomies and frequently report incidences of new medical renal disease directly to clinicians, but there remains room for improvement and educational gaps during residency training. Further efforts to standardize both this evaluation and renal pathology education will improve patient care.

Adenocarcinoma of the prostate with Gleason score 9-10 on core biopsy: correlation with findings at radical prostatectomy and prognosis.

PURPOSE: There is a paucity of data on the prognosis after radical prostatectomy for Gleason score 9-10 disease on needle biopsy. To our knowledge we report the largest study to date to specifically analyze the correlation of Gleason score 9-10 on needle core biopsy with radical prostatectomy outcomes. MATERIALS AND METHODS: We identified 259 men with Gleason score 9-10 on biopsy who underwent radical prostatectomy from 1987 to 2012 at our institution. Preoperative variables analyzed were age, race, preoperative prostate specific antigen, adenocarcinoma site, perineural invasion, number of total biopsy cores, number of total positive cores, number of positive cores with Gleason score 9-10, maximum percent of core length with Gleason score 9-10 and maximum percent of adenocarcinoma overall. We determined pathological outcomes on univariate and multivariate analysis, including organ confinement, seminal vesicle invasion, margin status, lymph node metastasis, and biochemical-free and cancer specific survival. RESULTS: Statistically significant predictors of radical prostatectomy outcome were organ confinement (total cores with Gleason score 9-10, maximum percent overall and perineural invasion), margin status (preoperative prostate specific antigen and clinical stage), seminal vesicle invasion (maximum percent overall, perineural invasion and clinical stage), lymph node metastasis (total number of cores with Gleason score 9-10 and clinical stage) and biochemical-free survival (maximum percent of Gleason score 9-10, maximum percent overall and clinical stage) (each p<0.05). CONCLUSIONS: In the highly select subset of patients who are good surgical candidates and have the appropriate combination of preoperative variables postoperative findings are sufficiently favorable to justify radical prostatectomy.

Multiple cores of Gleason score 6 correlate with favourable findings at radical prostatectomy.

OBJECTIVE: To establish whether the good prognosis of Gleason score 6 (GS6) is maintained in the setting of multiple involved cores. PATIENTS AND METHODS: In total, 6156 men (from 1 April 2000 to 30 April 2007) with GS6 on biopsy underwent radical prostatectomy (RP) at our institution. The number of positive cores was correlated with the outcome at RP. RESULTS: More positive cores correlated with less organ-confined disease (P < 0.001), positive margins (P < 0.012), increasing RP grade (P < 0.001) and increased seminal vesicles/lymph node involvement (P = 0.012). For men with data available, the actuarial risk of being biochemically free of disease at 5 years was 93.2% when ≤6 cores were positive (812 men followed to 5 years) vs 89.1% if >6 cores were positive (41 men followed to 2 years) (P = 0.6). Although the predicted 'cure rate' of >75% probability of a tumour showing no evidence of biochemical recurrence at 10 years after RP was statistically different between cases with ≤6 vs >6 positive cores (P < 0.0001), the outcome in both groups was still favourable (90.5% vs 84%). Partin-like tables were generated factoring in the number of positive cores to predict organ-confined disease as a guide for urologists to perform nerve-sparing surgery. For example, with T1c disease, there was a ≥75% probability of organ-confined disease with one to three positive cores regardless of prostate-specific antigen (PSA) level, and the same probability was present with four to six positive cores and a PSA level of 0-4 ng/mL. CONCLUSION: A low Gleason score on biopsy is a powerful prognostic finding, such that this favourable outcome is maintained even in the setting of multiple positive cores with GS6.

Validation of the new classification of pauci-immune glomerulonephritis in a United States cohort and its correlation with renal outcome.

BACKGROUND: Renal biopsies provide important diagnostic and prognostic information in ANCA associated glomerulonephritis. A new classification for prognostication of pauci-immune glomerulonephritis (GN) based on four categories (Mixed, Crescentic, Sclerotic and Focal) was proposed by an international working group of renal pathologists (IWGRP). The goal of our study was to apply the proposed classification system to a United States cohort of vasculitis patients and determine the association of IWGRP class with estimated glomerular filtration rate (eGFR) at one year. METHODS: Seventy-six cases of pauci-immune glomerulonephritis diagnosed from 1995 to 2011 from a single center were identified for this retrospective study. Clinical data were collected by abstraction from medical records. Histology was reviewed by a pathologist and classified according to the new classification. MDRD formula was used to calculate eGFR. We correlated IWGRP class to renal function at presentation and at one year. ×2, ANOVA, and linear regression analysis were performed as appropriate. RESULTS: Renal biopsies were categorized as focal: n = 20, crescentic: n = 18, mixed: n = 27, sclerotic: n = 11. The baseline e-GFR was lowest in the crescentic class and highest in the focal class. In linear regression analysis investigating e-GFR at 1 year; age and baseline e-GFR were independent predictors of e-GFR at 1 year. CONCLUSIONS: The e-GFR at diagnosis and age were predictors of e-GFR at 1 year. Pathologic class at diagnosis may also be a helpful tool in risk stratification at diagnosis.

Restoring leptin signaling reduces hyperlipidemia and improves vascular stiffness induced by chronic intermittent hypoxia.

Chronic intermittent hypoxia (IH) during sleep can result from obstructive sleep apnea (OSA), a disorder that is particularly prevalent in obesity. OSA is associated with high levels of circulating leptin, cardiovascular dysfunction, and dyslipidemia. Relationships between leptin and cardiovascular function in OSA and chronic IH are poorly understood. We exposed lean wild-type (WT) and obese leptin-deficient ob/ob mice to IH for 4 wk, with and without leptin infusion, and measured cardiovascular indices including aortic vascular stiffness, endothelial function, cardiac myocyte morphology, and contractile properties. At baseline, ob/ob mice had decreased vascular compliance and endothelial function vs. WT mice. We found that 4 wk of IH decreased vascular compliance and endothelial relaxation responses to acetylcholine in both WT and leptin-deficient ob/ob animals. Recombinant leptin infusion in both strains restored IH-induced vascular abnormalities toward normoxic WT levels. Cardiac myocyte morphology and function were unaltered by IH. Serum cholesterol and triglyceride levels were significantly decreased by leptin treatment in IH mice, as was hepatic stearoyl-Coenzyme A desaturase 1 expression. Taken together, these data suggest that restoring normal leptin signaling can reduce vascular stiffness, increase endothelial relaxation, and correct dyslipidemia associated with IH.

Human Adenovirus 11 in 2 Renal Transplant Recipients: Suspected Donor-Derived Infection.

BACKGROUND: Human adenovirus (HAdV) infections can lead to high mortality in solid organ transplant (SOT) recipients, with rare reports of donor-derived infection. METHODS: Two renal transplant recipients with HAdV-11 infection who received kidneys from the same donor are described. Whole-genome sequencing (WGS) was performed. RESULTS: WGS showed 100% nucleotide sequence identity for the 2 HAdV-11 isolates. The patients presented with distinct clinical syndromes, and both were treated with brincidofovir. CONCLUSIONS: Donor-derived HAdV infection is presumed to be low; however, disseminated HAdV in SOT recipients can be severe, and clinicians should be aware of the clinical course and treatment options.

The Paris system for reporting urinary cytology improves correlation with surgical pathology biopsy diagnoses of the lower urinary tract.

INTRODUCTION: The current study seeks to compare both the original diagnoses (OD) and the updated Paris system diagnoses (PD) of urinary cytology specimens to the corresponding surgical pathology (biopsy) diagnoses (SD) to determine which diagnostic paradigm (OD vs PD) has a stronger correlation to the SD. DESIGN: 56 cases from 34 patients that had a malignant SD associated with a corresponding cytology specimen from the same location within up to 90 days of the biopsy procedure were selected. We reviewed the cytology specimens and assigned a PD to each case. We then compared each OD and each PD to the corresponding SD. Correspondence was defined as when the SD had the same result or equal weight as either cytopathologic diagnosis. RESULTS: Of the 47 cases with an available SD, the PD alone corresponded in 32%, both PD and OD corresponded in 26%, neither corresponded in 42%. The OD in isolation did not correspond to the SD in any cases, indicating superior correlation with the PD as compared to the OD (P = 0.0002). Of the 15 cases where the PD corresponded, 11/15 were from the lower tract and the remaining 4 were from the upper tract, indicating superior correlation with the PD in specimens from the lower urinary tract (P = 0.034). In the 27 cases where the PD alone and "both" the PD and the OD correlated to the SD, 9/27 were from the upper tract and 18/27 were from the lower tract, indicating further support for increased correlation between the cytopathology and biopsy diagnoses in the lower urinary tract above the upper tract (P = 0.032). CONCLUSION: When applied, the PD has a stronger correlation to the SD, particularly when the biopsies are from the lower urinary tract. Further study with more cases is required to support this significant association.

Development of CD3 cell quantitation algorithms for renal allograft biopsy rejection assessment utilizing open source image analysis software.

Renal allograft rejection diagnosis depends on assessment of parameters such as interstitial inflammation; however, studies have shown interobserver variability regarding interstitial inflammation assessment. Since automated image analysis quantitation can be reproducible, we devised customized analysis methods for CD3+ T-cell staining density as a measure of rejection severity and compared them with established commercial methods along with visual assessment. Renal biopsy CD3 immunohistochemistry slides (n = 45), including renal allografts with various degrees of acute cellular rejection (ACR) were scanned for whole slide images (WSIs). Inflammation was quantitated in the WSIs using pathologist visual assessment, commercial algorithms (Aperio nuclear algorithm for CD3+ cells/mm2 and Aperio positive pixel count algorithm), and customized open source algorithms developed in ImageJ with thresholding/positive pixel counting (custom CD3+%) and identification of pixels fulfilling "maxima" criteria for CD3 expression (custom CD3+ cells/mm2). Based on visual inspections of "markup" images, CD3 quantitation algorithms produced adequate accuracy. Additionally, CD3 quantitation algorithms correlated between each other and also with visual assessment in a statistically significant manner (r = 0.44 to 0.94, p = 0.003 to < 0.0001). Methods for assessing inflammation suggested a progression through the tubulointerstitial ACR grades, with statistically different results in borderline versus other ACR types, in all but the custom methods. Assessment of CD3-stained slides using various open source image analysis algorithms presents salient correlations with established methods of CD3 quantitation. These analysis techniques are promising and highly customizable, providing a form of on-slide "flow cytometry" that can facilitate additional diagnostic accuracy in tissue-based assessments.

Biomarker, Molecular, and Technologic Advances in Urologic Pathology, Oncology, and Imaging.

Urologic pathology is evolving rapidly. Emerging trends include the expanded diagnostic utility of biomarkers and molecular testing, as well as adapting to the plethora of technical advances occurring in genitourinary oncology, surgical practice, and imaging. We illustrate those trends by highlighting our approach to the diagnostic workup of a few selected disease entities that pathologists may encounter, including newly recognized subtypes of renal cell carcinoma, pheochromocytoma, and prostate cancer, some of which harbor a distinctive chromosomal translocation, gene loss, or mutation. We illustrate applications of immunohistochemistry for differential diagnosis of needle core renal biopsies, intraductal carcinoma of the prostate, and amyloidosis and cite encouraging results from early studies using targeted gene expression panels to predict recurrence after prostate cancer surgery. At our institution, pathologists are working closely with urologic surgeons and interventional radiologists to explore the use of intraoperative frozen sections for margins and nerve sparing during robotic prostatectomy, to pioneer minimally invasive videoscopic inguinal lymphadenectomy, and to refine image-guided needle core biopsies and cryotherapy of prostate cancer as well as blue-light/fluorescence cystoscopy. This collaborative, multidisciplinary approach enhances clinical management and research, and optimizes the care of patients with urologic disorders.

Granulomatous Inflammation of the Penis and Scrotum Following Application of Topical Cream.

Granulomas are collections of histiocytes that develop as an inflammatory response to bacterial and fungal infections, as well as foreign substances. We discuss here the case of a 49-year-old male who presented with a penile and scrotal mass with granulomatous inflammation, after application of a topical cream for enhancement of erectile function. While granuloma formation can often be seen with penile injections, this case presents the rare development of a foreign body granuloma after topical cream application on the penis and scrotum.