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Naoyuki Fujita,1 Mitsuhiro Tambo,1 Takatsugu Okegawa,1 Eiji Higashihara,2 Kikuo Nutahara1 1Department of Urology, 2Department of Autosomal Dominant Polycystic Kidney Disease (ADPKD) Research, Kyorin University School of Medicine, Mitaka, Tokyo Purpose: Many physicians encounter confusion and difficulty in distinguishing testicular torsion (TT) from torsion of the appendix testis (TAT) in patients with acute scrotum because of the overlapping signs and symptoms. The objective of our study was to evaluate the clinical features and signs that can help distinguish TT from TAT. Patients and methods: We performed a retrospective study of patients with surgically confirmed TT and TAT at our institute from January 1990 to December 2013. Clinical findings, physical examination findings, climatic conditions, laboratory data, and color Doppler ultrasound (CDUS) findings were compared between the TT and TAT groups. Results: Seventy patients were included in this study (49 with TT and 21 with TAT). Patients with TT were significantly older than those with TAT (p < 0.001). The ambient temperature at onset was significantly lower in patients with TT than in patients with TAT (p = 0.038). Testicular swelling, high-riding testes, onset during sleep, high leukocyte counts, and high creatine phosphokinase levels were significantly more common in patients with TT than with TAT (p = 0.021, 0.032, 0.006, 0.003, and 0.043, respectively). Multivariate analysis showed that age and onset during sleep were significant independent factors for detection of TT. Eight patients (16.3%) underwent preoperative CDUS evaluation, and an absent or decreased blood signal in the involved testes was significantly correlated with the presence of TT (p = 0.018). Conclusion: In clinical features, age and onset during sleep might be helpful to distinguish TT from TAT. When supported by findings, urgent surgical exploration is warranted in patients with suspected TT based on symptoms and CDUS features. Keywords: acute scrotum, testicular torsion, torsion of appendix testis, color Doppler ultrasound

Hamazaki K, Higashihara E, Terachi T, et al. In Vivo 2006;20:397-401. The Study of EPA Effects on Prostate Cancer (SEEPC) Group has been conducting a clinical trial with patients who [...]

Introduction: Juxtaglomerular apparatus (JGA)-mediated homeostatic mechanism links to how sodium-glucose cotransporter 2 inhibitors (SGLT2is) slow progression of chronic kidney disease (CKD) and may link to how tolvaptan slows renal function decline in autosomal dominant polycystic kidney disease (ADPKD)., Area Covered: JGA-mediated homeostatic mechanism has been hypothesized based on investigations of tubuloglomerular feedback and renin-angiotensin system. We reviewed clinical trials of SGLT2is and tolvaptan to assess the relationship between this mechanism and these drugs., Expert Opinion: When sodium load to macula densa (MD) increases, MD increases adenosine production, constricting afferent arteriole (Af-art) and protecting glomeruli. Concurrently, MD signaling suppresses renin secretion, increases urinary sodium excretion, and counterbalances reduced sodium filtration. However, when there is marked increase in sodium load per-nephron, as in advanced CKD, MD adenosine production increases, relaxing Af-art and maintaining sodium homeostasis at the expense of glomeruli. The beneficial effects of tolvaptan on renal function in ADPKD may also depend on the JGA-mediated homeostatic mechanisms since tolvaptan inhibits sodium reabsorption in the thick ascending limb.The JGA-mediated homeostatic mechanism regulates Af-arts, constricting to relaxing according to homeostatic needs. Understanding this mechanism may contribute to the development of pharmacotherapeutic compounds and better care for patients with CKD.

Introduction: The effects of long-term and uninterrupted tolvaptan treatment on autosomal dominant polycystic kidney disease (ADPKD) are unclear. Therefore, a more than 3-year continuous treatment study was performed., Methods: From the Kyorin University cohort, 299 patients were surveyed and 179 patients were indicated for tolvaptan having a total kidney volume (TKV) ≥750 ml, TKV slope ≥5%/yr, and estimated glomerular filtration rate (eGFR) ≥15 ml/min per 1.73 m 2 . Among 179 patients, 118 patients consented to the study., Results: Retrospective pretreatment and prospective on-treatment periods had a median of 1.8 and 4.0 years, respectively. During the 5 treatment-years, the log 10 (TKV) slope/yr decreased from the pretreatment period ( P  < 0.0001) and the estimated height-adjusted TKV growth rate α (eHTKV-α, %/yr) decreased from baseline ( P  < 0.0001). The decline in eGFR improved in female patients ( P  < 0.0001), but not in males ( P  = 0.6321). Furthermore, during the 5 treatment-years, eGFR remained significantly better in the group with a percent decrease in eHTKV-α from baseline to the first treatment-year ≥ the median (2.94%) than in the group with a decrease <2.94%. The free-water clearance was higher in males than in females irrespective of treatment., Conclusion: The TKV growth rate decreased in 4 years with tolvaptan in both sexes. The insignificant effects of tolvaptan on the eGFR slope in males were likely due to androgen stimulation of cystogenesis and analytical difficulty of longitudinal changes in nonlinear trajectories of eGFR. The larger decrease in eHTKV-α in the first year was related to a better renal prognosis. The vasopressin-mediated water reabsorption was activated more in females than males irrespective of tolvaptan administration., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

Background: Adenosquamous carcinoma of the prostate (ASCP) is an extremely rare and aggressive prostate cancer variant, whose genomic characteristics have not been elucidated. Although liquid biopsy of circulating tumor cells (CTCs) is an emerging topic in oncology, no study has assessed CTCs in patients with ASCP., Case Presentation: A 76-year-old man presented with discomfort in his urethra. His prostate-specific antigen (PSA) level was 13.37 ng/mL. A computed tomography (CT) scan indicated a prostate mass with multiple lymph node and lung metastases. The patient underwent transurethral resection of the prostate and prostatic needle biopsy; both specimens demonstrated Gleason grade group 5 acinar adenocarcinoma of the prostate. Bone scintigraphy indicated bone metastasis in the ischium. Combined androgen blockade was implemented, and his serum PSA level rapidly decreased to 0.01 ng/mL. However, a CT scan 6 months after the initial diagnosis revealed worsening of the disease. The patient therefore underwent repeated prostatic needle biopsy; its specimen demonstrated prostatic adenocarcinoma together with squamous carcinoma components. As immunohistochemical analyses showed the tumor cells to be negative for CD56, chromogranin A, synaptophysin, and PSA, the definitive diagnosis was ASCP. Although the patient underwent chemotherapy (docetaxel and cabazitaxel), he died of the disease 3 months after the diagnosis of ASCP, or 13 months after the initial diagnosis of prostatic adenocarcinoma. His PSA values remained ≤ 0.2 ng/mL. CTCs from the patient's blood (collected before starting docetaxel) were analyzed and genomically assessed. It showed 5 cytokeratin (CK) + CTCs, 14 CK - CTCs, and 8 CTC clusters, per 10 mL. Next-generation sequencing identified a total of 14 mutations in 8 oncogenes or tumor suppressor genes: PIK3CB, APC, CDKN2A, PTEN, BRCA2, RB1, TP53, and CDK12. Of 14 mutations, 9 (64%) were detected on CK - CTCs and 5 (36%) were detected on CK + CTCs., Conclusions: This is the first report of CTC analysis and genomic assessment in ASCP. Although the prognosis of ASCP is dismal due to lack of effective treatment, genomic analysis of CTCs might lead to effective treatment options and improved survival., (© 2021. The Author(s).)

Objectives: the prevalence of intracranial aneurysms and arachnoid cysts is higher in patients with autosomal dominant polycystic kidney disease (ADPKD) than in the general population. A genotype correlation was reported for intracranial aneurysms, but it is unclear for arachnoid cysts. Therefore, the genotype correlation with intracranial aneurysms and arachnoid cysts was investigated in ADPKD., Materials and Methods: intracranial aneurysms and arachnoid cysts were screened by magnetic resonance imaging (MRI), and PKD genotypes were examined using next-generation sequencing for 169 patients with ADPKD., Results: PKD1-, PKD2- and no-mutation were identified in 137, 24 and 8 patients, respectively. Intracranial aneurysms and arachnoid cysts were found in 34 and 25 patients, respectively, with no significant difference in frequency. Genotype, sex, estimated glomerular filtration rate and age at ADPKD diagnosis significantly affected the age at brain MRI. The proportional hazard risk analyzed using the age at brain MRI adjusted by these four variables was 5.0-times higher in the PKD1 group than in the PKD2 group for arachnoid cysts (P = 0.0357), but it was not different for intracranial aneurysms (P = 0.1605). Arachnoid cysts were diagnosed earlier in the PKD1 group than in the PKD2 group (54.8 vs 67.7 years, P = 0.0231), but no difference was found for intracranial aneurysms (P = 0.4738) by Kaplan-Meier analysis., Conclusions: this study demonstrated the correlation between arachnoid cysts and PKD1 mutation. The reported association of arachnoid cysts with advanced renal disease may be due to the common correlation of these factors with PKD1 mutation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Although the albumin-to-globulin ratio (AGR) is a promising biomarker for various malignancies, few studies have investigated its prognostic significance for upper tract urothelial carcinoma (UTUC)., Methods: This retrospective study conformed to the REporting recommendations for tumour MARKer prognostic studies (REMARK) guideline. We reviewed 179 patients with UTUC who underwent radical nephroureterectomy at our institution between 2008 and 2018. Associations of preoperative clinicopathological factors, including the AGR, with cancer-specific survival (CSS) and overall survival (OS) were assessed. The Cox proportional hazards model was used for univariate and multivariable analyses. AGR was dichotomized as < 1.25 and ≥ 1.25, according to the most discriminatory cutoff determined from the receiver operating characteristic curve analysis., Results: During a median follow-up of 34 months after surgery, 37 patients died from UTUC and 13 died of other causes. The preoperative AGR significantly correlated with pathological T stage, pathological N stage, and adjuvant chemotherapy. Multivariate analyses demonstrated that a decreased (< 1.25) preoperative AGR was an independent poor prognostic factor for both CSS (hazard ratio [HR] = 2.81, P <  0.01) and OS (HR = 2.09, P <  0.05)., Conclusions: Preoperative AGR < 1.25 might serve as a useful prognostic marker for patients with UTUC undergoing radical nephroureterectomy.

Introduction: In the Mayo Imaging Classification (MIC) for autosomal dominant polycystic kidney disease (ADPKD), the height-adjusted total kidney volume (HtTKV) growth rate is estimated for classification. Estimated HtTKV slope, termed as eHTKV-α, is calculated by the equation [HtTKV at age t] = K(1+α/100) (t-A) , where K = 150 and A = 0 are used in MIC. If eHTKV-α is nearly stable during a standard-of-care period, the change in eHTKV-α from baseline can be used for estimation of the treatment effect on the HtTKV slope., Methods: The constancy of eHTKV-α (A = 0 and K = 150) was evaluated using 453 placebo-assigned subjects in the Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4 trial. A and K were sought out respectively by a converged pattern of regression lines of log10(HtTKV) plotted against age for subgroups divided according to MIC, and by change in eHTKV-α from baseline. A total of 239 standard-of-care patients from the Kyorin University Cohort (KUC) served as validation. Changes in eHTKV-α from baseline were evaluated in 809 tolvaptan-treated subjects in TEMPO 3:4., Results: In placebo-assigned subjects, eHTKV-α (A = 0 and K = 150) changed significantly from baseline at the third year. As regression lines of placebo-assigned subgroups converged around age 0, A was set as 0, which was confirmed by KUC. K = 130 was selected because of minimal change in eHTKV-α from baseline. The KUC validated the constancy of eHTKV-α (A = 0 and K = 130) but not that of eHTKV-α (A=0 and K=150). In tolvaptan-treated subjects, eHTKV-α remained significantly lower than baseline for 3 years., Conclusions: eHTKV-α (A = 0 and K = 130) was nearly stable from baseline through follow-up in standard-of-care adults. Treatment effects on the HtTKV slope can be estimated by changes in eHTKV-α from baseline., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Background: Tolvaptan was approved for the treatment of autosomal dominant polycystic kidney disease (ADPKD). However, the official indication of "rapidly progressive disease" is described differently in the clinical guidelines. We aim to define "rapidly progressive disease" by risk of ESRD, which is evaluated using estimated height-adjusted total kidney volume (HtTKV) growth rate., Methods: The risk of ESRD was retrospectively analyzed in 617 initially non-ESRD adults with ADPKD and observed with standard of care between 2007 and 2018. The estimated annual growth rate of the HtTKV, termed as eHTKV-α (%/year), is derived from the following equation: [HtTKV at age t] = K(1 + eHTKV-α/100)t, where K = 150 mL/m is used in Mayo Imaging Classification and K = 130 mL/m is proposed for individually stable eHTKV-α value from baseline. The accuracy of eHTKV-α to predict ESRD for censored ages was analyzed using time-dependent receiver-operating characteristic curves (ROC). The cutoff point of initially measured eHTKV-α to predict ESRD was assessed using Kaplan-Meier and Cox's proportional hazards models. Performance characteristics of the cutoff point for censored ages were calculated using time-dependent ROC and validated by the bootstrap method., Results: The area under the time-dependent ROC of eHTKV-α to predict ESRD at age 65 was 0.89 ± 0.04 (K = 130). The mean renal survival was less than 70 years at eHTKV-α ≥4.0%/year (K = 130). Mean renal survival was approximately 12 years shorter, and hazard ratio of ESRD was more than 5-time higher at this cutoff point than at lower point. Time-dependent sensitivity for age 65 and cutoff point of 4.0%/year (K = 130) was 93.4 ± 0.3%. Between cutoff points ≥4.0%/year (K = 130) and ≥3.5%/year (K = 150), there was no significant difference in performance characteristics and accuracy to predict ESRD., Conclusion: eHTKV-α well predicts ESRD. Initially, measured eHTKV-α ≥4.0%/year (K = 130) defines high-risk ESRD. Without additional conditions, a single eHTKV-α cutoff point identifies subjects that are most likely to benefit from tolvaptan., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Background: Autosomal dominant polycystic kidney disease is defined as an inherited disorder characterized by renal cyst formation due to mutations in the PKD1 or PKD2 gene, whereas tuberous sclerosis complex is an autosomal dominant neurocutaneous syndrome caused by mutation or deletion of the TSC2 gene. A TSC2/PKD1 contiguous gene syndrome, which is caused by a chromosomal mutation that disrupts both the TSC2 and PKD1 genes, has been identified in patients with tuberous sclerosis complex and severe early-onset autosomal dominant polycystic kidney disease. The tumor tissue of patients with breast cancer with contiguous gene syndrome has a high mutation burden and produces several neoantigens. A diffuse positive immunohistochemistry staining for cluster of differentiation 8 + in the T cells of breast cancer tissue is consistent with neoantigen production due to high mutation burden., Case Presentation: A 61-year-old Japanese woman who had been undergoing dialysis for 23 years because of end-stage renal failure secondary to autosomal dominant polycystic kidney disease was diagnosed as having triple-negative breast cancer and underwent mastectomy in 2015. She had a history of epilepsy and skin hamartoma. Her grandmother, mother, two aunts, four cousins, and one brother were also on dialysis for autosomal dominant polycystic kidney disease. Her brother had epilepsy and a brain nodule. Another brother had a syndrome of kidney failure, intellectual disability, and diabetes mellitus, which seemed to be caused by mutation in the CREBBP gene. Immunohistochemistry of our patient's breast tissue showed cluster of differentiation 8 and programmed cell death ligand 1 positivity., Conclusions: Programmed cell death ligand 1 checkpoint therapy may be effective for recurrence of triple-negative breast cancer in a patient with autosomal dominant polycystic kidney disease and tuberous sclerosis complex.

In the TEMPO 3:4 Trial, treatment with tolvaptan, a vasopressin V2 receptor antagonist, slowed the increase in total kidney volume and decline in estimated glomerular filtration rate (eGFR) in autosomal dominant polycystic kidney disease (ADPKD). We investigated whether plasma copeptin levels, a marker of plasma vasopressin, are associated with disease progression, and whether pre-treatment copeptin and treatment-induced change in copeptin are associated with tolvaptan treatment efficacy. This post hoc analysis included 1,280 TEMPO 3:4 participants (aged 18-50 years, estimated creatinine clearance ≥60 ml/min and total kidney volume ≥750 mL) who had plasma samples available at baseline for measurement of copeptin using an automated immunofluorescence assay. In placebo-treated subjects, baseline copeptin predicted kidney growth and eGFR decline over 3 years. These associations were independent of sex, age, and baseline eGFR, but were no longer statistically significant after additional adjustment for baseline total kidney volume. In tolvaptan-treated subjects, copeptin increased from baseline to week 3 (6.3 pmol/L versus 21.9 pmol/L, respectively). In tolvaptan-treated subjects with higher baseline copeptin levels, a larger treatment effect was noted with respect to kidney growth rate and eGFR decline. Tolvaptan-treated subjects with a larger percentage increase in copeptin from baseline to week 3 had a better disease outcome, with less kidney growth and eGFR decline after three years. Copeptin holds promise as a biomarker to predict outcome and tolvaptan treatment efficacy in ADPKD., (Copyright © 2019 International Society of Nephrology. All rights reserved.)