Clinical and Genetic Features of Autosomal Dominant Alport Syndrome: A Cohort Study.

RATIONALE & OBJECTIVE: Alport syndrome is a common genetic kidney disease accounting for approximately 2% of patients receiving kidney replacement therapy (KRT). It is caused by pathogenic variants in the gene COL4A3, COL4A4, or COL4A5. The aim of this study was to evaluate the clinical and genetic spectrum of patients with autosomal dominant Alport syndrome (ADAS). STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 82 families (252 patients) with ADAS were studied. Clinical, genetic, laboratory, and pathology data were collected. OBSERVATIONS: A pathogenic DNA variant in COL4A3 was identified in 107 patients (35 families), whereas 133 harbored a pathogenic variant in COL4A4 (43 families). Digenic/complex inheritance was observed in 12 patients. Overall, the median kidney survival was 67 (95% CI, 58-73) years, without significant differences across sex (P=0.8), causative genes (P=0.6), or type of variant (P=0.9). Microhematuria was the most common kidney manifestation (92.1%), and extrarenal features were rare. Findings on kidney biopsies ranged from normal to focal segmental glomerulosclerosis. The slope of estimated glomerular filtration rate change was-1.46 (-1.66 to-1.26) mL/min/1.73m2 per year for the overall group, with no significant differences between ADAS genes (P=0.2). LIMITATIONS: The relatively small size of this series from a single country, potentially limiting generalizability. CONCLUSIONS: Patients with ADAS have a wide spectrum of clinical presentations, ranging from asymptomatic to kidney failure, a pattern not clearly related to the causative gene or type of variant. The diversity of ADAS phenotypes contributes to its underdiagnosis in clinical practice.

Challenges of diagnosing homologous recombination deficiencies in metastatic prostate cancer: a six-year experience from a single institution.

PURPOSE: We evaluated the prevalence of homologous recombination deficiencies (HRD) to determine the efficacy of different techniques and clinical characteristics of patients. METHODS: This retrospective study included patients with metastatic prostate cancer who underwent molecular testing at our hospital between 2016 and 2022. We used tumor tissue, ctDNA, and lymphocytes for somatic or germline testing. We analyzed the clinical characteristics and survival outcomes. RESULTS: 144 patients were tested (113 somatic, 21 germline, and 10 both). Technical issues prevented the analysis of 23 prostatic samples (18.7%). 12 (8.3%) patients had HRD. BRCA2 was the most frequent mutation (66.7%). Patients with HRD were younger (57.5 years). Patients with BRCA mutations had poorer survival (31.9 vs 56.3 months, p = 0.048). CONCLUSION: In our institution, 8.3% of the patients had HRD. Tumor tissue analysis failed in 18.7% of tests. ctDNA analysis is an alternative detection method. BRCA mutations are correlated with poor prognosis.

Long-term outcomes of IgA nephropathy presenting with minimal or no proteinuria.

The long-term outcome of patients with IgA nephropathy who present with normal renal function, microscopic hematuria, and minimal or no proteinuria is not well described. Here, we studied 141 Caucasian patients with biopsy-proven IgA nephropathy who had minor abnormalities at presentation and a median follow-up of 108 months. None of the patients received corticosteroids or immunosuppressants. We reviewed renal biopsies using the Oxford classification criteria. In this sample, 46 (32%) patients had mesangial proliferation, whereas endocapillary proliferation, focal glomerulosclerosis, and tubulointerstitial abnormalities were uncommon. Serum creatinine increases >50% and >100% were observed in five (3.5%) patients and one (0.7%) patient, respectively; no patients developed ESRD. After 10, 15, and 20 years, 96.7%, 91.9%, and 91.9% of patients maintained serum creatinine values less than a 50% increase, respectively. Using Cox proportional hazards regression, the presence of segmental glomerulosclerosis was the only factor that significantly associated with a >50% increase in serum creatinine. Clinical remission occurred in 53 (37.5%) patients after a median of 48 months. Proteinuria>0.5 and >1.0 g/24 h developed in 21 (14.9%) and 6 (4.2%) patients, respectively. Median proteinuria at the end of follow-up was 0.1 g/24 h, with 41 (29.1%) patients having no proteinuria. At presentation, 23 (16.3%) patients were hypertensive compared with 30 (21.3%) patients at the end of follow-up; 59 (41.8%) patients were treated with renin-angiotensin blockers because of hypertension or increasing proteinuria. In summary, the long-term prognosis for Caucasian patients with IgA nephropathy who present with minor urinary abnormalities and normal renal function is excellent.

Correlation of X chromosome inactivation with clinical presentation of Fabry disease in a case report.

Fabry disease or also called Anderson-Fabry disease (FD) is a rare disease caused by pathogenic variants in the GLA gene, located on the X chromosome. This gene is involved in the metabolism of glycosphingolipids and its pathogenic variants cause a deficit or absence of α-galactosidase A causing the deposition of globotriaosylceramide throughout the body. Females have a variable phenotypic expression and a better prognosis than males. This is due to the X chromosome inactivation phenomenon. We present a clinical case of Fabry disease in a female with predominantly renal involvement and demonstrate how the X chromosome inactivation phenomenon is tissue dependent, showing preferential inactivation of the mutated allele at the renal level.

Parathyroid hormone-related protein is a hypertrophy factor for human mesangial cells: Implications for diabetic nephropathy.

Hypertrophy of human mesangial cells (HMC) is among the earliest characteristics in patients with diabetic nephropathy (DN). Recently, we observed the upregulation of parathyroid hormone (PTH)-related protein (PTHrP) in experimental DN, associated with renal hypertrophy. Herein, we first examined whether PTHrP was overexpressed in human DN, and next assessed the putative role of this protein on high glucose (HG)-induced HMC hypertrophy. As previously found in mice, kidneys from diabetic patients showed an increased tubular and glomerular immunostaining for PTHrP. In HMC, HG medium increased PTHrP protein expression associated with the development of hypertrophy as assessed by cell protein content. This effect was also induced by PTHrP(1-36). HG and PTHrP(1-36)-induced hypertrophy were associated with an increase in cyclin D1 and p27Kip1 protein expression, a decreased cyclin E expression, and the prevention of cyclin E/cdk2 complex activation. Both PTHrP neutralizing antiserum (α-PTHrP) and the PTH/PTHrP receptor antagonist (JB4250) were able to abolish HG induction of hypertrophy, the aforementioned changes in cell cycle proteins, and also TGF-ß1 up-regulation. Moreover, the capability of both HG and PTHrP(1-36) to induce HMC hypertrophy was abolished by α-TGFß1. These data show for the first time that PTHrP is upregulated in the kidney of patients with DN. Our findings also demonstrate that PTHrP acts as an important mediator of HG-induced HMC hypertrophy by modulating cell cycle regulatory proteins and TGF-ß1.

New role of the human equilibrative nucleoside transporter 1 (hENT1) in epithelial-to-mesenchymal transition in renal tubular cells.

Epithelial-to-mesenchymal transition (EMT) is an important pro-fibrotic event in which tubular epithelial cells are transformed into myofibroblasts. Nucleoside transporters (NT) are regulated by many factors and processes, some of which are involved in fibrosis, such as cytokines, inflammation, and proliferation. Equilibrative nucleoside transporter 1 (ENT1) has been proved to be the most widely expressed adenosine transporter. In that sense, ENT1 may be a key player in cell damage signaling. Here we analyze the role of human ENT1 (hENT1) in the EMT process in proximal tubular cells. Addition of the main inducer of EMT, the transforming growth factor-ß1, to HK-2 cells increased hENT1 mRNA and protein level expression. ENT1-mediated adenosine uptake was also enhanced. When cells were incubated with dipyridamole to evaluate the potential contribution of ENT1 to EMT by blocking its transport activity, EMT was induced. Moreover, the knock down of hENT1 with siRNA induced EMT and collagen production in HK-2 cells. Kidneys isolated from ENT1 knockout mice showed higher levels of interstitial collagen and α-SMA positive cells than wild-type mice. Our results point to a new potential role of hENT1 as a modulator of EMT in proximal tubular cells. In this sense, hENT1 could be involved in renal protection processes, and the loss or reduced expression of hENT1 would lead to an increased vulnerability of cells to the onset and/or progression of renal fibrosis.

Acute renal failure associated to paroxysmal nocturnal haemoglobinuria leads to intratubular haemosiderin accumulation and CD163 expression.

Decreased renal function has been observed in diseases with intravascular haemolysis, including paroxysmal nocturnal haemoglobinuria (PNH). However, the mechanisms via which haemoglobin enhances renal damage in this pathology are not fully known. We report a case of acute renal failure associated to PNH and extensive haemosiderin deposits in tubular cells. Renal biopsy also revealed a strong immunostaining of CD163 (a haemoglobin scavenger receptor expressed in macrophages) and oxidative stress markers (NADPH-p22 phox and haeme oxigenase-1) in areas with deposits of iron. This fact provides evidence for a pathogenic role for free haemoglobin in tubulointerstitial renal injury in human PNH disease.

[Lipid cell variant urothelial carcinoma of the renal pelvis. A case report and literature review]. / Carcinoma urotelial lipoideo de pelvis renal. Aportación de un nuevo caso y revisión de la literatura de esta variante de carcinoma urotelial.

There are many variants of urothelial carcinoma. One of the most infrequent is formed by cells with a lipid content and an adipose tissue appearance. Only 43 cases have been reported in the bladder, 2 in the renal pelvis and 1 case in the ureter. We present a third case in the renal pelvis; the patient is alive and free of disease 103 months post diagnosis.

Three cases of monoclonal gammopathy of renal significance after kidney transplantation. De novo C3 glomerulopathy. / Tres casos de gammapatía monoclonal de significado renal postrasplante renal: nefropatía c3 de novo.

Monoclonal gammopathy of renal significance includes all renal disorders caused by a monoclonal immunoglobulin secreted by a non-malignant B-cell clone. Patients with MGRS do not, by definition, meet criteria for multiple myeloma, with haematological disorders generally considered to be monoclonal gammopathy of undetermined significance. Nevertheless, the renal involvement can be serious and require specific treatment. Monoclonal gammopathy of renal significance is associated with a wide spectrum of disorders, including the recently discovered C3 glomerulopathy. Development of C3 glomerulopathy in the context of monoclonal gammopathy of renal significance after kidney transplantation is uncommon and very few cases have been published to date. We report on three cases of C3 glomerulopathy in the context of de novo monoclonal gammopathy after kidney transplantation.

Utility of a multiprobe fluorescence in situ hybridization assay in the detection of superficial urothelial bladder cancer.

We evaluated the performance of a multiprobe FISH (fluorescence in situ hybridization) assay for noninvasive detection of superficial urothelial carcinoma (UC) in the bladder, in comparison to urinary cytology. Voided urine samples from 74 patients with superficial UC were analyzed by both techniques. Urine samples from 19 patients with muscle-invasive tumors and from 19 healthy control subjects were also studied. For FISH analysis, labeled probes for chromosomes 3, 7, 9, and 17 were used to assess chromosomal abnormalities indicative of malignancy. We found a significant difference between the overall sensitivity of FISH and cytology in superficial UC detection (70.3 versus 35.1%, respectively; P < 0.0001). This significant difference was maintained when superficial UCs were broken down into low grade (52.8 versus 13.9%, respectively; P < 0.0005) and high grade (86.8 versus 55.3%, respectively; P < 0.0015) tumors. Overall specificity was 100% for cytology and 94.7% for FISH (difference not significant). Of patients with suspicious cytology, 69% were positive by FISH. Together, these findings suggest that FISH assay for chromosomes 3, 7, 9, and 17 has a higher sensitivity than cytology and a similar specificity in the detection of superficial UC--which could be useful for reducing some cystoscopies in the accurate follow-up usually performed in these patients.

Natural history of prostatic carcinoma: the pathologist's perspective.

The stem (basal) cells of prostate acini are considered the origin of prostate cancer. Between these cells and the final secretory cells, different intermediate or transit cells can be observed, and every one of them can evolve into malignant cells, explaining the biological variability of prostatic cancer. The exact changes between normal gland and prostatic intraepithelial neoplasia (PIN) are not yet known, but a post-inflammatory atrophy lesion is being studied in this respect. The PIN lesion is considered the pre-invasive change of prostatic cancer and its presence in needle biopsy is clinically used for follow-up of the patient. The progressive knowledge of the stromal invasion in prostate cancer (loss of some cell-cell adhesion molecules and expression of others) can be correlated with the Gleason grading system, and the molecular changes in the progression to androgen-independent carcinoma can be used as a prognostic marker in conjunction with the classical pathological markers.

Adhesion molecules expression as a potential marker of prostate cancer aggressivity. A TMA study of radical prostatectomy specimens.

Adhesion molecule disorders may be important in different cell control pathways, and consequently in neoplastic cell disorders. This paper will consider only some of the aspects of intercellular relationship. The main anchoring molecule of these two structures is E-cadherin, which is bound to a molecule complex (catenins and vinculin) that connects it to the actin of the cytoplasmatic cytoskeleton. This adhesion molecule complex maintains cell adhesion but it is also involved in differentiation phenomena and may be pathways of action of different growth factors. When we study the expression of E-cadherin according to the Gleason pattern, we verify progressive loss of the adhesion molecule as the Gleason grade increases (abnormal in 35% of Gleason < 7 score versus 75% in cases of Gleason > 7 score). This correlation reinforces the idea of using the expression of adhesion molecules as a prognostic factor. Considering the great interrelation between the various cell-cycle regulating systems, it is probable that an approach to this interweaving through regulation and de-regulation of the adhesion molecule expression may turn out to be one of the most useful pathways in the future.

Hepatic preconditioning after prolonged warm ischemia by means of S-adenosyl-L-methionine administration in pig liver transplantation from non-heart-beating donors.

BACKGROUND: This study ascertained the effect of S-adenosyl-L-methionine (SAMe) administration on the ischemia-reperfusion injury associated with pig liver transplantation from non-heart-beating donors (NHBDs) after prolonged warm ischemia. METHOD: Twenty-five animals underwent transplantation with an allograft from an NHBD. After donor cardiac arrest, cardiopulmonary bypass and normothermic recirculation (NR) were performed for 30 min. Ten animals were given SAMe during NR. Donors were cooled to 15 degrees C, and liver procurement was performed. RESULTS: SAMe reduced histologic liver damage 5 days after transplantation. The necrotic area affected 15.9%+/-14.5% of the liver biopsies in controls and 7.4%+/-9% in SAMe livers. Six of eight controls and only one of eight survivors in the SAMe group developed ischemic cholangitis. SAMe reduced apoptosis of hepatocytes 5 days after transplantation and apoptosis of sinusoidal endothelial cells at reperfusion and at 5 days. SAMe increased energy charge at the end of NR and favored the balance between adenosine and xanthine. It was also associated with higher portal blood flow (740+/-59.2 vs. 475.2+/-65.0 mL/min-1/m-2), hepatic hyaluronic acid extraction (132+/-72.2 vs. -205.8+/-64.6 microg/L), and lower levels of alpha-glutathione-S-transferase after reperfusion (2,601%+/-581% with respect to baseline vs. 6,488%+/-5,612%). CONCLUSION: SAMe administration during liver procurement from NHBDs prevents liver endothelial, parenchymal, and biliary tract damage. The protective role of SAMe may be partially mediated by the effect of adenosine during liver procurement.

Association of C4d deposition with clinical outcomes in IgA nephropathy.

BACKGROUND AND OBJECTIVES: Several studies have suggested that activation of the complement system is a contributing pathogenic mechanism in IgA nephropathy (IgAN). C4d staining is an inexpensive and easy-to-perform method for the analysis of renal biopsies. This study aimed to assess the clinical and prognostic implications of C4d staining in IgAN. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective cohort study included 283 patients with IgAN in 11 hospitals in Spain who underwent a renal biopsy between 1979 and 2010. The primary predictor was mesangial C4d staining. Secondary predictors included demographic, clinical, and laboratory characteristics, and Oxford pathologic classification criteria. The primary end point was the cumulative percentage of patients who developed ESRD, defined as onset of chronic dialysis or renal transplantation. C4d was analyzed by immunohistochemical staining using a polyclonal antibody. Kaplan-Meier and Cox proportional hazards analyses were performed to evaluate the effect of C4d staining on renal survival. RESULTS: There were 109 patients (38.5%) and 174 patients (61.5%) who were classified as C4d positive and C4d negative, respectively. Renal survival at 20 years was 28% in C4d-positive patients versus 85% in C4d-negative patients (P<0.001). Independent risk factors associated with ESRD were as follows: proteinuria (hazard ratio [HR] per every 1 g/d increase. 1.16; 95% confidence interval [95% CI], 1.03 to 1.31; P=0.01), eGFR (HR per every 1 ml/min per 1.73 m(2) increase, 0.96; 95% CI, 0.94 to 0.97; P<0.001), T2 Oxford classification (tubular atrophy/interstitial fibrosis, >50%; HR, 4.42; 95% CI, 1.40 to 13.88; P=0.01), and C4d-positive staining (HR, 2.45; 95% CI, 1.30 to 4.64; P=0.01). CONCLUSIONS: C4d-positive staining is an independent risk factor for the development of ESRD in IgAN. This finding is consistent with the possibility that complement activation is involved in the pathogenesis of this disease.

Carcinoma urotelial lipoideo de pelvis renal. Aportación de un nuevo caso y revisión de la literatura de esta variante de carcinoma urotelial / Lipid cell variant urothelial carcinoma of the renal pelvis. A case report and literature review

Múltiples son las variantes histológicas del carcinoma urotelial, la mayoría en carcinomas de alto grado, localmente avanzados. Una de las más infrecuentes es la formada por células epiteliales con contenido de lípidos y aspecto de tejido adiposo. De esta variante solo se han publicado 43 casos en vejiga, 2 en pelvis renal y un caso en uréter. Presentamos un tercer caso de pelvis renal. La paciente sigue viva y libre de enfermedad a los 103 meses de la nefroureterectomía. Se revisan los criterios diagnósticos y el impacto pronóstico

There are many variants of urothelial carcinoma. One of the most infrequent is formed by cells with a lipid content and an adipose tissue appearance. Only 43 cases have been reported in the bladder, 2 in the renal pelvis and 1 case in the ureter. We present a third case in the renal pelvis; the patient is alive and free of disease 103 months post diagnosis

Tres casos de gammapatía monoclonal de significado renal postrasplante renal: nefropatía c3 de novo / Three cases of monoclonal gammopathy of renal significance after kidney transplantation. De novo C3 glomerulopathy

La gammapatía monoclonal de significado renal incluye todas las enfermedades renales causadas por una inmunoglobulina monoclonal secretada por un clon de célula B no maligno. Por definición, los pacientes con gammapatía monoclonal de significado renal no cumplen criterios de mieloma múltiple y la alteración hematológica es generalmente considerada gammapatía monoclonal de significado incierto. No obstante, la dolencia que pueden causar a nivel renal puede ser importante, requiriendo un tratamiento específico. El espectro de la gammapatía monoclonal de significado renal es amplio, incluyendo una entidad reciente como la nefropatía C3. El desarrollo de una nefropatía C3 en el contexto de una gammapatía monoclonal de significado renal tras el trasplante renal no es frecuente y hasta el momento ha sido poco descrita. A continuación presentamos 3 casos de nefropatía C3 asociados a una gammapatía monoclonal de aparición de novo tras el trasplante renal

Monoclonal gammopathy of renal significance includes all renal disorders caused by a monoclonal immunoglobulin secreted by a non-malignant B-cell clone. Patients with MGRS do not, by definition, meet criteria for multiple myeloma, with haematological disorders generally considered to be monoclonal gammopathy of undetermined significance. Nevertheless, the renal involvement can be serious and require specific treatment. Monoclonal gammopathy of renal significance is associated with a wide spectrum of disorders, including the recently discovered C3 glomerulopathy. Development of C3 glomerulopathy in the context of monoclonal gammopathy of renal significance after kidney transplantation is uncommon and very few cases have been published to date. We report on three cases of C3 glomerulopathy in the context of de novo monoclonal gammopathy after kidney transplantation

Neoplasia intratubular testicular e infertilidad: azoospermia asociada a neoplasia intratubular testicular bilateral / Testicular intraepithelial neoplasia and infertility: azoospermia associated with bilateral testicular intraepithelial neoplasia

La neoplasia testicular intratubular es una lesión premaligna testicular asociada a tumores germinales primarios gonadales y extragonadales. La prevalencia de neoplasia testicular intratubular en pacientes infértiles llega al 2% en diferentes estudios. Presentamos el caso de un paciente azoospérmico con diagnóstico incidental de neoplasia testicular intratubular bilateral en la biopsia testicular realizada durante la recuperación quirúrgica de espermatozoides. En pacientes infértiles, las técnicas de recuperación espermática deben incluir el estudio anatomopatológico de parénquima testicular para descartar enfermedad maligna asociada. Los pacientes con alteración de la espermatogénesis tienen mayor riesgo de presentar otras alteraciones del desarrollo gonadal (neoplasias, hipogonadismo, entre otros) en el contexto de un síndrome de disgenesia testicular (AU)

Testicular intraepithelial neoplasia is a premalignant lesion associated to gonadal and extragonadal germ cell tumors. Testicular intraepithelial neoplasia prevalence in infertile men has reached 2% in some studies. This report presents the case of an azoospermic man with an incidental diagnosis of bilateral testicular intraepithelial neoplasia after testicular sperm extraction. In infertile men, sperm retrieving techniques have to include histological analysis of testicular tissue, to discard any chance of malignant component. Patients with spermatogenesis alterations have an increased risk to present other disruptions in gonadal development (neoplasms, hypogonadism, among others) in the context of testicular dysgenesis syndrome (AU)

Hipótesis patogénica del angiomiolipoma / Pathogenic hypothesis of angiomyolipoma. Its relationship with other injuries

Los carcinomas renales familiares tienen como una de sus principales características la multifocalidad y la bilateralidad. En las formas esporádicas del cáncer renal: Los carcinomas renales papilares son mucho más frecuentemente múltiples/bilaterales que los carcinomas de células claras. Los carcinomas de células claras multifocales tienen un mayor riesgo de bilateralidad asincrónica. Los carcinomas cromófobos con células de tipo oncocitoma son con mayor frecuencia múltiples y multifocales

Diet affect oxalic lithiasis patients, increasing the risk factors for stone formation. Upon completion of the metabolic study should give some dietary guidelines based on scientific data. Few studies have analyzed completely the oxalate content in foods of the human diet. It must be emphasized abundant fluid intake, reducing salt and animal protein, maintaining proper calcium intake. In this paper, some tables about oxalate content in various foods are attached. Most rich in oxalate (chard, spinach, cauliflower, tea, cocoa, kiwis) must be restricted

Multifocalidad del cáncer renal según subtipo histológico, tamaño tumoral y grado nuclear / Multifocality of renal cancer: histologic subtype, tumor size and nuclear grade

Los carcinomas renales familiares tienen como una de sus principales características la multifocalidad y la bilateralidad. En las formas esporádicas del cáncer renal: Los carcinomas renales papilares son mucho más frecuentemente múltiples/bilaterales que los carcinomas de células claras. Los carcinomas de células claras multifocales tienen un mayor riesgo de bilateralidad asincrónica. Los carcinomas cromófobos con células de tipo oncocitoma son con mayor frecuencia múltiples y multifocales (AU)

Diet affect oxalic lithiasis patients, increasing the risk factors for stone formation. Upon completion of the metabolic study should give some dietary guidelines based on scientific data. Few studies have analyzed completely the oxalate content in foods of the human diet. It must be emphasized abundant fluid intake, reducing salt and animal protein, maintaining proper calcium intake. In this paper, some tables about oxalate content in various foods are attached. Most rich in oxalate (chard, spinach, cauliflower, tea, cocoa, kiwis) must be restricted (AU)