Yolanda Arce

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.

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.

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.

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‐β1, 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. J. Cell. Physiol. 227: 1521–1528, 2012.

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‐β1 up‐regulation. Moreover, the capability of both HG and PTHrP(1–36) to induce HMC hypertrophy was abolished by α‐TGFβ1. 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‐β1. J. Cell. Physiol. 227: 1980–1987, 2012.

Aplicación clínica de las actuales clasificaciones del cáncer renal

Resumen De forma ideal la finalidad de las clasificaciones de las neoplasias es el reconocer grupos homogeneos de evolucion y pronostico y si es posible de igual tratamiento. Este es el motivo por el que de forma sistematica se van revisando y puliendo a traves de las nuevas metodologias. En el cancer renal la discriminacion de diferentes entidades ha sido relativamente rapida ya que los nuevos hallazgos geneticos y moleculares han reafirmado los criterios morfologicos de los distintos tipos celulares, y posiblemente se estan abriendo nuevas vias terapeuticas. Con la actual clasificacion de la oms se reconocen subtipos con un excelente pronostico (carcinoma renal quistico multilocular, carcinoma papilar renal de tipo 1, carcinoma mucinoso tubular y fusocelular), otros muy agresivos (carcinoma de ductos colectores de bellini, carcinoma medular) y que la transformacion sarcomatoide, aun en pequenas areas, tiene un impacto negativo sobre el pronostico. se han reconocido los carcinomas renales asociados a translocaciones cromosomicas (fusion genetica tfe3 o tfeb) propios de la infancia y las distintas formas de carcinoma renal familiar. en cuanto a la clasificacion de la uicc, hay una serie de aspectos en controversia (tamano, invasion venosa, invasion microvascular, invasion del tejido adiposo del seno renal) que tambien son comentados, ya que quizas en un futuro proximo pueden haber modificaciones del tnm

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.

Early Macrophage Infiltration and Sustained Inflammation in Kidneys From Deceased Donors Are Associated With Long-Term Renal Function.

Kidney transplants from living donors (LDs) have a better outcome than those from deceased donors (DDs). Different factors have been suggested to justify the different outcome. In this study, we analyzed the infiltration and phenotype of monocytes/macrophages and the expression of inflammatory and fibrotic markers in renal biopsy specimens from 94 kidney recipients (60 DDs and 34 LDs) at baseline and 4 months after transplantation. We evaluated their association with medium‐ and long‐term renal function. At baseline, inflammatory gene expression was higher in DDs than in LDs. These results were confirmed by the high number of CD68‐positive cells in DD kidneys, which correlated negatively with long‐term renal function. Expression of the fibrotic markers vimentin, fibronectin, and α–smooth muscle actin was more elevated in biopsy specimens from DDs at 4 months than in those from LDs. Gene expression of inflammatory and fibrotic markers at 4 months and difference between 4 months and baseline correlated negatively with medium‐ and long‐term renal function in DDs. Multivariate analysis point to transforming growth factor‐β1 as the best predictor of long‐term renal function in DDs. We conclude that early macrophage infiltration, sustained inflammation, and transforming growth factor‐β1 expression, at least for the first 4 months, contribute significantly to the difference in DD and LD transplant outcome.

Usefulness of the present renal cell carcinoma classifications

The purpose of classifying neoplasias is to recognize groups with similar progress and prognosis and, if possible, receiving the same treatment. This is why those classifications are systematically being submitted to review and improvement through the new technologies. Differentiation of various entities in renal cancer has been comparatively fast, as the new genetic and molecular discoveries have confirmed the morphologic criteria of the different cell types, thus making it possible to open new therapeutic pathways. Using the current WHO classification we recognize subtypes with excellent prognosis (Multilocular cystic renal carcinoma, Type I renal papillary carcinoma, Tubular and fusocellular mucinous carcinoma), other very aggressive ones (Bellinis collecting duct carcinoma, Medullary carcinoma), and also that the sarcomatoid transformation, even in small areas, impacts the prognosis negatively. Childhood-characteristic renal carcinomas associated with chromosome translocations have been recognized (genetic fusion TFE3 or TFEB), as well as the family forms of renal carcinoma. Regarding the UICC (International Union Against Cancer) classification, there are a series of aspects under argument (size, venous invasion, microvascular invasion, invasion of the adipous tissue of the renal sinus) that shall be discussed too, since it is possible that some modifications of the TNM might occur in the near future.

Biomarkers: New Tool to Detect Subclinical Inflammation?

Introduction Nowadays the gold standard test to detect kidney allograft inflammation is kidney biopsy. Because of subclinical inflammation has a very important roll on long term allograft survival some groups are performing follow-up biopsies to detect this inflammation early and to individualize the immunosuppressive treatment. Inflammation urinary biomarkers can become a new non invasive tool to detect this subclinical inflammation early. The aim of our work is to study the correlation between different subclinical lesions in follow-up biopsies and urinary biomarkers (miRNA-155, miRNA-210 and miRNA-142) Materials and Methods Prospective study where we have included kidney transplant (KT) patients from April 2014 until May 2015. We have determined in urine these biomarkers: miRNA-155, miRNA-210 and miRNA-142 one week after KT and one, two, three and six months after KT. We have performed follow-up biopsies at 4th month after KT and we have analysed the presence of tubulitis, interstitial infiltrate, arteritis and IFTA. Lastly we have correlationed these findings with urinary biomarkers levels. Results We have included 25 recipients from a first KT, all of them with low immunological risk. 60% man. Average age 45 years. 76% recipients from living donor. Average time on dyalisis: 10 months (50% preemptive kT). Induction immunosuppressive treatment: Basiliximab (two doses), tacrolimus, sodic micophenolate and prednisone. Average seric creatinine at 4 month after KT: 100umol/L. Anatomo-pathologic findings: 4% of biopsies with some degree of tubulitis, 63% with some degree of interstitial infiltrate, 9% with some degree of arteritis and 18% with some degree of IFTA. Correlation analysis: miRNA-155 levels are significantly higher in the patients with tubulitis. miRNA-142 levels are significantly higher in the patients with tubulitis, in the patients with arteritis and in the patients with interstitial infiltrate. miRNA-210 levels are significantly lower in the patients with tubulitis and in the patients with arteritis. There isn’t correlation between some biomarker and the presence of IFTA. Conclusion Urinary biomarkers can become in a future a new tool to detect subclinical inflammation early and could replace follow-up kidney biopsies. In this study, mi-RNA 142 would be the most associated with the presence of subclinical inflammation. On the other hand, tubulitis would be the lesion most detected for biomarkers. Are necessary more studies to confirm these results.