Maria Teresa Sciarrone Alibrandi

MicroRNA 193b-3p as a predictive biomarker of chronic kidney disease in patients undergoing radical nephrectomy for renal cell carcinoma

Background:A significant proportion of patients undergoing radical nephrectomy (RN) for clear-cell renal cell carcinoma (RCC) develop chronic kidney disease (CKD) within a few years following surgery. Chronic kidney disease has important health, social and economic impact and no predictive biomarkers are currently available. MicroRNAs (miRs) are small non-coding RNAs implicated in several pathological processes.Methods:Primary objective of our study was to define miRs whose deregulation is predictive of CKD in patients treated with RN. Ribonucleic acid from formalin-fixed paraffin embedded renal parenchyma (cortex and medulla isolated separately) situated >3 cm from the matching RCC was tested for miR expression using nCounter NanoString technology in 71 consecutive patients treated with RN for RCC. Validation was performed by RT–PCR and in situ hybridisation. End point was post-RN CKD measured 12 months post-operatively. Multivariable logistic regression and decision curve analysis were used to test the statistical and clinical impact of predictors of CKD.Results:The overexpression of miR-193b-3p was associated with high risk of developing CKD in patients undergoing RN for RCC and emerged as an independent predictor of CKD. The addition of miR-193b-3p to a predictive model based on clinical variables (including sex and estimated glomerular filtration rate) increased the sensitivity of the predictive model from 81 to 88%. In situ hybridisation showed that miR-193b-3p overexpression was associated with tubule-interstitial inflammation and fibrosis in patients with no clinical or biochemical evidence of pre-RN nephropathy.Conclusions:miR-193b-3p might represent a useful biomarker to tailor and implement surveillance strategies for patients at high risk of developing CKD following RN.

Deciphering Variability of PKD1 and PKD2 in an Italian Cohort of 643 Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary kidney disease. We analysed PKD1 and PKD2, in a large cohort of 440 unrelated Italian patients with ADPKD and 203 relatives by direct sequencing and MLPA. Molecular and detailed phenotypic data have been collected and submitted to the PKD1/PKD2 LOVD database. This is the first large retrospective study in Italian patients, describing 701 variants, 249 (35.5%) already associated with ADPKD and 452 (64.5%) novel. According to the criteria adopted, the overall detection rate was 80% (352/440). Novel variants with uncertain significance were found in 14% of patients. Among patients with pathogenic variants, in 301 (85.5%) the disease is associated with PKD1, 196 (55.7%) truncating, 81 (23%) non truncating, 24 (6.8%) IF indels, and in 51 (14.5%) with PKD2. Our results outline the high allelic heterogeneity of variants, complicated by the presence of variants of uncertain significance as well as of multiple variants in the same subject. Classification of novel variants may be particularly cumbersome having an important impact on the genetic counselling. Our study confirms the importance to improve the assessment of variant pathogenicity for ADPKD; to this point databasing of both clinical and molecular data is crucial.

La sindrome anemica-cardio-renale. Seconda parte: diagnostica

In Part One of this two-part series, the clinical and epidemiological aspects of the cardiorenal anemia syndrome (CRAS) were discussed. Anemia is a complication frequently associated with chronic heart failure (CHF) and chronic kidney disease (CKD). Part Two of this review focuses on the diagnostic elements of anemia in cardiorenal syndrome (CRS). Bone marrow biopsy remains the gold standard for the assessment of iron (Fe) stores. However, many other laboratory tests are available, both biochemical and hematological, that are less invasive, more practical and useful for the diagnosis and gradation of iron deficiency (ID). Biochemical tests are based on Fe metabolism and allow the identification of ID before the onset of anemia. Hematologic examinations, on the other hand, based on the morphologic characteristics of the red blood cells are more readily available. New tests are currently available for ID diagnosis before anemia is present. All of these tests are used to determine the type and cause of anemia in a patient with CRS. Unfortunately, there is no single test capable of establishing the diagnosis of ID with or without anemia, but it is necessary to resort to a combination of assessments adapted to the patient’s specific clinical situation. Indeed, every assessment aimed at evaluating the iron profile expresses a different aspect of each compartment of the total body Fe (deposit, transport, metabolic-functional, etc.). Using the various available tests improves diagnostic specificity and enhances differential diagnosis.

The cardiorenal anemia syndrome. Part one: epidemiology and clinical aspects

Anemia is a common complication associated with congestive heart failure (CHF) and chronic kidney disease (CKD), and is often reported as a component of the cardiorenal syndrome (CRS). The triad anemia, CHF and CKD has adverse prognostic implications that have led to the reformulation of the syndrome with the term “cardiorenal anemia syndrome” (CRAS). However, there is insufficient agreement about the definition of anemia in the CHF patient, probably due to the heterogeneity of the clinical criteria and the diversity of the patient populations in different studies. The evolution of drug therapy and technology (such as resynchronization of the left ventricle) has not stopped the increase in its incidence nor the associated health system costs. Unfortunately, the current guidelines do not provide specific recommendations for the adequate management of anemia in the cardiorenal patient. The pathophysiological mechanisms at the origin of anemia in CRS are complex and numerous. On the cardiovascular side the most important mechanisms are activation of the sympathetic and renin-angiotensin-aldosterone systems, antidiuretic hormone, and hemodilution, while those associated with CKD include reduction of the endogenous production of erythropoietin, chronic microinflammation, and iron deficiency. Consequently, anemia could represent a new clinical and therapeutic biomarker in CRS. A more comprehensive, 360-degree view, which stratifies the etiological, clinical and pathophysiological aspects, could significantly contribute to improving the prognosis of CRS patients.

Anemia in Patients with Chronic Kidney Disease: Current Screening and management Approaches

Anemia refers to an absolute reduction of the total number of circulating red blood cells (RBC), resulting in a reduction of hemoglobin (Hb) concentration. Anemia is a frequent complication in chronic kidney disease (CKD), and it is often accompanied by various clinical symptoms. The primary cause of anemia in CKD patients is the reduction in the erythropoietin production, which results in a decrease of signaling molecule that stimulates red blood cell production. Other possible causes of anemia in CKD include iron deficiency, inflammation, and the accumulation of uremic toxins. This chapter focuses the discussion on the strategy of the management of anemia in patients with CKD. Erythropoiesis-stimulating agents (ESAs) and adjuvant iron therapy represent the primary treatment for anemia in chronic kidney disease. The introduction of ESAs into clinical practice was a success goal, mediating an increase in hemoglobin concentrations without the risk for recurrent blood transfusions and improving quality of life substantially. Correspondence to: Rodolfo F Rivera, Division of Nephrology and Dialysis, San Gerardo Hospital, ASST Monza, Italy, Tel: +390392334304; E-mail: rodolfofrivera@gmail.com