Correction to: In search of potential predictors of erythropoiesis-stimulating agents (ESAs) hyporesponsiveness: a population-based study.

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In search of potential predictors of erythropoiesis-stimulating agents (ESAs) hyporesponsiveness: a population-based study.

BACKGROUND: Evidences show that around 20% of biosimilar or originator erythropoiesis-stimulating agents (ESAs) users are hyporesponsive. Controversial post-marketing data exist on the predictors of ESA hyporesponsiveness. The aim of this study was to identify predictors of ESA hyporesponsiveness in patients with chronic kidney disease (CKD) or cancer in clinical practice. METHODS: During the years 2009-2015, a multi-center, population-based, cohort study was conducted using claims databases of Treviso and Caserta Local Health Units (LHUs). All incident ESA users were characterized at baseline and the differences between the baseline hemoglobin (Hb) value, that is the Hb registered within 30 days prior to the first ESA dispensing (index date, ID) and each outcome Hb value (registered between 30 and 180 days after ID) were calculated and defined as delta Hb (ΔHb). Incident ESA users were defined as hyporesponsive if, during follow-up, they registered at least one ΔHb < 0 g/dL. Including all potential predictors of ESA hyporesponsiveness and stratifying by indication for use, univariate and multivariate binary logistic regression models and Receiver Operating Characteristic (ROC) curves were carried out. RESULTS: In general, 1080 incident ESA users (CKD: 57.0%; cancer: 43.0%) were identified. In CKD, predictors of ESA hyporesponsiveness were C-reactive protein (OR = 1.2, 95% CI: 1.0-1.5; P-value = 0.060) and high levels of baseline Hb (OR = 1.7, 95% CI: 1.2-2.2; P-value< 0,001), the latter being also predictor of ESA hyporesponsiveness in cancer (OR = 1.7, 95% CI: 1.1-2.4; P-value = 0.007). Both in CKD and in cancer, the type of ESA, biosimilar or originator, was not a predictor of ESA hyporesponsiveness. In CKD, concomitant use of iron preparations (OR = 0.3, 95% CI: 0.2-0.7; P-value = 0.002) and of high dosage of angiotensin-converting enzyme inhibitors/angiotensin II-receptor blockers (OR = 0.5, 95% CI: 0.3-0.9; P-value = 0.022) were protective factors against ESA hyporesponsiveness. CONCLUSIONS: The study confirmed traditional potential predictors of hyporesponsiveness to ESA. The use of biosimilar or originator ESA was not a predictor of hyporesponsiveness in an outpatient setting from two large Italian areas. A better knowledge of the predictors of ESA response would allow a better anemia management to improve patients' quality of life.

The Myth of Water and Salt: From Aquaretics to Tenapanor.

The impact of water intake has been studied in several renal diseases. For example, increasing water intake is useful to prevent primary and secondary nephrolithiasis. In autosomal dominant polycystic kidney disease, arginine vasopressin (AVP) is involved in the progression of the disease, and water intake could play a therapeutic role by inhibiting the synthesis of AVP, but its efficacy is still controversial. Conversely, the use of aquaretics, which are antagonists of AVP V2 receptors, results in the reduction of the increase rate of total kidney volume with a slower decline of glomerular filtration rate. In chronic kidney disease, AVP contributes to glomerular hyperfiltration, arterial hypertension, and synthesis of renin, resulting in renal sclerosis. Increased water intake could reduce AVP activation determining a potential protective effect on the kidney, but its efficacy has not yet been clearly demonstrated. On the other side, sodium and potassium play an important role in the control of arterial blood pressure and are involved in the development and progression of chronic kidney disease. Reduction of sodium intake and increase of potassium intake determine a decrease of arterial blood pressure with a beneficial effect on the kidney; however, adherence to sodium restriction is very poor. Regarding this, sodium-hydrogen exchanger isoform 3 inhibitors may reduce sodium absorption in the gut. The most recent sodium-hydrogen exchanger isoform 3 inhibitor, known as tenapanor, reduces extracellular fluid volume, left ventricular hypertrophy, albuminuria, and blood pressure in experimental studies and increases fecal loss of sodium in humans.

Novel avenues for treating diabetic nephropathy: new investigational drugs.

INTRODUCTION: At present, treatment of diabetic kidney disease (DKD) is still mainly based on drugs acting on glycemic and blood pressure control, as there is no validated therapy able to halt the progression of renal failure. Because of the high incidence of DKD, due to the increase of diabetes mellitus in general population, new therapeutic strategies are needed. Areas covered: We analysed ongoing and already completed clinical trials, from clinicaltrials.gov and PubMed, dealing with new therapies for DKD. Expert opinion: Among the drugs currently being explored, the most promising molecules are those that interfere with glucose-dependent pathways, in particular polyol, protein kinase, hexosamine and AGEs metabolic pathways, and impaired renal vascular regulation. One of the recent goals achieved by molecular biology is the development of monoclonal antibodies able to interfere with extracellular matrix accumulation and fibrosis. Other interesting therapies are under investigation and further studies with a greater number of patients will establish a better approach for diabetic nephropathy.

Pruritus and quality of life in renal transplant patients.

BACKGROUND: Pruritus has a negative impact on quality of life (QoL) in dialysis patients. The reversibility of this symptom after renal transplantation and its impact upon QoL has scarcely been studied in these patients. METHODS: Pruritus was evaluated by the Visual Analogue Scale (VAS), the Visual Rating Scale (VRS), and the Numerical Rating Scale (NRS) in 133 unselected renal transplant patients, 62 healthy subjects, and 29 hemodialysis patients. QoL was assessed by KDQOL-SF™ 1.3. The reversibility of pruritus was studied by applying retrospectively the VRS. RESULTS: The prevalence of pruritus by the VRS was 62% in hemodialysis patients, 32% in renal transplant patients, and 11% in healthy subjects (P<.001). The prevalence of pruritus among transplant patients was 32% by VRS and 38% by VAS and NRS. The prevalence of pretransplantation pruritus (68%) by the VRS recall questionnaire was higher than the prevalence of pruritus in the same patients after renal transplantation (32%, P<.01). Pruritus in transplant patients was associated with important dimensions of QoL, including social, emotional, and working limitations (P<.05 for the three comparisons). CONCLUSIONS: The prevalence of pruritus markedly reduces after renal transplantation but remains substantially higher than in the general population and impacts upon quality of life in these patients.

Renal biopsy: Still a landmark for the nephrologist.

Renal biopsy was performed for the first time more than one century ago, but its clinical use was routinely introduced in the 1950s. It is still an essential tool for diagnosis and choice of treatment of several primary or secondary kidney diseases. Moreover, it may help to know the expected time of end stage renal disease. The indications are represented by nephritic and/or nephrotic syndrome and rapidly progressive acute renal failure of unknown origin. Nowadays, it is performed mainly by nephrologists and radiologists using a 14-18 gauges needle with automated spring-loaded biopsy device, under real-time ultrasound guidance. Bleeding is the major primary complication that in rare cases may lead to retroperitoneal haemorrhage and need for surgical intervention and/or death. For this reason, careful evaluation of risks and benefits must be taken into account, and all procedures to minimize the risk of complications must be observed. After biopsy, an observation time of 12-24 h is necessary, whilst a prolonged observation may be needed rarely. In some cases it could be safer to use different techniques to reduce the risk of complications, such as laparoscopic or transjugular renal biopsy in patients with coagulopathy or alternative approaches in obese patients. Despite progress in medicine over the years with the introduction of more advanced molecular biology techniques, renal biopsy is still an irreplaceable tool for nephrologists.

Role of Vitamin D in Vascular Complications and Vascular Access Outcome in Patients with Chronic Kidney Disease.

Vitamin D has been known for a long time as a major factor involved in the calcium- phosphate balance and homeostasis, along with parathyroid hormone (PTH). While vitamin D effects on calcium and phosphate are fully known, recent studies attempted to link vitamin D status and cardiovascular diseases. The involvement of vitamin D on vascular remodeling is mediated by several mechanisms such as activation of renin-angiotensin-aldosterone system (RAAS), cell proliferation and anti-apoptotic cell pathways. This correlation is highlighted by the fact that the activated form of vitamin D (1,25 (OH)2 D3) can be synthesized by the same endothelial cells, due to the constitutive presence of endothelial 1α-hydroxylase. Vitamin D reduces the expression of angiotensin 2 receptor (AT2R) on the endothelial cell surface (AT2R), leading to a cascade of events that result in the synthesis of vasodilators, such as nitric oxide. The activation of vitamin D receptors (VDRs) on endothelial cells induces changes in the metabolic activity of the endothelium and is responsible for cell survival, proliferation and neoangiogenesis. Moreover, altered signaling of VDR due to gene polymorphisms has been demonstrated in patients with cardiac disorders and chronic kidney disease (CKD). Recently, vascular access outcome has been associated with vitamin D status. Future studies will help to better define the need of vitamin D supplementation for a better cardiovascular as well as vascular access outcome in patients with CKD.

The Management of Diabetes Mellitus in Patients with Chronic Kidney Disease: A Population-Based Study in Southern Italy.

BACKGROUND AND OBJECTIVES: Diabetes mellitus in patients with chronic kidney disease (CKD) is known as diabetic kidney disease (DKD). Pharmacological management of DKD is challenging due to reduced renal excretion of some antidiabetic drugs. The aim of this population-based study was to explore antidiabetic drug use in DKD patients from Southern Italy. METHODS: The Arianna database from Caserta Local Health Unit was used. Diabetic patients with incident CKD [first diagnosis date: index date (ID)] were identified by searching for specific ICD9-CM codes among hospital discharge diagnoses/procedures and/or indication of use associated with drug prescriptions. To evaluate any change in the use of antidiabetic drugs after the CKD diagnosis, the prevalence of antidiabetic drug use among DKD patients was calculated within 1 year prior to/after ID and after dialysis entry. A Kaplan-Meier analysis was used to assess the time to discontinuation of antidiabetic drugs after CKD diagnosis. The frequency of antidiabetic drugs contraindicated in renal disease in DKD patients was measured. RESULTS: Overall, 725 diabetic patients (mean age 72.8 ± 11.4 years) had incident CKD from 2006 to 2011. The use of combination antidiabetic drugs, biguanides and sulphonamides decreased by approximately 10, 7 and 5%, respectively, after the ID. The use of insulins increased by 10% after the ID and by 20% after entry into dialysis. The use of antidiabetic drugs not contraindicated in CKD decreased marginally after the diagnosis of CKD. CONCLUSION: In a general practice of Southern Italy the management of diabetes mellitus changed only marginally in newly diagnosed CKD patients, suggesting a therapeutic inertia on the part of prescribers.

[Periorbital purpura: a pathognomonic but late sign of AL amyloidosis]. / Porpora periorbitaria: un segnale patognomonico ma tardivo di amiloidosi AL.

INTRODUCTION: AL amyloidosis is the most common type of systemic amyloidosis and is caused by the deposition of an amyloidogenic protein composed of immunoglobulin light chains produced by a clonal population of plasma cells. CASE REPORT: We report the case of a 77-year-old woman with arterial hypotension, peripheral edema and renal failure. Electrocardiogram reveals low voltage on peripheral leads. Echocardiogram shows normal values for left ventricle size with increased wall thickness and cardiac wall reflectance with ground glass appearance. Serum immunofixation electrophoresis (IFE) is negative while urine IFE detects type monoclonal light chains. Abdominal Fat Pad biopsy is positive for Congo red with typical apple green birefringence after polarization under optical microscopy (OM) while ultrastructural analysis does not show presence of amyloid deposition. Two months later, the patient undergoes further worsening of general clinical condition and development of purpura in the periorbital area, at the base of the neck and in the anterior chest wall. DISCUSSION: This clinical case presents classic signs of AL amyloidosis, such as cardiac and renal involvement with the presence of a urine monoclonal component. Periorbital purpura is a pathognomonic sign of AL amyloidosis but it appears late. Final diagnosis is "AL amyloidosis with prevalent cardiac, renal and soft tissue involvement".

Nephro-oncology: a link in evolution.

A multidisciplinary approach represents the best method to interact with patients. Neoplastic and renal diseases are closely related to each other because of an increased risk of cancer among individuals with end-stage renal disease and because of the high prevalence of renal failure in cancer patients. Physicians should be able to know how to prevent and treat the possible complications which may appear during the course of neoplastic disease that may lead to kidney damage such as the Acute Tumor Lysis Syndrome, disorders of hydroelectrolitic balance, metabolic alterations in the calcium-phosphorus, anemia, interstitial and glomerular impairment due to chemotherapy. It is very important to know patients' renal function and directly monitor it, before and during treatment, using formulas for estimating glomerular filtration rate (GFR) and above all, specific biomarkers are more early and sensitive than the increase of creatinine, like neutrophil gelatinase-associated lipocalin. Additionally, physician should consider that alteration of GFR or substitutive renal treatments severely influence dosage of tumor markers and it could lead to wrong diagnosis of cancer. The aim of this article is to provide a review of problems related to cancer relevant in the development of renal failure and try to define the best therapeutic strategies to cope with possible kidney imbalances induced by cancer or its treatment.

Semaphorin 3A serum levels are influenced by haemodialysis: what clinical significance?

AIM: Semaphorin 3A urinary levels represent an early, predictive biomarker of acute kidney injury and positively correlate with albumin-to-creatinine ratio and serum creatinine in hypertensive patients with chronic kidney disease. Our purpose has been to evaluate semaphorin 3A serum levels in a cohort of haemodialysis (HD) patients, the influence of a single HD session on its concentrations, and the potential correlation with clinical and biochemical parameters. METHODS: We enrolled 18 patients receiving HD with Acetate-Free Biofiltration technique and 16 healthy subjects as controls. Peripheral venous blood samples were obtained from patients at different intervals: start of dialysis (pre-HD), middle, and end of the treatment (post-HD). We also collected dialysate samples by the Quantiscan monitoring system (Hospal, Bologna, Italy). RESULTS: Semaphorin 3A was significantly lower in HD patients at baseline compared to controls (median 19.50 (interquartile range 1.00-65.00) versus 97.50 (23.50-161.00) ng/mL, P = 0.0237). A statistically significant reduction was seen during a single HD session (from 19.50 (1.00-65.00) to 0.86 (0.82-4.21) ng/mL, P < 0.0001), with a reduction ratio of 65.92 ± 33.51%. The median concentration in dialysate was 54.00 (15.00-102.00) ng/mL. Pre-HD values were directly related to serum vitamin D (r = 0.872; P = 0.001) and inversely correlated with calcium levels (r = -0.426; P = 0.012) and calcium × phosphate product (r = -0.422; P = 0.0252). CONCLUSION: Semaphorin 3A removal during HD may be clinically relevant due to its involvement in different aspects of cell physiology and in bone remodelling. Semaphorin 3A both inhibits osteoclastic bone reabsorption and increases osteoblastic new bone formation, thus playing a dual osteoprotective role.