Acute Kidney Injury and Sepsis after Cardiac Surgery: The Roles of Tissue Inhibitor Metalloproteinase-2, Insulin-like Growth Factor Binding Protein-7, and Mid-Regional Pro-Adrenomedullin.

BACKGROUND: Identifying a panel of markers detecting kidney injury before the glomerular filtration rate reduction is a challenge to improving the diagnosis and management of acute kidney injury (AKI) in septic patients. This study evaluated the roles of tissue inhibitor metal proteinase-2, insulin growth factor binding protein-7 (TIMP2*IGFBP7), and mid-regional pro-adrenomedullin (MR-proADM) in patients with AKI. PATIENTS AND METHODS: This study was prospectively conducted in an intensive care unit (ICU) enrolling 230 patients who underwent cardiac surgery. Biomarkers were evaluated before and after 4 h of the cardiac surgery. RESULTS: Whereas urine and creatinine alterations appeared at 23.2 (12.7-36.5) hours after cardiac surgery, urinary TIMP2*IGBP7 levels were higher at 4 h in AKI patients (1.1 ± 0.4 mg/L vs. 0.08 ± 0.02 mg/L; p < 0.001). Its concentration > 2 mg/L increases AKI risk within the following 24 h, clearly identifying the population at high risk of renal replacement therapy (RRT). In patients with sepsis, MR-proADM levels were 2.3 nmol/L (0.7-7.8 nmol/L), with the highest values observed in septic shock patients (5.6 nmol/L (3.2-18 nmol/L)) and a better diagnostic profile than procalcitonin and C-reactive protein to identify septic patients. MR-proADM values > 5.1 nmol/L and urine TIMP2*IGBP7 levels > 2 mg/L showed a significantly faster progression to RRT, with a mean follow-up time of 1.1 days. CONCLUSIONS: TIMP2*IGBP7 and MR-proADM precociously diagnose AKI in septic patients after cardiac surgery, giving prognostic information for RRT requirement.

The Switch from Ferric Gluconate to Ferric Carboxymaltose in Hemodialysis Patients Acts on Iron Metabolism, Erythropoietin, and Costs: A Retrospective Analysis.

Background and Objectives: Iron deficiency and anemia characterize patients on chronic hemodialysis (HD). Available intravenous iron agents, such as ferric gluconate (FG) and ferric carboxymaltose (FCM), vary in dosing regimens and safety profiles. The aim of the present study was to analyze the modification of the iron status, the correction of anemia, and the economic implications after the shift from FG to FCM therapy in chronic HD patients. We evaluated, during the study, the variations in iron metabolism, assessing ferritin and transferrin saturation, erythropoietin-stimulating agent (ESA) doses and the number of administrations, the effects on anemic status, and consequent costs. Materials and Methods: A retrospective study was performed with a follow-up period of 24 months, enrolling forty-two HD patients. The enrolment phase started in January 2015, when patients were treated with iv FG, and continued until December 2015, when FG was discontinued, and, after a wash-out period, the same patients were treated with FCM. Results: The iron switch reduced the administered dose of ESA by 1610.500 UI (31% of reduction; p < 0.001) during the entire study period and reduced the erythropoietin resistance index (ERI) (10.1 ± 0.4 vs. 14.8 ± 0.5; p < 0.0001). The FCM group had the highest percentage of patients who did not require ESA treatment during the study period. The FCM patients were characterized by higher levels of iron (p = 0.04), ferritin (p < 0.001), and TSAT levels (p < 0.001) compared to the FG patients. The annual cost during FG infusion was estimated at EUR 105,390.2, while one year of treatment with FCM had a total cost of EUR 84,180.7 (a difference of EUR 21,209.51 (20%), saving EUR 42.1 per patient/month (p < 0.0001). Conclusions: FCM was a more effective treatment option than FG, reducing ESA dose requirements, increasing Hb levels, and improving iron status. The reduced ESA doses and the decreased number of patients needing ESA were the main factors for reducing overall costs.

Tolvaptan resistance is related with a short-term poor prognosis in patients with lung cancer and syndrome of inappropriate anti-diuresis.

Purpose: Tolvaptan (TVP), a vasopressin receptor antagonist, represents a therapeutic option in the syndrome of inappropriate anti-diuresis (SIAD). The aim of this study was to evaluate the effect of TVP to treat and solve hyponatremia in oncologic patients. Methods: 15 oncologic patients who developed SIAD have been enrolled. Patients receiving TVP belonged to group A, whereas group B was characterized by hyponatremic patients treated with hypertonic saline solutions and fluid restriction. Results: In group A, the correction of serum sodium was achieved after 3.7±2.8 days. In group B, the target levels were obtained more slowly, after 5.2±3.1 days (p: 0.01) than in group A. The hospital stay and incidence of re-hospitalization were higher in group B than in group A. In this latter, 37% of patients had hyponatremic relapses, notwithstanding the progressive increase of doses from 7.5 to 60 mg per day of TVP, revealing a complete lack of response to TVP. In these patients, a growth of tumor mass or new metastatic lesions has been revealed. Conclusion: TVP improved hyponatremia more efficiently and stably than hypertonic solutions and fluid restrictions. Positive consequences have been obtained about the rate of chemotherapeutical cycles concluded, hospital stay, rate of relapse of hyponatremia, and re-hospitalization. Our study also suggested potential prognostic information that could be deduced from TVP patients, in whom sudden and progressive hyponatremia occurred, despite TVP dosage increase. A re-staging of these patients to rule out tumor mass growth or new metastatic lesions is suggested.

Therapeutic Management of Children with Vesicoureteral Reflux.

Contrasting data refer to therapies for vesicoureteral reflux (VUR), such as surgical treatments and continuous antibiotic prophylaxis (CAP). This study evaluated the effectiveness of these approaches in children with VUR, analyzing the recurrence of febrile urinary tract infections (UTIs) and the resolution of VUR after the treatment. A total of 350 pediatric patients underwent contrast-enhanced voiding urosonography (ceVUS) to diagnose a VUR, whereas renal scintigraphy evaluated potential scars. After 12 months from the treatment, the VUR, the relapse of febrile UTIs, and reflux-related nephropathy were analyzed. Twenty-seven children had recurrent febrile UTIs after surgical therapy, with a greater rate of relapses observed in III and V VUR grades. Thirteen patients who underwent surgery had scars, independently of VUR grades and gender, with evidence of chronic renal failure at the end of the follow-up period. A total of 140 subjects were treated with CAP, and 30% of them continued to suffer from febrile UTIs. Ninety-five patients with VUR underwent ceVUS after 12 months, with persistent reflux in fifty-two patients. All of them had severe VUR, correlating with the age at diagnosis and gender. CAP therapy prevented scarring better than surgery, especially in children with III and V grades of VUR. A late onset of VUR or VUR involving neonatal patients is rarely a reversible process. This study identified predictors of success or failure of surgical or CAP therapies, evaluating the relapse of UTIs or persistent reflux after the treatment and giving prognostic information in children with VUR.

Fabry disease and kidney involvement: starting from childhood to understand the future.

The accumulation of globotriaosylceramide (Gb-3) in multiple organs, such as the heart, kidney, and nervous system, due to mutations in the galactosidase alpha (GLA) gene, represents the key point of Fabry disease (FD). The common symptoms appear in childhood or adolescence, including neuropathic pain, angiokeratoma, acroparesthesia, and corneal opacities. A multi-organ involvement induces a significant deterioration in the quality of life with high mortality in adulthood. The accumulation of Gb-3 involves all types of kidney cells beginning at fetal development, many years before clinical manifestations. A decline in the glomerular filtration rate is rare in children, but it can occur during adolescence. Pediatric patients rarely undergo kidney biopsy that could assess the efficacy of enzyme replacement therapy (ERT) behind its diagnostic role. To date, diagnosis is achieved by detecting reduced α-Gal-A activity in leukocytes and plasma, allowing for the early start of ERT. This review focuses on pediatric kidney involvement in FD, analyzing in depth its diagnostic processes and treatment options.

Febrile Urinary Tract Infections in Children: The Role of High Mobility Group Box-1.

BACKGROUND: Differentiating between febrile lower urinary tract infection (LUTI) and acute pyelonephritis (APN) is crucial for prompt clinical management. We investigated whether the high mobility group box-1 (HMGB1) could be a useful biomarker in differentiating between LUTI or APN. METHODS: We enrolled seventy-four pediatric patients with suspected LUTI/APN, according to the positive or negative renal scintigraphy (DMSA) scan. If the first DMSA findings were abnormal, a second DMSA was performed after six months. Voiding cystourethrography ruled out vesicoureteral reflux (VUR). RESULTS: Higher serum (s) HMGB1 levels characterized the APN group when compared to LUTI patients (13.3 (11.8-14.3) versus 5.9 (5.2-6.8) ng/mL, p: 0.02), whereas there were no differences according to urine (u) HMGB1 values. sHMGB1 correlated with C-reactive protein (CRP) levels (ß = 0.47; p: 0.02). Receiver operating characteristic curves identified the best diagnostic profile for detecting APN. sHMGB1 area under the curve was different from CRP (p: 0.01) and white blood cells (p: 0.003). After multivariate analyses, VUR (HR:4.81) and sHMGB1 (HR 1.16; p: 0.006) were independently associated with the risk of renal scarring development. CONCLUSIONS: sHMGB1 could represent a marker to differentiate APN from LUTI. Measurement of sHMGB1 could select children for early intervention or long-term follow-up.

Erythropoiesis and chronic kidney disease-related anemia: From physiology to new therapeutic advancements.

Erythropoiesis is triggered by hypoxia and is strictly regulated by hormones, growth factors, cytokines, and vitamins to ensure an adequate oxygen delivery to all body cells. Abnormalities in one or more of these factors may induce different kinds of anemia requiring different treatments. A key player in red blood cell production is erythropoietin. It is a glycoprotein hormone, mainly produced by the kidneys, that promotes erythroid progenitor cell survival and differentiation in the bone marrow and regulates iron metabolism. A deficit in erythropoietin synthesis is the main cause of the normochromic normocytic anemia frequently observed in patients with progressive chronic kidney disease. The present review summarizes the most recent findings about each step of the erythropoietic process, going from the renal oxygen sensing system to the cascade of events induced by erythropoietin through its own receptor in the bone marrow. The paper also describes the new class of drugs designed to stabilize the hypoxia-inducible factor by inhibiting prolyl hydroxylase, with a discussion about their metabolism, disposition, efficacy, and safety. According to many trials, these drugs seem able to simulate tissue hypoxia and then stimulate erythropoiesis in patients affected by renal impairment. In conclusion, the in-depth investigation of all events involved in erythropoiesis is crucial to understand anemia pathophysiology and to identify new therapeutic strategies, in an attempt to overcome the potential side effects of the commonly used erythropoiesis-stimulating agents.

High mobility group box 1 and tumor growth factor ß: useful biomarkers in pediatric patients receiving peritoneal dialysis.

BACKGROUND: Peritonitis, the most important limitation of peritoneal dialysis (PD), could be detected by biomarkers in dialysate effluent, representing a noninvasive method to indirectly assess the peritoneum status. The aim of our study was to test high mobility group box 1 (HMGB1) in PD patients, evaluating its role as precocious marker of peritoneum damage during peritonitis. Transforming growth factor (TGF)-ß was correlated with peritoneal transport characteristics. METHODS: Six patients, treated by ambulatory PD, were enrolled. Samples were collected at the onset of peritonitis (T1) and every day until its resolution (T-end). Serum (s) and peritoneal (p) white blood cell (WBC) count was also evaluated. Peritoneal Equilibration Test evaluated the filter activity of peritoneum. RESULTS: In patients with acute peritonitis, the highest serum and peritoneal HMGB1 values (64 ± 3.6 and 70 ± 5.3 ng/mL, respectively) were assessed, with a progressive decrease of their levels at the resolution time (T-end: sHMGB1:36 ± 2.5; pHMGB1:30.5 ± 7.0 ng/mL). While no differences of sWBC and pWBC were observed between baseline and T-end values, pHMGB1 levels remained higher at T-end than those observed at T0 (pHMGB1:30.5 ± 7.0 versus 6.9 ± 3.6; p < 0.0001). TGF-ß levels were higher in patients with low peritoneal permeability than in medium or high transporter patients (81 ± 15.5 versus 24.3 ± 7.5 pg/mL; p = 0.01). An inverse correlation was found between TGF-ß levels and dialysate/plasmatic creatinine values (r = -0.83; p = 0.03). CONCLUSION: HMGB1 represents a useful biomarker for peritoneum evaluation in PD patients. A prognostic role of this alarmin, as a marker of response to therapy, could be hypothesized. TGF-ß could predict the peritoneal transport status and dialysis technique adequacy.

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.

Phosphate binders for the treatment of chronic kidney disease: role of iron oxyhydroxide.

Chronic kidney disease-mineral bone disorder is frequent in patients with renal failure. It is characterized by abnormalities in mineral and bone metabolism with resulting hyperphosphatemia, low serum vitamin D, secondary hyperparathyroidism, altered bone morphology and strength, higher risk of bone fractures, and development of vascular or other soft tissue calcifications. Besides the recommendation to reduce phosphorus dietary intake, many drugs are currently available for the treatment of calcium/phosphate imbalance. Among them, phosphate binders represent a milestone. Calcium-based binders (calcium carbonate, calcium acetate) are effective in lowering serum phosphate, but their use has been associated with an increased risk of hypercalcemia and calcifications. Calcium-free binders (sevelamer hydrochloride, sevelamer carbonate, and lanthanum carbonate) are equally or slightly less effective than calcium-containing compounds. They would not induce an increase in calcium levels but may have relevant side effects, including gastrointestinal symptoms for sevelamer and risk of tissue accumulation for lanthanum. Accordingly, new phosphate binders are under investigation and some of them have already been approved. A promising option is sucroferric oxyhydroxide (Velphoro(®), PA21), an iron-based phosphate binder consisting of a mixture of polynuclear iron(III)-oxyhydroxide, sucrose, and starches. The present review is focused on pharmacology, mode of action, and pharmacokinetics of sucroferric oxyhydroxide, with a discussion on comparative efficacy, safety, and tolerability studies of this drug in chronic kidney disease and patient perspectives such as quality of life, satisfaction, and acceptability. Sucroferric oxyhydroxide has proven to be as effective as sevelamer in reducing phosphatemia with a similar safety profile and lower pill burden. Experimental and clinical studies have documented a minimal percentage of iron absorption without inducing toxicity. In conclusion, the overall benefit-risk balance of sucroferric oxyhydroxide is deemed to be positive, and this new drug may therefore represent a good alternative to traditional phosphate binders for the treatment of hyperphosphatemia in dialysis patients.

Delayed graft function and chronic allograft nephropathy: diagnostic and prognostic role of neutrophil gelatinase-associated lipocalin.

CONTEXT: Available markers are not reliable parameters to early detect kidney injury in transplanted patients. OBJECTIVE: Examine neutrophil gelatinase associated lipocalin (NGAL) in early detection of delayed graft function (DGF) and as a long-term predictor of graft outcome. PATIENTS AND METHODS: NGAL was evaluated in 124 transplanted patients. RESULTS: Urinary NGAL levels were associated to a 10% (HR: 1.10; 95% CI: 1.04-1.25; p < 0.001) and 15% (HR: 1.15; 95% CI: 1.09-1.26; p < 0.001) increased risk of DGF and allograft nephropathy progression, respectively. CONCLUSION: NGAL reflects the entity of renal impairment in transplanted patients, representing a biomarker and an independent risk factor for DGF and chronic allograft nephropathy progression.

Endocrinopathies, metabolic disorders, and iron overload in major and intermedia thalassemia: serum ferritin as diagnostic and predictive marker associated with liver and cardiac T2* MRI assessment.

INTRODUCTION: Endocrinopathies and metabolic disorders-characterized ß thalassemic (ßT) patients and the prevention and treatment of these comorbidities are important targets to be achieved. The aim of the study was to analyze the diagnostic and prognostic role of ferritin for endocrinopathies and metabolic disorders in ßT patients. The ability of iron chelators to treat iron overload and to prevent or reverse metabolic disorders and endocrinopathies was also evaluated. PATIENTS AND METHODS: Seventy-two ßT patients were treated with different chelation strategies during the study. Receiver operating characteristics analysis was employed to calculate the area under the curve for serum ferritin to find the best cutoff values capable of identifying endocrine dysfunction in thalassemic patients. Kaplan-Meier curves were generated to assess the incidence of endocrinopathy. Adjusted risk estimates for endocrinopathy were calculated using univariate followed by multivariate Cox proportional hazard regression analysis. RESULTS: High ferritin levels were observed in patients with hypothyroidism [1500 (872.5-2336.5) µg/L], hypogonadism [878 (334-2010) µg/L], and in patients with hypoparathyroidism or osteoporosis [834 (367-1857) µg/L]. A strict correlation between ferritin and T2* magnetic resonance imaging of heart (r = -0.64; P:0.0006) and liver (r = -0.40; P:0.03) values was observed. Patients with ferritin values above 1800 µg/L experienced a significantly faster evolution to hypothyroidism [log-rank (χ(2) ):7.7; P = 0.005], hypogonadism [log-rank (χ(2) ):10.7; P = 0.001], and multiple endocrinopathies [log-rank (χ(2) ):5.72; P = 0.02]. Ferritin predicted high risk of endocrine dysfunction independently of confounding factors (HR:1.23; P < 0.0001). The intensification of chelation therapy led to an amelioration of hypothyroidism. CONCLUSIONS: Ferritin represents a prognostic marker for ßT patients and a predictive factor for progression to endocrine dysfunctions. Intensive chelation therapy allows the reversibility of hypothyroidism.

Apelin beyond kidney failure and hyponatremia: a useful biomarker for cancer disease progression evaluation.

Apelin regulates angiogenesis, stimulating endothelial cell proliferation and migration. It is upregulated during tumor angiogenesis, and its overexpression was reported to increase tumor growth. Furthermore, apelin controls vasopressin release and body fluid homeostasis. The aim of this study was to examine the correlations between apelin expression and clinical outcomes in oncologic patients, such as cancer disease progression and patient's survival. Apelin levels were evaluated in a cohort of 95 patients affected by different varieties of cancer. Partial remission and stable disease were assigned to the 'no progression' group, comparing it with the progressor group. Patients were followed up for 2 years. Receiver operating characteristics analysis was employed for identifying the progression of the oncologic disease and Kaplan-Meier curves assessed the survival. Adjusted risk estimates for progression endpoint were calculated using Cox proportional hazard regression analysis. Oncologic patients had higher apelin levels compared with healthy subjects, and apelin was closely related to the stages of the disease. In the hyponatremia group, apelin values were significantly higher than patients with eunatremia. After the follow-up of 24 months, 41 patients (43%) reached the endpoint. Progressor subjects presented significantly increased apelin values at baseline compared with non-progressor. Univariate followed by multivariate Cox proportional hazard regression analysis showed that apelin predicted cancer progression independently of other potential confounders. In patients with cancer, apelin closely reflects the stage of the disease and represents a strong and independent risk marker for cancer progression.

Emerging markers of cachexia predict survival in cancer patients.

BACKGROUND: Cachexia may occur in 40% of cancer patients, representing the major cause of death in more than 20% of them. The aim of this study was to investigate the role of leptin, ghrelin and obestatin as diagnostic and predictive markers of cachexia in oncologic patients. Their impact on patient survival was also evaluated. METHODS: 140 adults with different cancer diagnoses were recruited. Thirty healthy volunteers served as control. Serum ghrelin, obestatin and leptin were tested at baseline and after a follow-up period of 18 months. RESULTS: Ghrelin levels were significantly higher in cancer patients than in healthy subjects (573.31 ± 130 vs 320.20 ± 66.48 ng/ml, p < 0.0001), while obestatin (17.42 ± 7.12 vs 24.89 ± 5.54 ng/ml, p < 0.0001) and leptin (38.4 ± 21.2 vs 76.28 ± 17.48 ng/ml, p < 0.0001) values were lower. At ROC analyses the diagnostic profile of ghrelin (AUC 0.962; sensitivity 83%; specificity 98%), obestatin (AUC 0.798; sensitivity 74.5%; specificity 81.5%) and leptin (AUC 0.828; sensitivity 79%; specificity 73%) was superior to that of albumin (AUC 0.547; sensitivity 63%, specificity 69.4%) for detecting cachexia among cancer patients. On Cox multivariate analyses ghrelin (HR 1.02; 95% CI 1.01 - 1.03; p < 0.0001) and leptin (HR 0.94; 95% CI 0.92 - 0.96; p < 0.0001) were significant predictors of death even after correction for other known risk factors such as presence of metastasis and chronic kidney disease. CONCLUSION: Ghrelin and leptin are promising biomarkers to diagnose cachexia and to predict survival in cancer patients.

High-mobility group box 1 (HMGB1) in childhood: from bench to bedside.

UNLABELLED: High-mobility group box protein 1 (HMGB1) is a nonhistone nuclear protein that has a dual function. Inside the cell, HMGB1 binds DNA, regulating transcription and determining chromosomal architecture. Outside the cell, HMGB1 activates the innate system and mediates a wide range of physiological and pathological responses. HMGB1 exerts these actions through differential engagement of multiple surface receptors, including Toll-like receptor (TLR)2, TLR4, and receptor for advanced glycation end products (RAGE). HMGB1 is implicated as a late mediator of sepsis and is also involved in inflammatory and autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Interestingly, HMGB1 was associated with tumor progression, becoming a potential therapeutic target, due to its involvement in the resistance to chemotherapy. Its implication on the pathogenesis of systemic vasculitis and inflammatory bowel diseases has also been evaluated. Moreover, it regulates neuroinflammation after traumatic brain injuries or cerebral infectious diseases. The aim of this review is to analyze these different roles of HMGB1, both in physiological and pathological conditions, discussing clinical and scientific implications in the field of pediatrics. CONCLUSION: HMGB1 plays a key role in several pediatric diseases, opening new scenarios for diagnostic biomarkers and therapeutic strategies development.

Relaxin: new pathophysiological aspects and pharmacological perspectives for an old protein.

Human relaxin-2 (hereafter simply defined as "relaxin") is a 6-kDa peptidic hormone best known for the physiological role played during pregnancy in the growth and differentiation of the reproductive tract and in the renal and systemic hemodynamic changes. This factor can also be involved in the pathophysiology of arterial hypertension and heart failure, in the molecular pathways of fibrosis and cancer, and in angiogenesis and bone remodeling. It belongs to the relaxin peptide family, whose members comprehensively exert numerous effects through interaction with different types of receptors, classified as relaxin family peptide (RXFP) receptors (RXFP1, RXFP2, RXFP3, RXFP4). Research looks toward the in-depth examination and complete understanding of relaxin in its various pleiotropic actions. The intent is to evaluate the likelihood of employing this substance for therapeutic purposes, for instance in diseases where a deficit could be part of the underlying pathophysiological mechanisms, also avoiding any adverse effect. Relaxin is already being considered as a promising drug, especially in acute heart failure. A careful study of the different RXFPs and their receptors and the comprehension of all biological activities of these hormones will probably provide new drugs with a potential wide range of therapeutic applications in the near future.

Thyroid dysfunction in thalassaemic patients: ferritin as a prognostic marker and combined iron chelators as an ideal therapy.

OBJECTIVE: Endocrine complications characterised patients with ß thalassaemia (ßT). In particular, thyroid dysfunction occurs frequently in ßT major, but its long-term natural history is poorly understood. DESIGN: A total of 72 ßT patients were followed for 8 years. The incidence of thyreopathies, defined as the primary study endpoint, was assessed. The aim of this study was to analyse the prognostic role of ferritin for thyreopathies in patients with major and intermedia ßT. The power of different iron chelators to treat iron overload and to prevent or reverse thyreopathies was also assessed. METHODS: Patients were treated with chelators with different chelation strategies during the study. Receiver operating characteristics analysis was employed to calculate the area under the curve for serum ferritin to find the best cutoff values capable of identifying thyroid dysfunction in thalassaemic patients. Kaplan-Meier curves were generated to assess incidence of thyreopathy. Adjusted risk estimates for thyreopathy were calculated using univariate followed by multivariate Cox proportional hazard regression analysis. RESULTS: PATIENTS WITH THYROID DYSFUNCTION WERE CHARACTERISED BY HIGHER FERRITIN WHEN COMPARED WITH PATIENTS WITHOUT THYREOPATHIES (1500 (8722336) VS 513 (370698) G/L; P0.0001). PATIENTS WITH FERRITIN VALUES ABOVE 1800G/L EXPERIENCED A SIGNIFICANTLY FASTER EVOLUTION TO ENDPOINT (LOG-RANK ((2)): 7.7; P=0.005). Ferritin predicted high risk of thyroid dysfunction independently of confounding factors (hazard ratio: 1.20; P<0.0001). The intensification of chelation therapy led to an amelioration of thyroid function. CONCLUSIONS: Ferritin represents a prognostic marker for ßT patients and a predictive factor for progression to thyroid dysfunction. Intensive chelation therapy allows the prevention and reversibility of thyroid complications.

Apelin and copeptin: two opposite biomarkers associated with kidney function decline and cyst growth in autosomal dominant polycystic kidney disease.

Vasopressin (AVP) plays a detrimental role in autosomal dominant polycystic kidney disease (ADPKD). Copeptin represents a measurable substitute for circulating AVP whereas apelin counteracts AVP signaling. The aim of this study was to investigate the predictive value of apelin and copeptin for the progression of ADPKD disease. 52 ADPKD patients were enrolled and followed until the end of the observation period or the primary study endpoint was reached, defined by the combined outcome of decrease of glomerular filtration rate associated with a total renal volume increase. Receiver operating characteristics (ROC) analysis was employed for identifying the progression of renal disease and Kaplan-Meier curves assessed the renal survival. Adjusted risk estimates for progression endpoint and incident renal replacement therapy (RRT) were calculated using Cox proportional hazard regression analysis. ADPKD patients were characterized by lower apelin levels and higher copeptin levels when compared with healthy subjects. These biomarkers were strictly correlated with osmolality and markers of renal function. At ROC analysis, apelin and copeptin showed a very good diagnostic profile in identifying ADPKD progression. After the follow up of 24 months, 33 patients reached the endpoint. Cox proportional hazard regression analysis showed that apelin predicted renal disease progression and incident RRT independently of other potential confounders. Apelin is associated with kidney function decline in ADPKD, suggesting that it may be a new marker to predict kidney outcome.

"Normoalbuminuric" diabetic nephropathy: tubular damage and NGAL.

The aim of this study was to demonstrate that neutrophil gelatinase-associated lipocalin (NGAL) increased before the onset of microalbuminuria in patients with type 1 diabetes mellitus (T1DM), representing an important biochemical parameter with high sensitivity and specificity to make a precocious diagnosis of "normoalbuminuric" diabetic nephropathy (DN). Serum NGAL (sNGAL) and urinary NGAL (uNGAL) levels were evaluated in a cohort of fifty patients affected by T1DM. They had no signs of clinical nephropathy. Thirty-five healthy subjects (HS) were recruited. sNGAL levels were significantly higher compared with those measured in HS [193.7 (103.2-405.4) vs. 46.4 (39.8-56.2) ng/ml; p < 0.0001], as were uNGAL levels [25.5 (14.2-40.2) vs. 6.5 (2.9-8.5) ng/ml; p < 0.0001]. sNGAL was found to be directly correlated with glycated hemoglobin. uNGAL also positively correlated with albuminuria, whereas an inverse correlation was found with uric acid. After multivariate analysis, significance was maintained for the correlation between uNGAL and microalbuminuria. In ROC analysis, sNGAL showed a good diagnostic profile such as uNGAL. NGAL increases in patients with T1DM, even before diagnosis of microalbuminuria representing an early biomarker of "normoalbuminuric" DN with a good sensitivity and specificity. NGAL measurement could be useful for the evaluation of early renal involvement in the course of diabetes.