Erdheim-Chester disease : from palliative care to targeted treatment

Erdheim-Chester disease (ECD) is a life-threatening multi-systemic non-Langerhans histiocytosis with cardiovascular complications as the leading cause of death. ECD affects the kidneys in up to 30% of cases, with fibrotic tissue deposition in the perirenal fat and renal hilum. Diagnosis is usually based on histological analysis of the pathologic tissue, which typically shows xanthogranulomatous infiltrates of foamy CD68+/CD1a-histiocytes surrounded by fibrosis. A consistent percentage of patients affected by ECD develop renal failure and hypertension as a consequence of renal artery stenosis and hydronephrosis. These conditions have been generally treated with the placement of stents and nephrostomies that frequently led to disappointing outcomes. Before the introduction of interferon-alpha (IFN\u3b1) treatment, the mortality rate was as high as 57% in the long term. Recent studies have granted new insights into the pathogenesis of ECD, which seems to bear a dual component of clonal and inflammatory disease. These advances led to use specific therapies targeting either the oncogenes (BRAFV600E) or the effectors of the immune response implicated in ECD (IL-1, TNF\u3b1). Drugs such as anakinra (recombinant human IL-1 receptor antagonist), infliximab (monoclonal antibody against TNF\u3b1) and vemurafenib (inhibitor of mutant BRAF) showed promising results in small single-centre series. Although larger trials will be needed to address the impact of these drugs on ECD prognosis and to select the most effective treatment, targeted therapies hold the premises to drastically change the outcome of this condition. \ua9 2014 The Author

Anti-Phospholipase A2 Receptor Antibodies in Membranous Nephropathy : from Bench to the Patient

Membranous Nephropathy (MN) is the leading cause of nephrotic syndrome in adults. Primary or idiopathic Membranous Nephropathy (iMN) has been considered as an organ-specific autoimmune disease with an unknown aetiology. By contrast, secondary membranous nephropathy has been described as the expression of a systemic autoimmune response to malignancy or bacterial/viral infections. In the majority of iMN cases, glomerular lesions are determined by autoantibodies against a podocyte membrane protein, the M-type of phospholipase A2 receptor 1 (PLA2R1). Several studies have suggested that the detection of anti-PLA2R1 in patients sera with nephrotic syndrome may be pathognomonic of iMN, thus obviating the need for a diagnostic renal biopsy and an extensive workup for underlying causes. Many authors inferred that the measurement of anti-PLA2R1 may change the diagnostic algorithm in patients with nephrotic syndrome and guide treatment decisions in patients with iMN. Measurement of anti-PLA2R1 antibodies is now possible through an easy to use, commercially available assay. The aim of this review is to describe the clinical relevance of anti-PLA2R1 assessment in patients with MN, and to extensively discuss the biotechnological methods available to measure them

McKittrick-Wheelock syndrome : a rare cause of acute renal failure and hypokalemia not to be overlooked

McKittrick-Wheelock syndrome is a rare disorder in which a colorectal tumor (usually a villous adenoma) determines secretory mucous diarrhea, which in turn leads to prerenal acute renal failure, hyponatremia, hypokalemia and metabolic acidosis. Even though the outcome is usually favorable with complete recovery after surgery, the diagnosis is often delayed, making the patient susceptible to life-threatening complications, mainly severe acidosis and hypokalemia. We present two paradigmatic cases with extreme electrolytes imbalance and complete recovery following the appropriate treatment. The pathogenesis of this degenerative condition is discussed in detail. \ua9 2014 Informa Healthcare USA, Inc. All rights reserved: reproduction in whole or part not permitted

Current Therapy in CKD Patients Can Affect Vitamin K Status

Chronic kidney disease (CKD) patients have a higher risk of cardiovascular (CVD) morbidity and mortality compared to the general population. The links between CKD and CVD are not fully elucidated but encompass both traditional and uremic-related risk factors. The term CKD-mineral and bone disorder (CKD-MBD) indicates a systemic disorder characterized by abnormal levels of calcium, phosphate, PTH and FGF-23, along with vitamin D deficiency, decreased bone mineral density or altered bone turnover and vascular calcification. A growing body of evidence shows that CKD patients can be affected by subclinical vitamin K deficiency; this has led to identifying such a condition as a potential therapeutic target given the specific role of Vitamin K in metabolism of several proteins involved in bone and vascular health. In other words, we can hypothesize that vitamin K deficiency is the common pathogenetic link between impaired bone mineralization and vascular calcification. However, some of the most common approaches to CKD, such as (1) low vitamin K intake due to nutritional restrictions, (2) warfarin treatment, (3) VDRA and calcimimetics, and (4) phosphate binders, may instead have the opposite effects on vitamin K metabolism and storage in CKD patients

The diverging roles of dendritic cells in kidney allotransplantation

Dendritic cells (DCs) are a family of antigen presenting cells that play a paramount role in bridging innate and adaptive immunity. In murine models several subtypes of DCs have been identified, including classical DCs, monocyte-derived DCs, and plasmacytoid DCs. Quiescent, immature DCs and some subtypes of plasmacytoid cells favor the expression of regulatory T cells, but in an inflammatory milieu DCs become mature and after intercepting the antigen migrate to lymphatic system where they present the antigen to na\uefve T cells. Transplant rejection largely depends on the phenotype and maturation of DCs. The ischemia-reperfusion injury causes the release of endogenous molecules that are recognized as danger signals by the pattern recognition receptor of the innate immunity with subsequent activation of inflammatory cells and mediators. In this environment DCs become mature and migrate to lymphonodes where they present the alloantigen to T cells and direct their differentiation towards Th1 and Th17 effector cells. On the other hand, manipulation of DCs may favor T cell differentiation towards tolerant Th2 and T regulators (Treg). Experimental studies in murine models showed the possibility of inducing an operational tolerance by injecting immature tolerogenic DCs. Recently, such a possibility has been also confirmed in primates. Although manipulation of DCs may represent an important step ahead in kidney transplantation, a number of technical and ethical issues should be solved before its clinical application

Cristalluria a 'Fascine di grano': complicanza della terapia con sulfametossazolo?

La cristalluria da farmaco \ue8 una causa da non sottovalutare di insufficienza renale acuta. Soprattutto i farmaci appartenenti alla categoria delle sulfonamidi sono noti per essere poco solubili in urine acide. Fra essi, la pi\uf9 nota \ue8 sicuramente la sulfadiazina, che produce una cristalluria specifica \u201ca fascine di grano\u201d, la cui insorgenza pu\uf2 essere prevenuta con adeguata idratazione e alcalinizzazione del paziente. Per quanto riguarda il sulfametossazolo, ci sono pochi report in letteratura e le immagini disponibili dimostrano che produce cristalli pleiomorfi. Riportiamo due casi in cui la cristalluria insorta in corso di terapia con sulfametossazolo assomiglia molto a quella della sulfadiazina. Il sulfametossazolo, ampiamente utilizzato nella pratica clinica in associazione al trimetoprim, \ue8 una nota causa di insufficienza renale acuta iatrogenica. Tuttavia, poco si conosce riguardo ai meccanismi di patogenicit\ue0. Il nostro caso, insieme a quelli descritti in precedenza, pu\uf2 appunto suggerire che la produzione di cristalli sia uno dei motivi per cui il sulfametossazolo \ue8 nefrotossico. Nei nostri casi la successiva sospensione del farmaco ha portato alla scomparsa della cristalluria.Drug-induced crystalluria is a cause of acute renal failure that has not to be overlooked. Especially sulfonamides are known to be little solubles in acidic urine. Among these drugs, sulfadiazine produces the so-called shocks of wheat crystals, whose formation can be avoided by opportune hydration and alkalinization of the patient. Sulfamethoxazole is another drug of this class that has seldom been reported to cause a pleomorphic crystalluria. We report the case of two patients treated with sulfamethoxazole who developed a crystalluria that is very similar to the sulfadiazine one. Sulfamethoxazole is widely used in clinical practice in association with trimethoprim and it is known to cause acute renal failure, although little is known about the pathogenesis of this nephrotoxicity. Our cases, along with the cases previously reported, may suggest that sulphamethoxazole can act as a nephrotoxic agent through crystals production. Notably, in our cases, discontinuation of the drug led to disappearance of the crystals

Renal dysfunction in acute congestive heart failure : a common problem for cardiologists and nephrologists

The term acute heart failure (AHF) refers to a clinical syndrome with typical symptoms and signs, in which a structural or functional heart abnormality leads to defective oxygen delivery. The term cardiorenal syndrome has been proposed to outline the strict interplay between cardiac and renal function. In the setting of acute cardiac decompensation, acute kidney injury (AKI) is generally referred to as cardiorenal syndrome type 1. In this review, we summarize the fundamental pathophysiological aspects of both AHF and AHF-related AKI. We also review the latest therapeutic options, including both pharmacological ones, such as loop diuretics, potassium-sparing diuretics and vaptans, and non-pharmacological ones, such as ultrafiltration, and their impact on patients\u2019 outcome. We discuss the pathophysiology of diuretic resistance, a common occurrence in these patients, reviewing the available strategies to treat it and highlighting how a close collaboration between cardiologists and nephrologists is frequently crucial for the management of this complication. Finally, we discuss three new promising non-pharmacological tools for the prevention of AHF recurrence, including two methods that exploit sympathetic denervation and one technique that acts by increasing vagal tone

Neurological Counterparts of Hyponatremia : Pathological Mechanisms and Clinical Manifestations

Hyponatremia, defined as a serum sodium concentration <135 mEq/L, represents the most frequent electrolyte disorder in older hospitalized patients. Early recognition of hyponatremia is mandatory, since it represents an independent risk factor that increases hospital mortality by 40 %. Delayed correction of hyponatremia may worsen brain edema, resulting in different degrees of neural damage. However, an overly rapid correction of serum sodium levels can lead to osmotic demyelination syndrome (ODS), a dreadful neurological picture. In recent years, hyponatremia and ODS have received growing attention both in terms of clinical management and pathophysiology, leading to the discovery of new drugs and treatment algorithms. In this review, we recapitulate the pathogenetic background, clinical manifestations, and treatment guidelines of hyponatremia, focusing on the neurological alterations. Neurological symptoms may be neglected when they manifest as early signs of mild hyponatremia, while brain damage can irremediably affect patients\u2019 conditions in the context of ODS

Plasma protein thiolation index (PTI) as a biomarker of thiol-specific oxidative stress in haemodialyzed patients

The role of oxidative stress in patients with end stage renal disease (ESRD), which occurs at significantly higher levels than in the general population, is often underestimated in clinical practice. Emerging evidence highlights the strong correlation of oxidative stress with chronic inflammation and cardiovascular disease, which are highly prevalent in most patients on maintenance haemodialysis (HD) and are a major risk factor for mortality in this population. In this study, total plasma thiols and plasma S-thiolated proteins were measured in patients with ESRD, before and after a regular HD session, and compared to age-matched healthy subjects. We found a significant decrease in the level of total plasma thiols and, conversely, a significant increase in the level of S-thiolated proteins in these patients. In most patients, post-HD plasma level of total thiols did not differ from the one in healthy subjects, whereas plasma level of S-thiolated proteins was lower in HD patients than in age-matched healthy controls. This suggests that a single HD session restores plasma thiol redox status and re-establishes the antioxidant capacity of plasma thiols. Additionally, we determined protein thiolation index (PTI), i.e., the molar ratio between the sum of all low molecular mass thiols bound to S-thiolated plasma proteins and protein free cysteinyl residues. Patients with ESRD had a significantly higher PTI compared to age-matched healthy subjects and HD was associated with a decrease in PTI to normal, or lower than normal, levels. Although this study is limited in size, our results suggest that PTI is a useful indicator of thiol-specific oxidative stress in patients with ESRD on maintenance HD. This study also emphasizes that PTI determination is a cheap and simple tool suitable for large-scale clinical studies that could be used for routine screening of thiol-specific oxidative stress