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Background Immunoglobulin A deficiency (IgAD) is the most common form of primary immunodeficiency in western countries. It can be associated with the development of autoimmune diseases both in adults and in children even though the exact pathophysiology is not fully defined. Case Presentation We report here a case of a young patient who developed nephrotic syndrome secondary to membranoproliferative glomerulonephritis associated with the incidental finding of IgAD. We began corticosteroid therapy and angiotensin-converting enzyme inhibitor, and we observed partial remission of the nephrotic syndrome after about nine months; nonetheless, in the following follow-up visits, a progressive decline of renal function was found. Conclusion Our case extends the spectrum of hitherto described glomerulonephritides associated with IgAD which were described until now.

Peritoneal dialysis (PD) is an efficient renal replacement therapy for patients with end-stage renal disease. Even if it ensures an outcome equivalent to hemodialysis and a better quality of life, in the long-term, PD is associated with the development of peritoneal fibrosis and the consequents patient morbidity and PD technique failure. This unfavorable effect is mostly due to the bio-incompatibility of PD solution (mainly based on high glucose concentration). In the present review, we described the mechanisms and the signaling pathway that governs peritoneal fibrosis, epithelial to mesenchymal transition of mesothelial cells, and angiogenesis. Lastly, we summarize the present and future strategies for developing more biocompatible PD solutions.

Peritoneal dialysis (PD) is a viable but under-prescribed treatment for uremic patients. Concerns about its use include the bio-incompatibility of PD fluids, due to their potential for altering the functional and anatomical integrity of the peritoneal membrane. Many of these effects are thought to be due to the high glucose content of these solutions, with attendant issues of products generated during heat treatment of glucose-containing solutions. Moreover, excessive intraperitoneal absorption of glucose from the dialysate has many potential systemic metabolic effects. This article reviews the efforts to develop alternative PD solutions that obviate some of these side effects, through the replacement of part of their glucose content with other osmolytes which are at least as efficient in removing fluids as glucose, but less impactful on patient metabolism. In particular, we will summarize clinical studies on the use of alternative osmotic ingredients that are commercially available (icodextrin and amino acids) and preclinical studies on alternative solutions under development (taurine, polyglycerol, carnitine and xylitol). In addition to the expected benefit of a glucose-sparing approach, we describe an ‘osmo-metabolic’ approach in formulating novel PD solutions, in which there is the possibility of exploiting the pharmaco-metabolic properties of some of the osmolytes to attenuate the systemic side effects due to glucose. This approach has the potential to ameliorate pre-existing co-morbidities, including insulin resistance and type-2 diabetes, which have a high prevalence in the dialysis population, including in PD patients.

Peritoneal dialysis is an efficient renal replacement therapy for uremic patients but is currently under-prescribed. This is partly due to the unfavorable effects on peritoneal morphology and function (bioincompatibility) of current glucose-based solutions. Use of standard solutions can cause several peritoneal alterations including inflammation, mesothelial to mesenchymal transition, and neo-angiogenesis. The final step is fibrosis, which reduces the peritoneal filtration capacity and can lead to ultrafiltration failure and transfer of the patient to hemodialysis. Bioincompatibility can be local (peritoneum) but also systemic, due to the excessive absorption of glucose from the dialysate. Several strategies have been adopted to improve the biocompatibility of peritoneal dialysis solutions, based on the alleged causal factors. Some new solutions available on the market contain low glucose degradation products and neutral pH, others contain icodextrin or aminoacids. Clinical benefits have been associated with the use of these solutions, which however have some limitations and a debated biocompatibility profile. More recent strategies include the use of cytoprotective agents or osmo-metabolic agents in the dialysate. In this article, we review the different approaches currently under development to improve the biocompatibility of peritoneal dialysis solution and hence the clinical outcome and the viability of the technique.

Peritoneal dialysis (PD) is a feasible and effective renal replacement therapy (RRT) thanks to the dialytic properties of the peritoneal membrane (PM). Preservation of PM integrity and transport function is the key to the success of PD therapy, particularly in the long term, since the prolonged exposure to unphysiological hypertonic glucose-based PD solutions in current use is detrimental to the PM, with progressive loss of peritoneal ultrafiltration capacity causing technique failure. Moreover, absorbing too much glucose intraperitoneally from the dialysate may give rise to a number of systemic metabolic effects. Here we report the preliminary results of the first clinical experience based on the use in continuous ambulatory PD (CAPD) patients of novel PD solutions obtained through partly replacing the glucose load with other osmotically active metabolites, such as L-carnitine and xylitol. Ten CAPD patients were treated for four weeks with the new solutions. There was good tolerance to the experimental PD solutions, and no adverse safety signals were observed. Parameters of dialysis efficiency including creatinine clearance and urea Kt/V proved to be stable as well as fluid status, diuresis, and total peritoneal ultrafiltration. The promising tolerance and local/systemic advantages of using L-carnitine and xylitol in the PD solution merit further research.

Cancer patients have an incidence of about 60% kidney disease development and are at elevated risk of acute renal damage. Kidney disease in these patients is frequently associated with nephrotoxicity from the ongoing oncological treatment. New anticancer therapeutic strategies, such as targeted therapies and immunotherapies, offer substantial benefits in the treatment of many neoplasms. However, their use is associated with significant nephrotoxicity, which qualitatively differs from that seen with traditional cytotoxic chemotherapy, while the underlying mechanisms are complex and still to be clearly defined. Nephrologists need to be knowledgeable about the array of such renal toxicities for effective collaboration with the oncologist in the prevention and management of kidney involvement. Renal adverse effects may range from asymptomatic proteinuria to renal failure, and their prompt identification and timely treatment is essential for optimal and safe care of the patient. In this article, after presenting clinical cases we discuss the differing renal toxicity of three novel anticancer agents (aflibercept, dasatinib, and nivolumab) and possible measures to counter it.

Background and Aims High amounts of glucose as the main osmotic agent for peritoneal dialysis (PD) could be harmful, as it may significantly increase cardiovascular morbidity and mortality. Glucose has long-term detrimental effects on the peritoneum, which ultimately may result in ultrafiltration failure, worsening fluid overload and cardiovascular disease. The absorption of glucose from the dialysate accentuates the disturbances of the carbohydrate metabolism, which is already impaired in the uremic state, leading to insulin resistance. XyloCore (Iperboreal Pharma, Pescara, Italy), is a low glucose containing PD solution (PDS) proposed as an alternative to glucose PDS only regimen. It has been formulated replacing most of the glucose with two crystalloid agents, D-xylitol and L-carnitine. PDS containing osmolar agents like xylitol and L-Carnitine added to glucose, used for the nocturnal exchange, may lead to a significant reduction of glucose level in PDS during the night dwell, while preserving or even improving the depurative efficacy of the standard PDS containing 2.5% glucose. The reduction of glucose level could be further enhanced if the PDS with xylitol and carnitine will be used for the diurnal exchanges and a PDS with icodextrin will substitute the standard PDS containing glucose 2.5% for the nocturnal dwell. The aims of the study are to evaluate the effects of (I) the XyloCore PDS IPX15 [containing glucose (0.5%), xylitol (1.5%) and L-carnitine (0.02%) as osmotic agents, as compared to the standard 2.5% glucose PDS] for the nocturnal exchange, and (II) the XyloCore PDS IPX07 [containing glucose (0.5%), xylitol (0.7%) and L-carnitine (0.02%), as compared to the standard 1.5% glucose PDS] for the diurnal (short dwell) exchanges. Method Prospective, randomized, controlled clinical trial in stable ESRD patients treated by CAPD (study protocol registered as NCT 04001036). Key inclusion criteria are: ESRD treated for at least three months with CAPD, stable clinical condition within the four weeks before the screening, hemoglobin ≥ 9g/dL, absence of acute peritonitis and/or peritoneal catheter infection in the three months before. Key exclusion criteria are: androgen therapy, active infections, congestive heart failure stage III and IV NYHA; major cardiovascular events in the last 3 months, clinically relevant cardiac arrhythmia; clinically relevant abnormal hepatic tests; treatment with L-carnitine in the previous three months, pregnancy, life expectancy of less than one year, allergy to L-carnitine or xylitol. The sample size is 40 patients. Treatment duration is 4 weeks plus a 4 weeks safety follow up with no treatment. Primary end-point is the daily peritoneal ultrafiltration volume. Secondary end-points are the peritoneal equilibration test (D/P creatinine, D/P glucose), weekly total Kt/V urea, weekly total creatinine clearance, Adverse Events. Results Two centers participate in the study. One center has so far recruited 10 patients, 6 in the IPX15 group and 4 in the IXP07 group. The six patients in the IXP15 group were 4 males and 2 males, aged 69.5 ±5.1 years. The four patients in the IXP07 were all male, mean age 56 ± 12 years. One patient already completed the study period. Results for Kt/V, creatinine clearance, D/P creatinine, D/P glucose, ultrafiltration volume, at time (T) 0 are 1.17, 85.6, 0.75, 0.18, 400 ml, respectively; at T28 (days) are 3.1, 80, 0.82, 0.23, 400 ml respectively, and at T56 are 3.5, 80, 0.77, 023, 450 ml, respectively. D/P glucose results indicate that this patient is a high transporter and D/P creatinine that the patient was an average/ high transporter. There were no adverse events reported and tolerability has been excellent so far. Conclusion In the first 10 ESRD patients included in the study, XyloCore PDS used for 4 weeks has been well tolerated without significant adverse events. The study is in progress.

In order to effectively develop personalized medicine for kidney diseases we urgently need to develop highly accurate biomarkers for use in the clinic, since current biomarkers of kidney damage (changes in serum creatinine and/or urine albumin excretion) apply to a later stage of disease, lack accuracy, and are not connected with molecular pathophysiology. Analysis of urine peptide content (urinary peptidomics) has emerged as one of the most attractive areas in disease biomarker discovery. Urinary peptidome analysis allows the detection of short and long-term physiological or pathological changes occurring within the kidney. Urinary peptidomics has been applied extensively for several years now in renal patients, and may greatly improve kidney disease management by supporting earlier and more accurate detection, prognostic assessment, and prediction of response to treatment. It also promises better understanding of kidney disease pathophysiology, and has been proposed as a “liquid biopsy” to discriminate various types of renal disorders. Furthermore, proteins being the major drug targets, peptidome analysis may allow one to evaluate the effects of therapies at the protein signaling pathway level. We here review the most recent findings on urinary peptidomics in the setting of the most common kidney diseases.

The success and the quality of hemodialysis therapy are mainly related to both clearance and biocompatibility properties of the artificial membrane packed in the hemodialyzer. Performance of a membrane is strongly influenced by its interaction with the plasma protein repertoire during the extracorporeal procedure. Recognition that a number of medium-high molecular weight solutes, including proteins and protein-bound molecules, are potentially toxic has prompted the development of more permeable membranes. Such membrane engineering, however, may cause loss of vital proteins, with membrane removal being nonspecific. In addition, plasma proteins can be adsorbed onto the membrane surface upon blood contact during dialysis. Adsorption can contribute to the removal of toxic compounds and governs the biocompatibility of a membrane, since surface-adsorbed proteins may trigger a variety of biologic blood pathways with pathophysiologic consequences. Over the last years, use of proteomic approaches has allowed polypeptide spectrum involved in the process of hemodialysis, a key issue previously hampered by lack of suitable technology, to be assessed in an unbiased manner and in its full complexity. Proteomics has been successfully applied to identify and quantify proteins in complex mixtures such as dialysis outflow fluid and fluid desorbed from dialysis membrane containing adsorbed proteins. The identified proteins can also be characterized by their involvement in metabolic and signaling pathways, molecular networks, and biologic processes through application of bioinformatics tools. Proteomics may thus provide an actual functional definition as to the effect of a membrane material on plasma proteins during hemodialysis. Here, we review the results of proteomic studies on the performance of hemodialysis membranes, as evaluated in terms of solute removal efficiency and blood-membrane interactions. The evidence collected indicates that the information provided by proteomic investigations yields improved molecular and functional knowledge and may lead to the development of more efficient membranes for the potential benefit of the patient.

Immune suppressed renal transplant patients are more prone to developing oral tissue alterations due to medications associated with a pleiotropic set of side effects involving the oral cavity. Drug-induced gingival overgrowth (DIGO) is the most commonly encountered side effect resulting from administration of calcineurin inhibitors such as cyclosporine-A (CsA), the standard first-line treatment for graft rejection prevention in transplant patients. Pathogenesis of gingival overgrowth (GO) is determined by the interrelation between medications and a pre-existing inflammatory periodontal condition, the main modifiable risk factor. Severity of gingival hyperplasia clinical manifestation is also related to calcium channel blocker association, frequently provided in addition to pharmacological therapy of transplant recipients. Specifically, nifedipine-induced enlargements have a higher prevalence rate compared to amlodipine-induced enlargements, 47.8% and 3.3% respectively. Available epidemiological data show a gender difference in prevalence, whereby males are generally more frequently affected than females. The impact of GO on the well-being of an individual is significant, often leading to complications related to masticatory function and phonation, a side effect that may necessitate switching to the tacrolimus drug that, under a similar regimen, is associated with a low incidence of gingival lesion. Early detection and management of GO is imperative to allow patients to continue life-prolonging therapy with minimal morbidity. The purpose of this study was threefold: firstly, to determine the prevalence and incidence of GO under the administration of CsA and Tacrolimus, secondly, to assess the correlation between periodontal status before and after periodontal therapy and medications on progression or recurrence of DIGO, and finally, to analyse the effect of immunosuppressant in association to the channel blocker agents on the onset and progression of gingival enlargement. We compared seventy-two renal transplant patients, including 33 patients who were receiving CsA, of which 25% were also receiving nifedipine and 9.72% also receiving amlodipine, and 39 patients who were receiving tacrolimus, of which 37.5% were also receiving nifedipine and 5.55% also receiving amlodipine, aged between 35 and 60 years. Medical and pharmacological data were recorded for all patients. Clinical periodontal examination, in order to establish the inflammatory status and degree of gingival enlargement, was performed at baseline (T0), 3 months (T1), 6 months (T2), and 9 months (T3). All patients were subjected to periodontal treatment. Statistically significant correlation between the reduction of the mean value of periodontal indices and degree of gingival hyperplasia at the three times was revealed. The prevalence of GO in patients taking cyclosporine was higher (33.3%) in comparison with those taking tacrolimus (14.7%). In accordance with previous studies, this trial highlighted the clinical significance of the pathological substrate on stimulating drug-induced gingival lesion, confirming the key role of periodontal inflammation in pathogenesis of gingival enlargement, but did not confirm the additional effect of calcium-channel blocker drugs in inducing gingival enlargement.

Calcific uremic arteriolopathy, also known as calciphylaxis (CUA), is a rare and potentially fatal condition that occurs in 1-4% of the population with chronic renal failure, most often on dialysis treatment. The pathogenesis is not yet clear although several hypotheses have been advanced, most importantly the alteration of the calcium phosphorus metabolism. Administration of sodium thiosulfate (STS) is the emerging therapy. Below, we report the case of an elderly chronic kidney patient on conservative therapy suffering from CUA who has been successfully treated with STS.

Red blood cells (RBCs) have been found to synthesize and release both nitric oxide (NO) and cyclic guanosine monophosphate (cGMP), contributing to systemic NO bioavailability. These RBC functions resulted impaired in chronic kidney disease (CKD). This study aimed to evaluate whether predialysis (conservative therapy, CT) and dialysis (peritoneal dialysis, PD, hemodialysis, HD) therapies used during CKD progression may differently affect NO-synthetic pathway in RBCs. Our data demonstrated that compared to PD, although endothelial-NO-synthase activation was similarly increased, HD and CT were associated to cGMP RBCs accumulation, caused by reduced activity of cGMP membrane transporter (MRP4). In parallel, plasma cGMP levels were increased by both CT and HD and they significantly decreased after hemodialysis, suggesting that this might be caused by reduced cGMP renal clearance. As conceivable, compared to healthy subjects, plasma nitrite levels were significantly reduced by HD and CT but not in patients on PD. Additionally, the increased carotid intima-media thickness (IMT) values did not reach the significance exclusively in patients on PD. Therefore, our results show that PD might better preserve the synthetic NO-pathway in CKD-erythrocytes. Whether this translates into a reduced development of uremic vascular complications requires further investigation.

Mario Bonomini,1,2 Sara Di Silvestre,3,4 Pamela Di Tomo,3,4 Natalia Di Pietro,2,4 Domitilla Mandatori,3,4 Lorenzo Di Liberato,1 Vittorio Sirolli,1,2 Francesco Chiarelli,2,4 Cesare Indiveri,5 Assunta Pandolfi,3,4 Arduino Arduini6 1Unit of Nephrology and Dialysis, 2Department of Medicine and Aging Sciences, 3Department of Medical, Oral and Biotechnological Sciences, 4Aging Research Center andTranslational Medicine, CeSI-MeT, University “G. d’Annunzio”, Chieti-Pescara, 5Department DiBEST (Biologia, Ecologia, Scienze della Terra), Unit of Biochemistry and Molecular Biotechnology, University of Calabria, Arcavacata di Rende CS, Italy; 6CoreQuest, Manno, Switzerland Background: The use of glucose as the only osmotic agent in peritoneal dialysis (PD) solutions (PDSs) is believed to exert local (peritoneal) and systemic detrimental actions, particularly in diabetic PD patients. To improve peritoneal biocompatibility, we have developed more biocompatible PDSs containing xylitol and carnitine along with significantly less amounts of glucose and have tested them in cultured Human Vein Endothelial Cells (HUVECs) obtained from the umbilical cords of healthy (C) and gestational diabetic (GD) mothers. Methods: Primary C- and GD-HUVECs were treated for 72 hours with our PDSs (xylitol 0.7% and 1.5%, whereas carnitine and glucose were fixed at 0.02% and 0.5%, respectively) and two glucose-based PDSs (glucose 1.36% or 2.27%). We examined their effects on endothelial cell proliferation (cell count), viability (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay), intracellular nitro-oxidative stress (peroxynitrite levels), Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 membrane exposure (flow cytometry), and HUVEC-monocyte interactions (U937 adhesion assay). Results: Compared to glucose-based PDSs, our in vitro studies demonstrated that the tested PDSs did not change the proliferative potential both in C- and GD-HUVECs. Moreover, our PDSs significantly improved endothelial cell viability, compared to glucose-based PDSs and basal condition. Notably, glucose-based PDSs significantly increased the intracellular peroxynitrite levels, Vascular Cell Adhesion Molecule-1 and Intercellular Adhesion Molecule-1 membrane exposure, and endothelial cell–monocyte interactions in both C- and GD-HUVECs, as compared with our experimental PDSs. Conclusion: Present results show that in control and diabetic human endothelial cell models, xylitol–carnitine-based PDSs do not cause cytotoxicity, nitro-oxidative stress, and inflammation as caused by hypertonic glucose-based PDSs. Since xylitol and carnitine are also known to favorably affect glucose homeostasis, these findings suggest that our PDSs may represent adesirable hypertonic solution even for diabetic patients in PD. Keywords: carnitine, peritoneal dialysis solution, inflammation, nitro-oxidative stress, endothelial cells, xylitol&nbsp

Peritoneal dialysis (PD) is an established home care, cost-effective renal replacement therapy (RRT), which offers several advantages over the most used dialysis modality, hemodialysis. Despite its potential benefits, however, PD is an under-prescribed method of treating uremic patients. Infectious complications (primarily peritonitis) and bio-incompatibility of PD solutions are the main contributors to PD drop-out, due to their potential for altering the functional and anatomical integrity of the peritoneal membrane. To improve the clinical outcome of PD, there is a need for biomarkers to identify patients at risk of PD-related complications and to guide personalized interventions. Several recent studies have shown that proteomic investigation may be a powerful tool in the prediction, early diagnosis, prognostic assessment, and therapeutic monitoring of patients on PD. Indeed, analysis of the proteome present in PD effluent has uncovered several proteins involved in inflammation and pro-fibrotic insult, in encapsulating peritoneal sclerosis, or even in detecting early changes before any measurable modifications occur in the traditional clinical parameters used to evaluate PD efficacy. We here review the proteomic studies conducted thus far, addressing the potential use of such omics methodology in identifying potential new biomarkers of the peritoneal membrane welfare in relation to dialytic prescription and adequacy.

Paradoxical embolism refers to a potential condition in which an embolus arising from a venous source crosses into the systemic circulation through a right-to-left cardiac shunt causing an arterial embolism. A 39-year-old woman carrier of a central venous catheter (CVC) without evident risk factors for stroke, developed an acute right homonymous hemianopia during hemodialysis. On neuroimaging, an infarct in the territory of the left posterior cerebral artery was demonstrated. Transesophageal echocardiography revealed a patent foramen ovale (PFO) and a large fluctuating thrombus in the right atrium on the tip of the CVC, thus allowing a diagnosis of ischemic stroke from paradoxical embolism. Oral anticoagulation therapy was started and the PFO was closed. This case emphasizes the potential risk of paradoxical embolism in patients with CVCs and PFO. This condition should be prevented and identified in patients with specific risk factors, such as long-term catheterization and hemodialysis.

Patients suffering from chronic renal failure have a higher burden of cardiovascular events, which increases in a dose-dependent fashion as renal function worsens. Increased cardiovascular risk in these patients is thought to be mediated by the simultaneous presence of both traditional and non-traditional cardiovascular risk factors, the latter being associated with renal impairment. Red blood cells are usually considered as carries of nutrients for tissues and respiratory gases, less so as compartments essential to vascular integrity. However, erythrocyte number, size, and integrity seem to severely affect cardiovascular morbidity and mortality as established in recent clinical studies with large patient cohorts. In particular, the role of red blood cells in chronic renal failure tends only to be considered exclusively in relation to a change in their number. However, these cells in the uremic milieu are prone to many alterations, which may adversely affect the cardiovascular system. In this review, we highlight the main qualitative erythrocyte alterations that may have a pathophysiologic role in the elevated cardiovascular risk of chronic renal failure.

The advantages of peritoneal dialysis (PD) over hemodialysis (HD) are well-documented. Notwithstanding, only a small proportion of patients with end-stage renal disease (ESRD) are managed with PD. This may be related to the high glucose load that PD solutions in current use have on the patient. The effects of such excess glucose include the relatively early limitation of the ultrafiltration capacity of the peritoneal membrane, and the metabolic effects associated with hyperglycemia, e.g., decreased insulin sensitivity. This article describes the advantages that may be realized by the glucose-sparing effects of substituting part of the glucose load with other osmotically active metabolites, particularly L-carnitine. The latter is anticipated to have metabolic advantages of its own, especially as in PD patients, high plasma concentrations can be achieved in the absence of renal clearance. Besides its better biocompatibility, L-carnitine demonstrates anti-anemia action due to its effects on erythropoiesis, and positive effects on the longevity and deformability of erythrocytes. Observations from our trials on the use of carnitine-enriched PD solutions have demonstrated the effectiveness of L-carnitine as an efficient osmolyte in PD, and its favorable effect on the insulin sensitivity of the patients. The significance of these findings for future developments in the use of PD in the management of patients with ESRD is discussed.

Cutaneous calciphylaxis is a potentially fatal condition characterized by calcium deposition in dermal arterioles and the subsequent development of livedo reticularis, plaques, and extremely painful ulcers. This condition may be present in up to 4% of end-stage renal disease patients. Several treatments, which mainly attempt to control calcium phosphate metabolism, are available for this condition. We describe two patients treated with sodium thiosulfate with good results. Moreover, we also performed a PubMed literature search of sodium thiosulfate treatment for calciphylaxis. We found 41 cases of which most (> 90%) presented a rapid and sustained resolution, indicating this drug is a very good candidate for the treatment of this condition.

Excessive intraperitoneal absorption of glucose during peritoneal dialysis has both local cytotoxic and systemic metabolic effects. Here we evaluate peritoneal dialysis solutions containing L-carnitine, an osmotically active compound that induces fluid flow across the peritoneum. In rats, L-carnitine in the peritoneal cavity had a dose-dependent osmotic effect similar to glucose. Analogous ultrafiltration and small solute transport characteristics were found for dialysates containing 3.86% glucose, equimolar L-carnitine, or combinations of both osmotic agents in mice. About half of the ultrafiltration generated by L-carnitine reflected facilitated water transport by aquaporin-1 (AQP1) water channels of endothelial cells. Nocturnal exchanges with 1.5% glucose and 0.25% L-carnitine in four patients receiving continuous ambulatory peritoneal dialysis were well tolerated and associated with higher net ultrafiltration than that achieved with 2.5% glucose solutions, despite the lower osmolarity of the carnitine-containing solution. Addition of L-carnitine to endothelial cells in culture increased the expression of AQP1, significantly improved viability, and prevented glucose-induced apoptosis. In a standard toxicity test, the addition of L-carnitine to peritoneal dialysis solution improved the viability of L929 fibroblasts. Thus, our studies support the use of L-carnitine as an alternative osmotic agent in peritoneal dialysis.

Background: Spinal cord stimulation (SCS) has been proposed for the treatment of ischemic pain and the prevention or delay of amputation in patients with peripheral arterial occlusive disease (PAOD) who are unsuitable for vascular reconstruction. PAOD is common in patients with end-stage renal disease and is associated with substantial morbidity and mortality. Furthermore, many patients are not candidates for limb-sparing procedures and have to undergo primary amputation. Methods: We report our experience with SCS in 8 hemodialysis patients with chronic lower-limb ischemia and not suitable for either primary surgical or angioplastic intervention or reintervention. Intensity of ischemic pain, quality of life, use of analgesic medications, limb survival, and outcome of skin ischemic lesions were evaluated before implantation of an SCS device and after 6 and 12 months of follow-up. Results: No complications from SCS device implantation occurred. Both intensity of pain and quality of life significantly improved during follow-up. SCS allowed a decrease in pain medication intake in all patients. Limb survival at 1 year was 75%. Ischemic skin lesions before implantation of an SCS device did not ameliorate during the follow-up period, but the appearance of new lesions was not observed. Conclusion: Implantation of an SCS device in patients with end-stage renal disease with critical limb ischemia dramatically improves quality of life and pain relief. In patients assessed at Leriche-Fontaine stage 2 or 3, the treatment might delay the appearance of ischemic skin lesions and amputation. At these stages, presumed long-term benefits could justify the cost of SCS.

Background. The exposure of phosphatidylserine (PS) on the outer leaflet of the erythrocyte membrane may have several pathophysiological consequences, including the development of a procoagulant phenotype, a finding that seems relevant to the thrombotic risk seen in many disorders. Methods. Because PS externalization increases in erythrocytes from patients suffering from chronic uraemia, which is frequently associated with a prothrombotic state, the possible relationship between erythrocyte PS exposure, erythrocyte procoagulant activity and plasma levels of several haemostatic markers was studied in a group of haemodialysed patients. Results. Uraemic erythrocytes displayed increased procoagulant activity, which proved to be correlated directly with erythrocyte PS exposure. Pre-incubation of uraemic erythrocytes with annexin V, a protein with high affinity and specificity for PS, strongly inhibited in vitro thrombin generation induced by erythrocytes as compared with untreated red cells. Thrombin generation and activation of fibrinolysis were found to occur in uraemic patients, as substantiated by increased plasma levels of markers for thrombin generation (prothrombin fragment F1.2 and thrombin– antithrombin complex) and fibrinolysis (D-dimer and plasmin–antiplasmin complex), respectively. Significant correlations between prothrombin fragment F1.2 and D-dimer suggested that hyperfibrinolysis was secondary to thrombin generation. Correlations were also found between erythrocyte PS levels and plasma levels of haemostatic markers, including prothrombin fragment F1.2 (P ¼ 0.007), thrombin–antithrombin complex (P ¼ 0.00009), plasmin–antiplasmin complex (P ¼ 0.0009) and D-dimer (P ¼ 0.005). Conclusions. Our study suggests that increased PS exposure may cause a pathological erythrocyte procoagulant phenotype, which may be a factor inducing a hypercoagulable state in uraemia.

Carnitine metabolism in patients on peritoneal dialysis (PD), particularly automated PD (APD), has not been extensively evaluated. Here, we examined levels of a large number of carnitine species in plasma from adult uremic patients treated with continuous ambulatory PD (CAPD) or APD, vetting whether L-carnitine may be used in the solution bag for APD therapy.Plasma levels of carnitine and its esters were measured by high-performance liquid chromatography/tandem quadrupole mass spectrometry in 14 patients on CAPD (3 × 1.5 % glucose daily and icodextrin overnight), 16 patients on APD (tidal modality), and 8 age- and gender-matched healthy controls. PD groups did not differ with regard to demographic characteristics, renal function, dialysis features, peritoneal function, or biochemistry. In five APD patients, we also examined the safety and efficacy of L-carnitine (5 g) addition to one night-dwell solution bag over five consecutive days.Several abnormalities were found in plasma carnitine species of PD patients as compared to controls, mainly represented by a reduction of free carnitine and an increase in acetyl-carnitine, dicarboxylic and other carnitines. The main carnitine species (free carnitine, acetyl-carnitine) were significantly lower in plasma from APD than CAPD patients. APD patients tolerated L-carnitine supplementation well, laboratory, physical and dialysis parameters proving stable.Plasma carnitine metabolism is abnormal in patients on PD, and may be influenced by the PD modality. Given the good tolerability and potential advantages of carnitine used in the PD fluid, L-carnitine-containing solution bags in APD treatment definitely merit further evaluation.

The current treatment of chronic inflammatory bowel diseases involves the administration of different immunosuppressive drugs, whose use is associated with several side effects. Among the treatment alternatives, clinicians are attracted by leukapheresis, a method able to selectively remove from the circulation molecules involved in the onset and maintenance of inflammation. From 2007 to 2008, six patients were recruited from our clinics; four patients were affected by ulcerative colitis and two by Crohn's disease. They presented symptoms including abdominal pain and diarrhea despite treatment with steroids and sulfasalazine. Leukapheresis sessions were performed weekly (1 hour/week) for five consecutive weeks. The leukapheresis sessions resulted in a significant improvement in the patients' clinical as well as general conditions. The abdominal pain disappeared and significant reduction of diarrhea and fecal calprotectin levels was observed. No side effects occurred. The clinical benefits were supported by resolution of ulcerative lesions. After six months of follow-up no disease relapse was observed. The leukapheresis treatment has also prevented surgical interventions in all patients enrolled in the study. Our results suggest that leukapheresis may be helpful in patients affected by inflammatory bowel diseases, allowing early reduction of immunosuppressive drug administration.

Objective We evaluated the ability of a recently developed peritoneal dialysis (PD) connector to prevent the risk of bacterial transfer to the fluid path after simulated touch and airborne contamination. Methods Staphylococcus epidermidis ATCC1228 and Pseudomonas aeruginosa ATCC27853 strains were used. For touch contamination, 2 μL of a standardized inoculum [1x108 colony-forming units (CFU) per milliliter] were deposited on top of the pin closing the fluid path of the patient connector. For airborne contamination, the patient connector was exposed for 15 seconds to a nebulized standardized inoculum. To simulate the patient peritoneum and effluent, the patient connector was pre-attached to a 2-L bag of sterile PD solution. After contamination, the patient connector was attached to the transfer set, the pin was captured, flow control was turned to simulate “patient drain” into the empty bag, and then “patient fill” using the bag pre-attached to the connector. Finally, a new pin was recaptured. The PD solution collected in the bag pre-attached to the connector was run through a 0.20-μm filter for colony counts. Results No infected connector transferred bacteria to the fluid path, regardless of the challenge procedure or the strain used. Conclusions Our results show that the new PD connector may fully obviate the risk of bacterial infection, even in the presence of heavy contamination. Further studies are in progress to test our PD connector in a clinical setting.

L-carnitine is an important compound involved both in the transfer of activated long-chain fatty acids across the mitochondrial membrane and in the modulation of the acyl coenzyme A/free coenzyme A ratio in various intracellular compartments. These processes activate several metabolic and cellular functions, and L-carnitine supplementation proved able to reduce insulin resistance and improve lipid metabolism, muscle tropism and erythrocyte rheology. Thus, L-carnitine may be considered a conditional drug rather than a conditional vitamin. Several studies examined the effects of L-carnitine supplementation in dialysis patients. Most of these studies were performed in hemodialysis patients, with controversial conclusions: positive results were countered by the finding of minimal or even no effects. The results were, moreover, often biased by the small number of patients, the lack of control groups, the difference in the measured biochemical data, and the lack of evaluation of patients' compliance and intestinal drug absorption. In addition, at present it is still uncertain what is the adequate level of plasma carnitine to be considered as the target of carnitine supplementation in dialysis patients. In peritoneal dialysis, the small number of published papers provided controversial results as well. Some authors observed significant lowering of apolipoprotein B without changes in cholesterol, triglycerides, free fatty acids, phospholipids and apoliporotein A after administration for short periods of high-dose oral L-carnitine to adult or, more often, pediatric patients. Others did not observe any positive effect. In vitro studies demonstrated that peritoneal dialysis solutions containing Lcarnitine cause less damage to mesothelial and endothelial cells than glucosebased- only peritoneal dialysis solutions. More recently, L-carnitine was used as an osmotic agent in experimental dialysis solutions for human use: the peritoneal ultrafiltration was similar to that induced by glucose solutions. In addition, intraperitoneal administration allows the measurement of absorbed carnitine, thus establishing a correct dose/effect ratio. Ongoing clinical studies in peritoneal dialysis patients on the metabolic effect of glucose plus carnitine solutions, as compared to standard solutions, seem to suggest positive results.

Background. Activated uraemic platelets expose the aminophospholipid phosphatidylserine (PS) at their outer surface, which generates a cell procoagulant phenotype and seems at least partly due to an increase in cell caspase-3 activity. L-Carnitine (LC) may decrease surface-exposed PS in stored apheresis platelets and inhibit the activity of recombinant caspases, but its effects on platelet activation response with PS externalization have not been ascertained in chronic renal failure. In the present study, we investigated in vitro and in vivo the effects of LC on PS exposure in platelets from chronic uraemic patients. Methods. Platelet PS-exposure was assayed by flow cytometry using annexin V. Caspase activity in platelets was determined by the cleaving activity of the specific substrate DEVD-pNA and by a flow cytometric assay using rhodamine-fluorescence. The effects of LC in vivo were examined in a prospective cross-over trial including 10 patients on maintenance haemodialysis (HD) who were randomly allocated to two different treatment groups: LC (2 g i.v.) for 4 months followed by placebo (2 g i.v.) for another 4 months (group A), or placebo followed by LC (group B). Results. PS-exposing platelets in blood samples obtained from HD patients were significantly higher than in healthy subjects (P < 0.001) under both unstimulated and agonist-stimulated conditions. When uraemic platelets were pre-incubated with LC before agonist stimulation, platelet PS exposure proved to be significantly reduced (� 13.7% for 0.5 mM LC and � 25% for 5 mM LC). Pre-incubation of uraemic platelets with LC again significantly decreased the cells’ caspase activity (P < 0.05). In HD patients (Group A), LC supplementation was associated with a significant decrease (P < 0.05) in platelet PS exposure followed by a progressive increase during treatment with placebo. In the other group of patients, while no change in platelet PS exposure was observed during the first 4 months of treatment with placebo, a significant reduction (P < 0.05) in PS-positive platelets occurred after 2 and 4 months of LC therapy. Conclusion. Our data show that LC may reduce, possibly via inhibition of caspase activity, the exposure of PS in activated uraemic platelets. These findings may have implications for the thrombophilic tendency of uraemia.

The appearance of phosphatidylserine, an amin- ophospholipid normally confined to the inner monolayer, at the outer leaflet of red cell membrane may have several patho- physiologic implications. This study examines erythrocyte phosphatidylserine exposure in chronic renal failure (CRF) patients on conservative treatment or on dialysis, to assess possible alterations to phospholipid asymmetry in a condition associated with a state of deranged red cell function. A signif- icant increase in phosphatidylserine-expressing erythrocytes was found in undialyzed patients with CRF (2.32%) and pa- tients on hemodialysis (3.06%) and on peritoneal dialysis (2.14%) compared with control subjects (0.68%). In undia- lyzed CRF patients, a strong correlation (r 5 0.903) was found between the percentage of phosphatidylserine-expressing red cells and the serum creatinine concentration. The increased exposure of phosphatidylserine in uremic erythrocytes may be due to inhibition of phosphatidylserine transport from the outer to the inner leaflet of plasma membrane and may promote an increased erythrophagocytosis. In reconstitution experiments, normal erythrocytes showed an increase in phosphatidylserine- expressing cells when incubated in uremic plasma (3.2% after 2h versus 1.1% at beginning of incubation), whereas phos- phatidylserine-positive uremic erythrocytes decreased when resuspended in normal plasma (2.03% after 2 h and 1.65% after 8h versus 2.9% at beginning of incubation). Preliminary characterization of the putative uremic compound(s) indicates a molecular weight between 10,000 and 20,000, as well as heat instability. These findings show an impairment of erythrocyte membrane phospholipid asymmetry in CRF patients, regard- less of the dialysis treatment. Such abnormality seems related to the uremic state and could contribute to the red cell pathol- ogy present in CRF.