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The increasing availability of novel biological anticancer agents has greatly improved the outcome of several cancer patients; unfortunately, data regarding efficacy, safety and pharmacokinetics of many of these agents in patients with chronic renal disease or on hemodialysis are scanty. Furthermore these results are controversial and a treatment strategy has not yet been established. Therefore, the Associazione Italiana di Oncologia Medica and the Societa italiana di Nefrologia undertook the present work aiming at providing health professionals with a tool for easier clinical management of target therapies in this setting of patients. A web-based search of MEDLINE/PubMed library data published from 2000 to June 2018 has been performed. More than one hundred papers, including recommendations and expert opinions, were selected and discussed by the authors. A panel of experts provided additional biological and clinical information, helping in clarifying some issues in the absence of clear-cut information from the literature.

Background Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes.Methods We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1.73 m(2) of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0.75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0.75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for >= 30 days) or end-stage kidney disease (eGFR = 90 days, chronic dialysis for >= 90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials. gov, number NCT01858532.Findings Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2.2 years (IQR 1.4-2.9). 79 (6.0%) of 1325 patients in the atrasentan group and 105 (7.9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0.65 [95% CI 0.49-0.88]; p=0.0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3.5%) of 1325 patients in the atrasentan group and 34 (2.6%) of 1323 patients in the placebo group (HR 1.33 [95% CI 0.85-2.07]; p=0.208). 58 (4.4%) patients in the atrasentan group and 52 (3.9%) in the placebo group died (HR 1.09 [95% CI 0.75-1.59]; p=0.65).Interpretation Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Living donor kidney transplantation (LDKT) is the best therapy for patients with chronic renal failure. Its advantages, compared with cadaveric transplantation, include the possibility of avoiding dialysis, the likelihood of best outcome, and donor pool expansion. Careful assessment of potential donors is important to minimize the risks and ensure success. However, the proportion of donors disqualified has been poorly investigated. The aim of this work is to describe our experience and present the main reasons for missed donation.This was a single-center, retrospective study of all potential donors and recipients evaluated for LDKT between January 2008 and December 2017.During the period of study, 81 donor-recipient pairs were evaluated. Of these, 45.7% were disqualified and 37 LDKTs were carried out. LDKT was the first choice in 68% of cases and preemptive in 20%; 60% of transplants were among family members. Sex distribution revealed a prevalence of females in the donor group (69%) and males in the recipient group (70%). The mean living donor age was 53 ± 9.5 years; the mean recipient age was lower in recipients listed in the living transplant program than those listed for cadaver transplantation (45.8 ± 13.4 vs 54.2 ± 11.08; P .0001). Reasons for denial included hypertension (18.9%), deceased donor transplant performed during the study period (16.2%), urologic pathology (13.5%), incompatibility (13.5%), withdrawal of consent by donor or recipient (13.5%), psychological unsuitability (8.1%), donor cancer (5.4%), and reduced renal clearance (2.7%).LDKT is considered an option especially for younger recipients. Of the potential kidney living donors, 45.7% were disqualified during the evaluation, with medical reasons being the primary cause.

BACKGROUND Information on physical and mental wellness in renal transplantation is limited. Therefore, we performed a cross-sectional study to evaluate and describe the different components of physical performance and quality of life (QoL) in a cohort of kidney-transplanted patients. METHODS Physical performance and QoL were determined through the administration of validated tests and questionnaires [muscle strength, dynamometer handgrip, tactile sensitivity, visual analogue scale (VAS) for pain, Timed Up and Go (TUG) test, Fatigue Severity Scale (FSS) and the 36-item Short Form Health Survey]. The patients were divided into three groups based on time elapsed since transplantation: early (in the first 6 months), middle (from 7 to 60 months) and late (>60 months). RESULTS Of 132 enrolled patients, 11 patients (8.3%) presented a severe reduction of muscle strength, 63 patients (47%) had significant bilateral impaired handgrip and tactile sensitivity was altered in 23 patients (17.4%). TUG assessment showed significant mobility limitation in 29 patients (21.9%). The FSS presented a pathological value in 50 patients (37.3%), while the mean VAS was 1.8 ± 2.7. There were no significant differences in physical performance parameters among the three patient groups. There were inverse correlations among different components of physical performance and age, comorbidity and dialysis vintage, and there was a direct correlation with renal function. During the first months after transplantation there were limitations in physical, social and emotional activities. Overall, the self-perceived physical performance was significantly lower in transplanted patients with respect to the normal reference level. CONCLUSION Kidney-transplanted patients may present different degrees of impairment in physical performance and quality of life. Systematic functional assessment is essential to identify patients needing intensive and personalized rehabilitation programmes.

Acute kidney injury (AKI) is emerging as a predictor of poor stroke outcome, however, it is often not recognized. The aim of our study was to evaluate post-stroke AKI burden, AKI risk factors and their influence in post-stroke outcome. From 2013 to 2016, 440 individuals with stroke diagnosis admitted in Stroke Unit, Foundation IRCCS Policlinico San Matteo (Pavia, Italy), were retrospectively enrolled. AKI cases identified by KDIGO criteria through the electronic database and hospital chart review were compared with the ones reported in discharge letters or in administrative hospital data base. Mortality data were provided by Agenzia Tutela della Salute of Pavia. We included 430 patients in the analysis. Median follow-up was 19.2 months. We identified 79 AKI cases (18% of the enrolled patients, 92% classified as AKI stage 1), a fivefold higher number of cases than the ones reported at discharge. 37 patients had AKI at the admission in the hospital, while 42 developed AKI during the hospitalization. Cardioembolic (p = 0.01) and hemorrhagic (p = 0.01) stroke types were associated with higher AKI risk. Admission National Institutes of Health Stroke Scale (NIHSS, p

Human cytomegalovirus (HCMV)-specific T-cell response in kidney transplant recipients (KTR) helps to identify patients at risk for severe infection. To assess the T-cell response, this study compared our in-house developed reference test, based on T-cell (both CD4+ and CD8+) stimulation by autologous HCMV-infected dendritic cells (iDC) and subsequent detection by cytokine flow cytometry (CFC-iDC), with the Quanti-FERON-CMV (QF-CMV) assay. Fifty-three HCMV-seropositive KTR were enrolled. At the DNAemia peak, 33 (62%) had low viral load (LVL,3x105 DNA copies/mL) self-resolving infection, 19 (36%) high viral load (HVL,3x105 DNA copies/mL) infection treated with antivirals, and one LVL patient (2%) tissue-invasive disease alone. Both assays showed a delayed recovery of HCMV-specific T-cell immunity in HVL vs LVL patients. Immune reconstitution kinetics did not significantly differ between the two assays in HVL patients. QF-CMV and CFC-iDC showed comparable sensitivities, but QF-CMV had a lower (although not significantly) specificity. Indeed, 7/19 HVL patients (37%) were erroneously considered protected from severe infection by QF-CMV, whereas CFC-iDC misidentified only 3/19 (16%) patients as protected. Although our reference test takes longer to complete, it appears slightly better at predicting patients at risk for severe HCMV infection. Moreover, QF-CMV may provide false negative results with some HLA types.

Immune correlates of protection against human cytomegalovirus (HCMV) infection are still debated. This study aimed to investigate which arm of the immune response plays a major role in protection against HCMV infection in kidney transplant recipients (n = 40) and heart transplant recipients (n = 12). Overall, patients were divided into 2 groups: one including 37 patients with low viral load (LVL), and the other including 15 patients with high viral load (HVL). All LVL patients resolved the infection spontaneously, whereas HVL patients were all treated with one or more courses of antivirals. In HVL patients, viral DNAemia, which was more than 100 times higher than LVL, appeared and peaked at significantly earlier times, but disappeared much later than in LVL patients. During a 1-year follow-up, all LVL patients had levels of HCMV-specific CD4+ (and CD8+ ) T cells significantly higher than HVL patients. On the contrary, titers of neutralizing antibodies and enzyme-linked immunosorbent assay-IgG antibodies to gB, gHgLgO, and pentamer gHgLpUL128L were overlapping in the 2 patient groups. In conclusion, while a valid HCMV-specific T-cell response was detected in more than 90% of LVL patients, >90% of HVL patients lacked an adequate T-cell response. Antibody responses did not appear to be associated directly or indirectly with protection.

Background In the context of kidney transplantation (KT), multidisciplinary interventions, including assessment and management of psychosocial aspects, are important to improve transplant's outcome. The aim of this study was to describe a multidisciplinary team approach to KT, with a specific focus on early detection and treatment of psychological distress and psychopathologic conditions in the early phase postsurgery. Methods The multidisciplinary team in kidney transplantation was implemented in January 2016. In this team approach, all transplant recipients are invited to 3 scheduled appointments for a multidisciplinary evaluation at 1, 3, and 6 months posttransplant, including a psychiatric interview, with the aim to assess the patient's adjustment after transplantation and provide support when necessary. Results This pilot study involved all 41 KT recipients consecutively referred for the first multidisciplinary appointment after transplantation. Five subjects (12% of the study sample) presented with a current psychiatric diagnosis. Psychopharmacologic treatment was confirmed or introduced for all these patients. Further psychological support was suggested to 4 other patients (10%). Conclusion KT significantly improves patients' quality of life. However, the percentage of subjects receiving psychopharmacologic treatment and referred for further psychological and psychiatric support (22%) suggests the need for careful monitoring of psychosocial aspects over the long term.

Chronic pyelonephritis : a misunderstood cause of renal allograft loss Although urinary tract infections (UTI) are the most frequent infections in kidney transplant patients, there are no sufficient data about the prevalence of acute and chronic pyelonephritis and organ or patient survival. We present the clinical case of a young woman with a kidney transplant admitted to our Nephrology Clinic because of an acute worsening of renal function and a history of recurrent UTI. The renal biopsy showed medul lary tissue with a severe tubule-interstitial damage, suggestive for acute rejection, insomuch that steroids were prescribed. Due to the lack of any clinical improvement, a second biopsy was performed, showing a histological picture of chronic pyelonephritis with a severe and advanced damage. Subsequently, because of the severe renal failure the patient underwent peritoneal dialysis and transplant nephrectomy. This clinical case is exemplificative of the possible adverse outcomes of recurrent UTI that might lead in a short time to organ failure, highlighting the importance of a definitive histologic diagnosis.

Although mushroom poisoning is a rare cause of acute renal injury, in some cases it may lead to the development of a severe and irreversible renal failure. Orellanus syndrome is the most important example of organic renal damage related to mushroom consumption. It is caused by the ingestion of orellanine, the main toxin of different types of Cortinarius mushrooms (Cortinarius speciosissimus, C. orellanus, C. orellanoides, etc.), and it is characterized by progressive clinical phases with a predominant kidney involvement, finally requiring renal replacement therapy in about 10% of cases. Renal damage is often late and associated with a histological picture of interstitial nephritis. Diagnosis is essentially clinical and no specific therapy has been shown to be effective in preventing and treating renal damage. Here, we describe the case of a patient with mixed wild mushroom poisoning, presenting the typical clinical signs and course of the Orellanus syndrome. This case offers us the opportunity to review the main clinical features of this severe and little-known intoxication.

This review is intended to be a guide for the physician to evaluate and prepare a donor / recipient couple for living kidney transplantation. Although it is intended to be exhaustive, it will not be able to respond at all possible and different cases, but it may apply at most of them. Renal transplantation is considered the choice treatment for patients with chronic renal failure and if the kidney transplant is performed pre-emptive it is associated with better organ and patient survival. The main aim of the program is to evaluate the risks of donor and recipient and to ensure the donor safety and well-being. Eligibility for living transplant can only be granted when the risks are acceptable, well defined and the couple is adequately informed. The review includes clinical and legal procedures needed to transplantation. Early conditions that contraindicate the transplant must be removed, to avoid unnecessary exams, excessive waste of time, money. The sequence of the exams has been ordered so that costly and invasive surveys are carried out only after other simple and essential investigations have confirmed the transplant suitability. Special attention should be paid to the renal function measurement, proteinuria, hematuria, hypertension, obesity, pre diabetes, renal calculus, and cancers. To give eligibility for living transplant is often not easy, but a careful study can avoid many complications and improve the transplant outcome.

Toll-like receptor 4 (TLR4) promotes inflammation in hemodialysis patients (HD). A soluble form of extracellular TLR4 (sTLR4) has been recently characterized, which showed the ability to attenuate TLR4 signalling. In this study, we describe the sTLR4 profile in regular HD patients.In a cross-sectional study we enrolled forty prevalent HD patients (68.2 ± 16.3 years, twenty-five males) with a median dialysis vintage of 41 months. Nineteen patients were undergoing standard bicarbonate HD (BHD) and 21 patients on-line hemodiafiltration (HDF). Ten healthy sex-matched subjects constituted the controls (C).Before and after the HD session, serum was tested for sTLR4 levels by ELISA. Moreover, clinical and biochemical data were collected, including body mass index, albumin, and C-reactive protein (CRP) levels. Body composition was expressed as a 3-compartment model, providing lean tissue index and fat tissue index (FTI).Describe the profile of sTLR4 in HD patients, evaluating the correlations among sTLR4 levels and the main clinical characteristics, inflammatory and nutritional parameters.Patients with subclinical inflammation (i.e., high CRP levels without clinical symptomatology) presented higher sTLR4 levels (0.42 ± 0.25 ng/mL) with respect to both C and not inflamed HD patients (0.23 ± 0.19 ng/mL, P .05). There was a significant direct correlation between predialysis sTLR4 and body mass index, FTI (r = 0.55), and CRP levels (r = 0.52) and inverse correlation with lean tissue index and albumin (r = -0.4). In multivariate analysis, sTLR4 resulted directly associated with FTI (P = .038). Notably, sTLR4 levels resulted higher in bicarbonate hemodialysis versus hemodiafiltration (0.37 ± 0.18 vs. 0.19 ± 0.21 ng/mL, P .05).sTLR4 correlates with inflammatory and nutritional parameters, presenting as a new potential player in modulating subclinical inflammation in HD patients.

Background The overall risk of some cancers is increased in patients receiving regular dialysis treatment due to chronic oxidative stress, a weakened immune system and enhanced genomic damage. These patients could benefit from the same antineoplastic treatment delivered to patients with normal renal function, but a better risk/benefit ratio could be achieved by establishing specific guidelines. Key considerations are which chemotherapeutic agent to use, adjustment of dosages and timing of dialysis in relation to the administration of chemotherapy. Methods We have reviewed available data present in the literature, including recommendations and expert opinions on cancer risk and use of chemotherapeutic agents in patients with end-stage renal disease. Experts selected by the boards of the societies provided additional information which helped greatly in clarifying some issues on which clear-cut information was missing or available data were conflicting. Results Data on the optimal use of chemotherapeutic agents or on credible schemes of polychemotherapy in haemodialysed patients are sparse and mainly derive from case reports or small case series. However, recommendations on dosing and timing of dialysis can be proposed for the most prescribed chemotherapeutic agents. Discussion The use of chemotherapeutic agents as single agents, or in combination, can be safely given in patients with end-stage renal disease. Appropriate dosage adjustments should be considered based on drug dialysability and pharmacokinetics. Coordinated care between oncologists, nephrologists and pharmacists is of pivotal importance to optimise drug delivery and timing of dialysis.

This chapter provides an historical perspective of living donor nephrectomy from the early days to current applications. The selection criteria for living donors, the various types of surgical approaches available, with particular reference to the laparoscopic technique, and the immediate and long-term results of these procedures, are presented.

Kidney donation after circulatory death (DCD) is a less than ideal option to meet organ shortages. Hypothermic machine perfusion (HMP) with Belzer solution (BS) improves the viability of DCD kidneys, although the graft clinical course remains critical. Mesenchymal stromal cells (MSC) promote tissue repair by releasing extracellular vesicles (EV). We evaluated whether delivering MSC‐/MSC‐derived EV during HMP protects rat DCD kidneys from ischaemic injury and investigated the underlying pathogenic mechanisms. Warm ischaemic isolated kidneys were cold‐perfused (4 hrs) with BS, BS supplemented with MSC or EV. Renal damage was evaluated by histology and renal gene expression by microarray analysis, RT‐PCR. Malondialdehyde, lactate, LDH, glucose and pyruvate were measured in the effluent fluid. MSC‐/EV‐treated kidneys showed significantly less global ischaemic damage. In the MSC/EV groups, there was up‐regulation of three genes encoding enzymes known to improve cell energy metabolism and three genes encoding proteins involved in ion membrane transport. In the effluent fluid, lactate, LDH, MDA and glucose were significantly lower and pyruvate higher in MSC/EV kidneys as compared with BS, suggesting the larger use of energy substrates by MSC/EV kidneys. The addition of MSC/EV to BS during HMP protects the kidney from ischaemic injury by preserving the enzymatic machinery essential for cell viability and protects the kidney from reperfusion damage.

Costimulatory pathways play a key role in immunity, providing the second signal required for a full activation of adaptive immune response. Different costimulatory families (CD28, TNF-related, adhesion and TIM molecules), characterized by structural and functional analogies, have been described. Costimulatory molecules modulate T cell activation, B cell function, Ig production, cytokine release and many other processes, including atherosclerosis. Patients suffering from renal diseases present significant alterations of the costimulatory pathways, which might make them particularly liable to infections. These alterations are further pronounced in patients undergoing kidney transplantation. In these patients, different costimulatory patterns have been related to distinct clinical features. The importance that costimulation has gained during the last years has led to development of several pharmacological approaches to modulate this critical step in the immune activation. Different drugs, mainly monoclonal antibodies targeting various costimulatory molecules (i.e. anti-CD80, CTLA-4 fusion proteins, anti-CD154, anti-CD40, etc.) were designed and tested in both experimental and clinical studies. The results of these studies highlighted some criticisms, but also some promising findings and now costimulatory blockade is considered a suitable strategy, with belatacept (a CTLA-4 fusion protein) being approved as the first costimulatory blocker for use in renal transplantation. In this review, we summarize the current knowledge on costimulatory pathways in the setting of kidney transplantation. We describe the principal costimulatory molecule families, their role and clinical significance in patients undergoing renal transplantation and the new therapeutic approaches that have been developed to modulate the costimulatory pathways.

L'iperbilirubinemia severa si associa spesso al danno renale acuto (AKI), soprattutto in pazienti con livelli di bilirubinemia pari a 20–25 mg/dL. Considerando la potenziale tossicità renale della bilirubina, è possibile che la rimozione di tale sostanza dal plasma rappresenti un modo per migliorare la funzione renale nei pazienti con AKI associato a iperbilirubinemia. Qui presentiamo il caso di un uomo di 47 anni, ricoverato per ittero ingravescente e ascite. All'anamnesi il paziente presentava una mielofibrosi idiopatica, associata a epatopatia con valori di bilirubina stabili intorno ai 4 mg/dL. Al momento del ricovero, la bilirubinemia era pari a 45 mg/dL, con valori di creatininemia di 2.1 mg (valore precedente 0.7 mg/dL). La biopsia epatica mostrava un quadro di severa colangite linfogranulocitaria. Per il peggioramento del quadro ematochimico (bilirubinemia 59.7 mg/dL e creatininemia 4 mg/dL), una volta escluse cause funzionali di insufficienza renale e la sindrome epato-renale, sospettando un danno renale da iperbilirubinemia, abbiamo iniziato il trattamento con plasma adsorbimento/perfusione (PAP). Tale metodica si basa sulla rimozione selettiva della bilirubina dal plasma mediante una specifica resina adsorbente. Dopo il trattamento, si assisteva a una riduzione dei livelli di bilirubina sierica fino a 24 mg/dL, associata a un significativo miglioramento della funzione renale. Tuttavia, circa dieci giorni dopo l'inizio della PAP, il paziente decedeva per shock settico. Questo caso rappresenta un'ulteriore prova della potenziale nefrotossicità della bilirubina, suggerendo che la PAP potrebbe essere una valida opzione terapeutica nei pazienti con danno renale acuto secondario a iperbilirubinemia.

Background Information on physical performance in renal transplantation is limited because of the shortage of specifically designed evaluation instruments. Therefore, we elaborated and validated the Global Performance Status (GloPerSta) score to provide a new and comprehensive tool, exploring the different components of physical performance in kidney transplant patients. Methods We elaborated the GloPerSta score on the basis of the data obtained from a cross-sectional study, in which we evaluated the physical performance of a cohort of kidney transplant patients. The results of these analyses were weighted to describe the different contribution of any single test, via the generation of a structural equation model, resulting in the definition of the GloPerSta. Then, to internally validate this score, we studied its correlation with clinical parameters and quality of life (evaluated as KDQOL-SF, Kidney Disease Quality of Life-Short Form) in the same patient population. Results We enrolled 132 patients in whom the functional tests revealed a great heterogeneity. GloPerSta allowed the stratification of the patients in 3 different physical performance categories (low: score 0–11; medium: 12–22; high: 23–33). Internal validation showed that GloPerSta was directly and significantly correlated with the quality of life and allograft function, independent of the time from transplantation. Conclusions The GloPerSta is a reliable tool to assess physical performance in a kidney transplant population. Its application might be of help in identifying patients needing intensive and personalized rehabilitation programs.

Urinalysis is a key part of the clinical evaluation of patients with kidney disease. It can provide several useful information for the diagnosis and management of diseases of kidneys and urinary tract. In particular, urine color can be affected by the presence of blood, infection and endogenous metabolites, such as bilirubin, or exogenous, for instance those derived from drugs. Therefore, the analysis of urine color may be helpful in identifying different clinical conditions. Here we report a case of a patient who presented purple-colored urine, the so-called " Purple urine bag syndrome", discussing the predisposing factors and the pathogenesis of this condition. We believe that this information can be useful to clinicians who might face this particular situation.

Hepatocyte growth factor (HGF) is a pleiotropic cytokine which exerts a variety of effects on several cells, being involved in the regulation of many biological processes, such as inflammation, tissue repair, morphogenesis, angiogenesis, tumour propagation, immunomodulation of viral infections and cardio-metabolic activities. Patients undergoing regular hemodialysis (HD) present elevated levels of HGF, mainly due to the leukocyte activation associated with HD treatment. High HGF levels might account for specific clinical features of HD patients, i.e. mild liver damage in course of HCV-infection and high cardiovascular risk profile. Moreover, in patients with acute kidney injury, the induction of HGF may represent a crucial step to promote renal recovery, which can have important prognostic consequences in the short and long-term. In this review we discuss the mechanisms underlying HGF production in HD patients, the role of HGF in this particular patient population and the potential clinical implications derived from the study of HGF in HD patients.

Cardiovascular autonomic dysfunction, evaluated as baroreflex sensitivity (BRS), could be acutely corrected by slow breathing or oxygen administration in patients with type 1 diabetes, thus suggesting a functional component of the disorder. We tested this hypothesis in patients with the type 2 diabetes with or without renal impairment. Twenty-six patients with type 2 diabetes (aged 61.0 +/- A 0.8 years, mean +/- A SEM; duration of diabetes 10.5 +/- A 2 years, BMI 29.9 +/- A 0.7 kg/m(2), GFR 68.1 +/- A 5.6 ml/min) and 24 healthy controls (aged 58.5 +/- A 1.0 years) were studied. BRS was obtained from recordings of RR interval and systolic blood pressure fluctuations during spontaneous and during slow, deep (6 breaths/min) controlled breathing in conditions of normoxia or hyperoxia (5 l/min oxygen). During spontaneous breathing, diabetic patients had lower RR interval and lower BRS compared with the control subjects (7.1 +/- A 1.2 vs. 12.6 +/- A 2.0 ms/mmHg, p

Cytomegalovirus (CMV) infection is a common complication following solid organ transplantation that may severely affect the outcome of transplantation. Ganciclovir (GCV) and its prodrug valganciclovir are successfully used to prevent and treat CMV infection; however, in a small percentage of patients, CMV gene mutations may lead to drug resistance. GCV resistance is defined as increasing CMV viremia or progressive clinical disease during prolonged antiviral therapy, due to CMV gene mutation. This has emerged as a new challenge, especially because alternative drugs such as cidofovir and foscarnet have a number of important side effects. Here we report the case of a kidney transplanted patient who experienced life-threatening CMV disease, which initially appeared to be GCV-resistant, but was instead found to be associated with inadequate antiviral drug levels. The patient was then successfully treated by monitoring plasma GCV levels. We suggest using plasma GCV monitoring in the management of all cases of critical CMV disease, in which GCV resistance is suspected.

Autoimmunity to heat shock protein 60 (HSP60) has been related to atherosclerosis. Chlamydia pneumoniae (CP), the most studied infectious agent implicated in promoting atherosclerosis, produces a form of HSP60, which can induce an autoimmune response, due to high antigenic homology with human HSP60 (hHSP60). In this study, we evaluated the correlations among anti-hHSP60 antibodies, CP infection, and cardiovascular disease (CVD) in a high-risk population, such as patients undergoing hemodialysis (HD). Thirty-two patients (67.9 ± 13.9 years; male/female, 23:9) on regular HD were enrolled. Global absolute cardiovascular risk (GCR) was assessed using the Italian CUORE Project’s risk charts, which evaluate age, gender, smoking habits, diabetes, systolic blood pressure, and serum cholesterol. The occurrence of cardiovascular events during a 24-month follow-up was recorded. Seropositivity to CP and the presence of anti-hHSP60 antibodies were tested by specific enzyme-linked immunosorbent assays. Inflammation was assessed by measurement of C-reactive protein (CRP) serum levels. Fifteen healthy sex and age-matched (61.9 ± 9.5 years; male/female, 11:4) subjects were the control group. Fifteen of 32 patients resulted seropositive for CP. CP + patients were older than CP−, while they did not differ for GCR, CRP, and dialytic parameters. CVD incidence was significantly higher in CP+ (9 CP+ vs 2 CP−, p

The Scatter Factors are two homologous proteins, named Scatter Factor/Hepatocyte Growth Factor and Macrophage Stimulating Protein. Their receptors are the products of two oncogenes, Met and Ron, respectively. The Scatter Factors induce movement, stimulate proliferation, regulate apoptosis and are morphogenic, i.e. operate an integrated program that seems tailored to drive organ development and to regenerate injured tissues. On the other hand, Scatter Factors may be responsible for pathologic tissue remodeling, infiltration of inflammatory cells, and tumor growth and diffusion. The review describes the involvement of Scatter Factors in renal disease, including acute renal failure, glomerulonephritis, chronic fibrosing nephropathies, dialysis, renal transplantation and renal tumors, and discusses the double-faced role of Scatter Factors, that play either a protective or a pathogenic role.

While sirolimus (SRL) is thought to be a non-nephrotoxic agent, cyclosporine A (CsA) toxicity is a serious problem in kidney transplantation. We compared the effects of the two drugs on T-helper (Th) subsets in kidney transplant patients. We examined 24 first cadaver kidney recipients equally randomized to receive SRL/mycophenolate mofetil (MMF)/methylprednisolone (MP), or cyclosporine with either MMF or MP. The Th1 and Th2 subsets in peripheral blood were separated based on their production of interferon-gamma (INFgamma) or interleukin (IL)-4/IL-5. The lymphocytes were stimulated with phytohemoagglutinin or with allogenic CD3-depeted and irradiated antigen-presenting cells. Furthermore, the conversion potential of Th0 to Th1 was determined by measuring IL-12 and IL-18 levels after lipopolysaccharide challenge. When peripheral blood lymphocytes taken from SRL-treated patients were stimulated by phytohemoagglutinin, there were significantly lower INFgamma-producing cells compared with the lymphocytes taken from patients treated with CsA. The number of IL-4/IL-5-producing cells did not differ among the patient groups. Release of IL-12 but not IL-18 from peripheral lymphocytes following treatment with lipopolysaccharide was significantly lower in the SRL-treated patients. These results show that compared with CsA, SRL caused a significant decrease in the Th1 lymphocyte subset associated with a significant reduction of IL-12 release.

Macrophage-stimulating protein (MSP) is a scatter factor that causes cell proliferation and migration, and receptor origin nantaise (RON) is its receptor. RON is expressed in macrophages and mesangial cells, and MSP is produced by renal tubular cells. This study investigated whether MSP/RON participate in the pathogenesis of anti-Thy 1 nephritis, a glomerular disease that is characterized by invasion of circulating monocytes into glomeruli and migration and proliferation of mesangial cells. In vivo, renal function and histopathology were studied in rats that had anti-Thy 1 disease and were untreated and treated with a neutralizing anti-MSP antibody. In vitro, whether monocytes express RON and whether MSP has a chemotactic effect on monocytes were studied. In vivo, in anti-Thy 1 disease, MSP was expressed de novo in glomeruli, and neutralization of MSP attenuated the rise in serum creatinine and proteinuria, stopped glomerular neutrophil and monocyte influx, protected from glomerular injury, and lessened mesangial cell overgrowth. In vitro, unstimulated monocytes did not express RON, but the stimulation with LPS induced de novo RON expression. LPS-stimulated monocytes were attracted by MSP. These results demonstrate a pathogenic role of the MSP/RON system in anti-Thy 1 nephritis.

Few data are available regarding the prevalence of burnout among dialysis health care workers. Aims of the present study were to assess and compare burnout levels in a sample of nurses and physicians working in dialysis units, and to investigate their relationships with quality of life, in a cross-sectional observational study.A total of 344 workers from 10 dialysis centres in Northern Italy completed a battery of questionnaires including the Maslach Burnout Inventory, the MOS-36 Item Short Form Health Survey [SF36: physical (PCS) and mental (MCS) component scores] and the 30-item General Health Questionnaire (GHQ30). Data on social and demographic characteristics and working conditions were also collected. General Estimating Equations models were used for the analysis.Overall, burnout scores were lower than the Italian normative sample, with no significant differences between physicians and nurses. However, 30% of nurses had high emotional exhaustion vs 18% of physicians (adjusted OR 2.38, P = 0.003). Emotional exhaustion was also predicted by number of worked hours and months worked in dialysis in the previous 2 years. Depersonalisation was predicted by male gender and bad relationship with coworkers. Having no children and having a permanent hospital position predicted low personal accomplishment. PCS was lower in nurses (50.0 vs 53.3, P0.001), while no significant difference was found for MCS and GHQ30. Lower PCS was associated with emotional exhaustion (P = 0.007) and GHQ305 with depersonalization (P = 0.032).Although burnout is not a general problem in dialysis health care providers, a subgroup of them may be identified, who would benefit from supportive measures to prevent this condition. Nurses appeared more burned-out in the emotional exhaustion scale than physicians.

Hepatocyte growth factor (HGF) is a glycoprotein that induces in vitro epithelial tubular cell growth, motility, scattering and branching morphogenesis. The cell machineries that account for HGF biological effects are still unclear. In previous study, we found that HGF upregulated in epithelial tubular cell line (HK2) 3 genes: potassium channel KCNA1, calcium channel (transient receptor potential channel, subfamily C, member 6, TRPC6) and Na(+)/H(+) exchanger-1 (NHE1). In this study, we validated these results with reverse transcription PCR and WB analysis. To investigate whether KCNA1, TRPC6, NHE1 mediate the changes induced by HGF in HK2, we studied the effects of their inhibitors: 4-aminopyridine, charybdotoxin, dendrotoxin K inhibitors of KCNA1, lanthanum, N-(p-amylcinnamoyl) anthranilic acid inhibitors of TRPC6, 5-(N-ethyl-N-isopropyl)amiloride, cariporide inhibitors of NHE1. The inhibitors prevented HGF-induced growth, migration, cytoskeletal reorganization and tubulogenesis in HK2. These results indicate that KCNA1, TRPC6 and NHE1 are cell machineries that are exploited by HGF to effect its biological outcome in renal tubular cells.

Regulatory T cells (Tregs), defined as CD4+CD25+highFoxP3+CD127- cells, could promote tolerance in renal transplantation (Tx). In an open-label, randomized, controlled trial 62 de-novo Tx recipients received induction with basiliximab and cyclosporine A (CsA) for the first month after Tx and then were assigned to treatment with sirolimus (SRL) or CsA and followed up for 2 years. The primary endpoint was to evaluate the effects of induction and maintenance treatments on circulating Tregs, while the secondary endpoint was the assessment of Treg renal infiltration and the relationship between Treg count and clinical outcomes. There were no significant differences in either circulating or tissue Treg number between the two groups. At 1 month post-Tx, all patients presented a profound Treg depletion, followed by a significant increase in Tregs that resulted stable during the follow-up. The same trend was also observed for non-activated Tregs (CD69-) and for other immunocompetent cells (CD4+ and CD8+ T cells, B cells and NK cells). Moreover, the Treg count did not correlate either with renal function or with acute rejection and graft loss. Initial immunosuppression is crucial to regulate circulating Tregs, regardless of subsequent immunosuppressive maintenance regimens. Strategies aiming to promote tolerance should consider the effects of different induction regimens.

Absolute and human cytomegalovirus (HCMV)-specific CD4+ and CD8+ T-cell counts were monitored in 38 solid organ (20 heart, 9 lung and 9 kidney) transplant recipients during the first year after transplantation by a novel assay based on T-cell stimulation with HCMV-infected autologous dendritic cells. According to the pattern of T-cell restoration occurring either within the first month after transplantation or later, patients were classified as either early (n = 21) or late responders (n = 17). HCMV-specific CD4+ and CD8+ T-cell counts were consistently lower in late compared to early responders from baseline through 6 months after transplantation. In addition, in late responders, while HCMV infection preceded immune restoration, HCMV-specific CD4+ restoration was significantly delayed with respect to CD8+ T-cell restoration. The number of HCMV-specific CD4+ and CD8+ T-cells detected prior to transplantation significantly correlated with time to T-cell immunity restoration, in that higher HCMV-specific T-cell counts predicted earlier immune restoration. Clinically, the great majority of early responders (18/21, 85.7%) underwent self-resolving HCMV infections (p = 0.004), whereas the great majority of late responders (13/17, 76.5%) were affected by HCMV infections requiring antiviral treatment (p =

Until now, hepatocytes have been the only known cell source of macrophage-stimulating protein (MSP), and tissue macrophages have been the cells on which the biologic effects of MSP have been proved. To extend the understanding of the biologic meaning of MSP, it was investigated whether MSP operates in the kidney. MSP protein was evaluated by Western blot in supernatant of cultured human tubular cells (HK2) and human mesangial cells (HMC). MSP mRNA was investigated in HK2 by reverse transcription-polymerase chain reaction (RT-PCR). The expression of the MSP receptor, RON, was evaluated in HMC and HK2 by Western blot. RON mRNA was investigated in HMC by RT-PCR. The expression of MSP and RON in normal human renal tissue was studied by immunohistochemistry. HMC were stimulated with recombinant MSP (rMSP) and HK2 supernatant to study cell growth, migration, and the capacity to invade an artificial collagen matrix and synthesize interleukin-6 (IL-6). HK2 produced MSP and expressed RON in a form that was phosphorylated by rMSP. HMC expressed RON but did not produce MSP. MSP in HK2 supernatant and rMSP induced in HMC phosphorylation of RON, growth, migration, invasion, and IL-6 synthesis. In normal human kidney, tubules expressed MSP and RON. These results indicate a novel field of operation for MSP and suggest a pathogenic role of the MSP/RON system in renal disease. In fact, MSP released by tubular cells may recruit monocytes/ macrophages in inflammatory tubulointerstitial disorders. In addition, MSP either circulating or as paracrine product may sustain glomerular mesangioproliferative disease.

Background: Ecthyma gangrenosum (EG) is an unusu- al, potentially fatal cutaneous disease, commonly as- sociated with Pseudomonas aeruginosa septicemia. Case report: We report the case of a 61-year-old man admitted to the Nephrology Department for fever, leukopenia and inguinal and scrotal painful lesions. Physical examination revealed inguinal and scrotal macules, nodules, blisters and ulcers with central ne- crosis. P. aeruginosa was isolated from an ulcer. EG was diagnosed. Because of the severe leukopenia, granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered until the white blood cell count significantly increased. Based on antibiogram, intravenous ceftazidime and teicoplanin were given for 11 days. Cutaneous manifestations were com- pletely healed in about 2 months. Conclusion: We suggest that the combination of GM- CSF with appropriate antibiotics can resolve EG and avoid or minimize the risk of septicemia in immuno- suppressed patients.

M. Gregorini, M. Castello, T. Rampino, P. Esposito, R. Rosso, G. Borroni, A. Dal Canton. Erythema nodosum in kidney transplant recipient: a rare complication of pneumonia treatment. Transpl Infect Dis 2011. All rights reserved Abstract: Erythema nodosum (EN) is a cutaneous inflammatory reaction, usually reported in young women, but it is rarely observed among transplant patients. Localization in the lower extremities is typical, mostly involving the anterior surfaces of the legs. Several viral, bacterial, mycotic, and non-infectious etiologies, such as autommune disorders, drugs, inflammatory bowel diseases, sarcoidosis, pregnancy, and malignancies, have been found. We describe the case of a young woman kidney transplant recipient developing bilateral, erythematous, warm nodules localized on the anterior surface of her legs after antibiotic treatment for pneumonia with levofloxacin. Her immunosuppression was sirolimus and mycophenolate mofetil. EN was diagnosed by skin biopsy; microscopic examination showed septal panniculitis with granulomas. As a complete remission of the lesions was obtained in our patient after interruption of levofloxacin therapy, we suspect that levofloxacin was involved in the pathogenesis of EN. In fact, the management of EN is based on the treatment of underlying or associated conditions.

Mineral and bone disorders (MBD) in patients undergoing hemodialysis (HD) are a major clinical complication. Current therapeutic strategies do not attain the expected results. The Italian audit on mineral metabolism was implemented to investigate MBD management through a “patient-oriented” approach. Clinical and laboratory data pertinent to MBD from 509 prevalent adult patients on chronic HD were recorded and examined (audit), after which individual strategies were elaborated to improve MBD control. Their effectiveness was evaluated 6 months after the audit (Post-6). The audit disclosed poor MBD control in a high percentage of patients (56 %). Low compliance to treatment was the major determinant of failure (in 43.5 % of cases). Logistic regression showed a direct correlation between high degree of compliance and the achievement of therapeutic targets, e.g. parathyroid hormone: odds ratio (OR) 2.48, p = 0.015. In contrast, a minority of the proposed interventions (14.7 %) included strategies to improve patient compliance. At Post-6, despite a significant increase in drug prescription (p

T-helper (Th) lymphocytes consist of Th1 and Th2 subsets. Th1 cells are effectors of cell-mediated immunity and secrete interferon-gamma (IFN-gamma), which recruits new Th1 cells in cooperation with interleukin-12 (IL-12; produced by monocytes) and inhibits Th2 differentiation. Th2 cells produce IL-4 and IL-10, which inhibit IFN-gamma secretion and cell immunity. We investigated whether the impaired immune response in uremia is associated with an altered balance of Th1/Th2. Peripheral-blood mononuclear cells (PBMCs) were collected from patients with chronic renal failure (CRF) on conservative treatment (CRF patients), patients with end-stage renal disease (ESRD) on regular hemodialysis therapy (ESRD-HD patients), and healthy controls (CON). CD4(+) cells were isolated from PBMCs by negative selection using a magnetic labeling system. PBMCs and purified CD4(+) cells were cultured in Iscove's medium and Iscove's medium plus mitogens (phytohemagglutinin and lipopolysaccharide). IFN-gamma, IL-12, IL-4, and IL-10 were measured in supernatant. The constitutive release of IL-4 and IL-10 by PBMCs and CD4(+) cells of CRF and ESRD-HD patients was increased by five to eight times in comparison with CON (P < 0.001). Constitutive IFN-gamma release by PBMCs of ESRD-HD patients was undetectable, although they secreted an increased amount of IL-12. Mitogen-stimulated release of IFN-gamma by PBMCs and CD4(+) cells of CRF and ESRD-HD patients was blunted (average PBMCs: CON, 115.8 pg/2 x10(6) cells; CRF, 81.8 pg/2 x10(6) cells; ESRD-HD, 9.3 pg/2 x10(6) cells; CD4(+) cells: CON, 358.0 pg/5 x 10(5) cells; CRF, 165.4 pg/5 x 10(5) cells; ESRD-HD, 43.5 pg/5 x 10(5) cells). The ability of PBMCs of ESRD-HD patients to secrete IFN-gamma was recovered after IL-4 and IL-10 neutralization. Uremia is associated with a prevalence of Th1 over Th2 cells and a configuration of cytokine network that depresses cell-mediated immunity.

Sibutramine, a serotonin reuptake inhibitor, currently is used in treatment of obesity. The known side effects of sibutramine, ie, hypertension and tachycardia, depend on its adrenergic and serotoninergic effects. We describe a case of life-threatening hyponatremia associated with sibutramine use in an obese woman. We hypothesize that sibutramine, through its effect on neurotransmitters, may induce antidiuretic hormone secretion and lead to a syndrome of inappropriate antidiuretic hormone secretion. We advise careful monitoring of water-electrolytic balance during sibutramine therapy.

Hepatocyte growth factor (HGF) is a potent mitogen for tubular cells. Experimental injury to the kidney is associated with HGF release both locally and by distant organs stimulated by circulating ‘injurins’. In this study, the serum HGF concentration was measured in patients with acute renal failure (ARF). Normal subjects and chronic renal failure patients either not on dialysis or on regular dialysis treatment served as controls. Human mesangial cells were incubated with sera from ARF patients and controls. The serum HGF concentration was strikingly increased in ARF patients (478 ± 68 ng/dl) and was normal in chronic renal failure patients not on dialysis (20 ± 3 ng/dl) and in those on regular dialysis treatment (25 ± 3 ng/dl). Serum of ARF patients strongly stimulated HGF release from mesangial cells (1,384 ± 55 ng/ml) in comparison with normal serum (67 ± 10 ng/ml). These results indicate that in ARF HGF participates in tubular repair both as an endocrine factor, released in the circulation, and as a paracrine substance, diffusing to the tubules from the mesangium.