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We report the first case of renal antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis treated with autologous mesenchymal stromal cells (MSCs). A 73-year-old man was admitted to the hospital for malaise, weight loss, and oliguria. His serum creatinine level was 2.7 mg/dL but it rapidly increased to 7.8 mg/dL; urinalysis showed proteinuria and hematuria, and the ANCA to myeloperoxidase with a perinuclear pattern (pANCA) titer was high (132 IU/mL). Renal biopsy showed necrotizing crescentic glomerulonephritis. Standard immunosuppressive therapy (cyclophosphamide and corticosteroids) was ineffective. Rituximab therapy was started, but it was discontinued after the third dose to minimize the risk of systemic spread of a severe oral Candida infection and to prevent superinfections that were facilitated by leukopenia. The patient received autologous MSCs, 1.5 × 10 6 cells/kg body weight, intravenously. After 7 days, his serum creatinine level decreased to 2.2 mg/dL, pANCA titer decreased to 75 IU/mL, and urinalysis findings normalized. Eight months later, he received a second MSC infusion because his serum creatinine level increased. In 1 week, his creatinine level decreased to 1.9 mg/dL and his pANCA titer decreased to 14 IU/mL. Immunosuppressive therapy was subsequently withdrawn. At the last follow-up visit, 12 months after the second MSC infusion, the patient remained in clinical remission without any therapy. Infusion of MSCs induced expansion of the T-lymphocyte subset expressing a regulatory T-cell phenotype (CD4 + CD25 + Foxp3 + ) and a notable reduction in interferon-γ, interleukin 6, and tumor necrosis factor serum levels.

Background It is important to ensure an adequate sodium and volume balance in neurosurgical patients in order to avoid the worsening of brain injury. Indeed, hyponatremia and polyuria, that are frequent in this patient population, are potentially harmful, especially if not promptly recognized. Differential diagnosis is often challenging, including disorders, which, in view of similar clinical pictures, present very different pathophysiological bases, such as syndrome of inappropriate antidiuresis, cerebral/renal salt wasting syndrome and diabetes insipidus. Case presentation Here we present the clinical report of a 67-year-old man with a recent episode of acute subarachnoid haemorrhage, admitted to our ward because of severe hyponatremia, hypokalemia and huge polyuria. We performed a complete workup to identify the underlying causes of these alterations and found a complex picture of salt wasting syndrome associated to primary polydipsia. The appropriate diagnosis allowed us to correct the patient hydro-electrolyte balance. Conclusion The comprehension of the pathophysiological mechanisms is essential to adequately recognize and treat hydro-electrolyte disorders, also solving the most complex clinical problems.

Haemophilia A and B are genetic X-linked bleeding disorders, caused by mutations in genes encoding factors VIII and IX, respectively. Clinical manifestations of haemophilia are spontaneous haemorrhage or acute bleeding caused by minor trauma, resulting in severe functional consequences that can culminate in a debilitating arthropathy. Life expectancy and quality of life of patients with haemophilia have dramatically improved over the last years, mainly for new therapeutic options and the awareness to the risk of HCV and HIV infections. Different clinical problems arise from this important change in history of patients with haemophilia. In particular, ageing-related diseases, such as diabetes, hypertension and cancer, and chronic viral infections are emerging as new challenges in this patient population. Among the different types of chronic illnesses, renal diseases are of special interest as they involve some difficult management issues. In fact, decisions regarding adequate preventive strategies and viral infection treatment, the choice of the dialytic modality, placement of vascular access and prescription of dialytic treatments are particularly complicated, because only few data are available. In this review, we discuss the pathogenesis of renal damage in patients with haemophilia, especially in those with blood-transmitted viral infections, and the major issues about the management of renal diseases, including problems related to dialytic treatment and kidney transplantation, providing practical algorithms to guide the clinical decision-making process.

To the Editor: van Slambrouck et al.1 proposed the term bile cast nephropathy to describe the high prevalence of tubular bile casts in the kidneys of patients with jaundice and renal injury of different origin, suggesting a potential direct nephrotoxicity of bilirubin. This observation not only highlights an important pathogenetic mechanism, but also leads to hypothesize that bilirubin removal per se could improve renal function in jaundiced patients. Recently, we had the possibility to explore this intriguing hypothesis.

P. Esposito, G. Bedino, F. Montagna, M. Gregorini, T. Rampino,A. Dal Canton. Ganciclovir-resistant cytomegalovirus infection intransplanted patients: utility of drug monitoring.Transpl Infect Dis 2013: 15: E122–E123. All rights reservedP. Esposito, G. Bedino, F. Montagna,M. Gregorini, T. Rampino, A. DalCanton

To evaluate the effects of hemodialysis treatment on the spontaneous cell release of interleukin-2 receptor (IL-2R), we studied 19 hemodialyzed patients (HD), 9 non hemodialyzed patients with chronic uremia (UR, glomerular filtration rate: 8.4 +/- 1.8 ml/min), and 8 healthy control subjects (C). We measured the release of IL-2R in the supernatant of peripheral blood mononuclear cells (PBMC) cultured for 24 hrs in Iscove's medium as well as the plasma levels of IL-2R. A significant increase of IL-2R release was detected in the supernatant of PBMC harvested from HD patients (32.4 +/- 2.4 and 34.2 +/- 5.6 U/3 x 10(6) PBMC daily before and after HD, respectively) as compared with UR (16.6 +/- 5.2 U/3 x 10(6) PBMC daily) and C (21.4 +/- 3.8 U/3 x 10(6) PBMC daily). Similarly, IL-2R plasma levels were significantly higher in HD (378.5 +/- 164.6 U/ml) than in UR (189.5 +/- 89.3 U/ml) and C (11.2 +/- 2.68 U/ml). To summarize, the current study demonstrates: a) an enhancement of spontaneous IL-2R cell release in HD patients; b) an increase of sIL-2R plasma levels in UR patients possibly related to reduced metabolism and/or urinary excretion, because it was not associated with high IL-2R cell release; and c) a further increment of IL-2R systemic levels in HD likely secondary to the high cell release of IL-2R. Therefore, a chronic T cell activation with increased release of IL-2R secondary to the dialysis procedure is suggested.

Sirolimus is currently used to prevent rejection of solid organ transplant, and sirolimus-eluting stents have shown promise for the prevention of coronary artery restenosis. Thrombocytopenia is a well-known adverse effect of sirolimus limiting its use. Herein we report on a patient in whom sirolimus caused a platelet-independent hemostasis defect. The patient was a 52-year-old woman who underwent renal transplant with consequent normal kidney function. The immunosuppressive regimen included basiliximab, steroids, and cyclosporine induction later shifted to sirolimus and mycophenolate due to biopsy findings of tubular necrosis on day 6 posttransplantation. At discharge the serum creatinine was 0.7 mg/dL. Four months after transplantation the patient was admitted to our hospital because of fever (37.5 degrees C to 38 degrees C), anorexia, and asthenia. Blood analysis showed: creatinine 1.7 mg/dL, Hb 9.6 g/dL, WBC 6 x 10(3)/microL, PLT 123 x 10(3)/microL, liver function tests normal, LDH 720 mU/mL, fibrinogen 628 mg/dL, d-dimer 0.42 ng/mL, FDP > 40 ng/mL, INR 1.10, PT 87%, aPTT 40 seconds. Cultures and tests for infection were negative. Serum sirolimus level was 25.9 ng/mL. The following day the serum creatinine rose to 2.3 mg/dL and diuresis fell to 20 mL/h. Multiple bleeding times (Ivy test) performed before the renal biopsy were repeatedly over 30 minutes (normal 3 to 5 minutes), despite normal platelet count and platelet function studies. There was no spontaneous aggregation and in vitro aggregation was normal (collagen, ADP, adrenalin, and ristocetin induced). Coagulation studies showed a defect in fibrin formation and a reduction of fibrinolysis. Suspension of sirolimus treatment was followed by remission of fever, improvement of renal function (serum creatinine 1.2 mg/dL), and normalization of bleeding time.

We studied Mesenchymal Stromal Cells (MSC) effects in experimental Unilateral Ureteral Obstruction (UUO), a fibrogenic renal disease. Rats were divided in 5 groups: sham, UUO, MSC treated-UUO, ACEi treated-UUO, MSC+ACEi treated- UUO. Data were collected at 1, 7, 21 days. UUO induced monocyte renal infiltration, tubular cell apoptosis, tubular atrophy, interstitial fibrosis and overexpression of TGFβ, Renin mRNA (RENmRNA), increase of Renin, Angiotensin II (AII) and aldosterone serum levels. Both lisinopril (ACEi) and MSC treatment prevented monocyte infiltration, reduced tubular cell apoptosis, renal fibrosis and TGFβ expression. Combined therapy provided a further suppression of monocyte infiltration and tubular injury. Lisinopril alone caused a rebound activation of Renin-Angiotensin System (RAS), while MSC suppressed RENmRNA and Renin synthesis and induced a decrease of AII and aldosterone serum levels. Furthermore, in in-vitro and in-vivo experiments, MSC inhibit Human antigen R (HuR) trascription, an enhancer of RENmRNA stability by IL10 release. In conclusion, we demonstrate that in UUO MSC prevent fibrosis, by decreasing HuR-dependent RENmRNA stability. Our findings give a clue to understand the molecular mechanism through which MSC may prevent fibrosis in a wide and heterogeneous number of diseases that share RAS activation as common upstream pathogenic mechanism.

Objectives Acute kidney injury (AKI) is associated with a high mortality and morbidity rate. In this study we investigated whether dialysis membranes influence the recovery of renal function, through the regulation of hepatocyte growth factor (HGF). Design and methods 21 patients were enrolled and assigned to hemodialysis (HD) with cellulose (CE, N = 11) versus polymethylacrylate (PMMA, N = 10) membranes in alternating order. HGF and IL-1 were measured in serum and in peripheral blood mononuclear cells (PBMC) supernatants collected immediately before the first HD session (T0), at 15 minutes (T15), at 240 minutes (T240) and after the last HD, when renal recovery occurred. Eight healthy volunteers were the controls (CON). Results Time to renal function recovery was lower in CE than in PMMA patients. Serum HGF in HD patients was significantly higher than in CON. HGF levels were higher in CE than in PMMA patients at T15 (13.4 ± 2.7 vs 8.9 ± 3.0 ng/mL, P = 0.004) and T240. At recovery, HGF levels decreased. IL-1 serum levels showed a similar trend (at T15 CE: 20.5 ± 2.9 vs PMMA: 16.9 ± 3.2 pg/mL, P = 0.005). HGF release significantly increased in the course of HD, resulting in higher levels in CE than that in PMMA patients. Considering all the patients, basal HGF release negatively correlated with time to renal recovery ( r 2 = 0.42, P Conclusions Here we demonstrated that dialysis membranes influence the cytokine profile in AKI patients, HGF release being higher in patients treated with the CE membrane, in comparison to PMMA. Our results suggest that treatment with CE might improve clinical outcomes, possibly through increased release of HGF.

Human cytomegalovirus (HCMV) end-organ disease in solid-organ transplant recipients (SOTR) may be associated with either high or low HCMV load in blood. In transplantation Centers where the preemptive therapy approach is adopted, antiviral therapy of systemic HCMV infections is initiated upon reaching pre-determined cut-off levels of viral DNA in blood, whereas no guidelines are provided for local end-organ infection/disease. In the latter case, clinicians often start antiviral treatment without defining the etiology of local symptoms. Here, we describe 14 cases of SOTR, in which a documented HCMV end-organ disease was observed. Nine patients had a systemic viral load lower than the cut-off for preemptive therapy and were treated based on viral load of local HCMV disease. The remaining five patients had a systemic viral load greater than the preemptive therapy cut-off and were efficiently treated for both the systemic and the local HCMV disease. Thus, HCMV infection in the post-transplant period must be monitored virologically both in blood and locally. End-organ disease in preemptively treated patients, seems to be associated with lack of development (primary HCMV infection) or reconstitution (reactivated infection) of HCMV-specific CD4+ and CD8+ T-cell immunity or with its functional impairment.

A 31-year-old Caucasian male was referred for panhypopituitarism resulting from a surgically removed craniopharyngioma. The patient had been previously submitted to kidney transplantation for end-stage renal disease from X-linked Alport syndrome (ATS). Subsequent quantitative fluorescent polymerase chain reaction analysis indicated a 47,XXY karyotype consistent with Klinefelter syndrome (KS). The relevance of this unique case stems from several issues: 1) KS was an unexpected finding because of a previous diagnosis of hypogonadotropic hypogonadism resulting from craniopharyngioma; 2) the discovery of a de novo p.G406S substitution causing ATS; and 3) the multifactor origin of severe sexual dysfunction. This is the first description of the co-occurrence of KS, ATS, and craniopharyngioma.

CD40 and its ligand (CD40L) regulate several cellular functions, including T and B-cell activation. The soluble form of CD40 (sCD40) antagonizes CD40/CD40L interaction. Patients undergoing hemodialysis (HD) present elevated sCD40 serum levels, which underlying molecular mechanisms are unknown. We studied sCD40 serum and urinary levels, CD40 membrane and gene expression and membrane shedding in HD, uremic not-HD patients (UR) and healthy subjects (N). We found that in HD sCD40 serum levels were higher than UR and N, being significantly elevated in anuric patients, and that sCD40 correlated to renal function in UR subjects, who presented also a reduced sCD40 urinary excretion rate. HD and UR presented reduced CD40 membrane and gene expression. The concentration of TNF-α converting enzyme (TACE), responsible for CD40 cleavage was not different between HD and N. Therefore the reduced renal clearance is the main cause of elevated sCD40 levels in HD. This finding could have relevant clinical implications.

MSC (mesenchymal stromal cells) can differentiate into renal adult cells, and have anti-inflammatory and immune-modulating activity. In the present study, we investigated whether MSC have protective/reparative effects in anti-Thy1 disease, an Ab (antibody)-induced mesangiolysis resulting in mesangioproliferative nephritis. We studied five groups of rats: (i) rats injected with anti-Thy1.1 Ab on day 0 (group A); (ii) rats injected with anti-Thy1.1 Ab on day 0+MSC on day 3 (group B); (iii) rats injected with anti-Thy1.1 Ab on day 0+mesangial cells on day 3 (group C); (iv) rats injected with saline on day 0+MSC on day 3 (group D); and (v) rats injected with saline on day 0 (group E). Rats were killed on days 1, 3, 7 and 14. MSC prevented the increase in serum creatinine, proteinuria, glomerular monocyte influx and glomerular histopathological injury. Furthermore, MSC suppressed the release of IL-6 (interleukin-6) and TGF-β (transforming growth factor-β), modulated glomerular PDGF-β (platelet-derived growth factor-β), and reset the scatter factors and their receptors, potentiating HGF (hepatocyte growth factor)/Met and inactivating MSP (macrophage-stimulating protein)/Ron (receptor origin nantaise). Few MSC were found in the kidney. These results indicate that MSC improve anti-Thy 1 disease not by replacing injured cells, but by preventing cytokine-driven inflammation and modulating PDGF-β and the scatter factors, i.e. systems that regulate movement and proliferation of monocytes and mesangial cells.

Immunomodulating cell therapy represents a new perspective for the control of cellular immune responses that determine the occurrence of acute rejection (ACR) in allo-transplantation. Mesenchymal stem cells (MSC) demonstrate immunoregulatory effects by inactivating T-cell components that regulate tissue damage in transplantation models. The presumed mechanism of action is recruitment of cells by a cytokine network. The purpose of this study was to test which route of administration (intra-arterial vs intravenous) was the most effective route to achieve immunomodulating effects in experimental rat kidney transplantation. Transgenic Sprague-Dawley rats (SD) expressing the enhanced green fluorescent protein (EGFP) at the somatic level were used as MSC donors: Allogeneic Fischer to Lewis grafts (n = 4 per group) were performed in rats after bilateral nephrectomy. In Gr B, 3 x 10(6) MSCs were infused into the renal graft artery, whereas in Gr C, they were infused into the tail vein. The untreated Gr A were a control group. No immunosuppressive therapy was administered. The animals were sacrificed at day 7 postoperatively. Biochemical analysis for renal function, histological (Banff criteria) and immunohistological (anti-EGFP-Immunoglobulin) analysis were performed on the transplanted animals. In Gr B, functional recovery was more rapid (creatinine: Gr B vs Gr C, P < .05). The inflammatory infiltrate in the graft was less in Gr B vs Gr C, with preservation of tubules, arteries, and glomeruli (P < .01). Intra-arterial infusion of MSCs was more effective to control ACR.

Mesenchymal stem cells (MSC) are multipotent cells that differentiate into various mature cell lineages. MSC show immunomodulatory effects by inhibiting T-cell proliferation. We evaluated the effect of the infusion of MSC in rats experimental kidney transplantation. Sprague-Dawley transgenic rats (SD) able to express the green fluorescent protein (EGFP) were used as MSC donors. Syngeneic (Lewis to Lewis, n = 10) and allogeneic (Fischer to Lewis, n = 10) kidney transplantations were performed after bilateral nephrectomy. Five transplanted rats who received syngeneic grafts, were treated with 3 x 10(6) MSC (Gr B), while the other 5 did not received MSC (Gr A). Five rats with allogenic grafts received 3 x 10(6) MSC (Gr C) and another 5 did not receive MSC (Gr D). The MSC were infused directly into the renal artery of the graft. No immunosuppressive therapy was provided. The animals were killed after 7 days. Biochemical analysis for renal function, histological (Banff criteria) and immunohistological analysis (ED1+ and CD8+) were performed on treated animals. MSC improved kidney function in Gr B and D vs Gr A and C. The tubular damage appeared to be less severe among Gr B and Gr D with respect to Gr A and C (P < .01). Vasculitis was more accentuated in Gr A and C (P < .01). MSCs reduced the inflammatory infiltrate; in Gr B and D, the number of ED1+ cells was lower than in Gr A and C (P < .005), which was also observed for CD8+ cells (P < .05). Our study demonstrated that the infusion of MSC attenuated histological damage from acute rejection by reducing the cellular infiltration.

A promising way to increase the number of kidneys for transplantation is to expand the donor pool by including non-heart-beating donors (NHBDs). The centers involved in NHBD transplantation programs have reported a 16-40% increase in kidney transplants. A key issue with NHBD is the significantly higher rate of delayed graft function (DGF) and primary non-function (PNF) compared with that associated with heart-beating donor (HBD) transplants. However, although transplants from NHBD are associated with a greater incidence of early adverse events, long-term graft survival appears to be similar to that observed after transplants from HBDs. In addition, the use of extracorporeal membrane oxygenation and mechanical perfusion, the careful selection of recipients and donors, and an adequate therapeutic strategy may at least partially reduce the risk of PNF and DGF and improve transplant outcome.

Summary We investigated Toll-like receptors (TLR-3, -4 and -7) expression in circulating mononuclear cells of patients with immunoglobulin A nephropathy (IgAN), a disease with debated relationships with mucosal immunity. TLR-4 expression (detected by fluorescence activated cell sorter) and mRNA transcriptional levels (Taqman) were significantly higher in patients with IgAN than in healthy controls (P = 0·00200 and P = 0·0200). TLR-3 and TLR-7 were not modified significantly. In IgAN patients proteinuria was correlated significantly with TLR-4 expression (P = 0·0312). In a group of nephrotic syndromes, TLR-3, -4 and -7 expression was similar to healthy controls. A significant difference in TLR-4 expression and mRNA levels was found between very active IgAN patients (proteinuria > 1 g/1·73 m2/day in association with severe microscopic haematuria) and inactive patients (proteinuria

Background. Elevated plasma levels of cytokines have been associated with an increased risk of congestive heart failure (CHF) even in people without history of myocardial infarction. Here we have tested the hypothesis that effective removal of pro-inflammatory cytokines in patients with advanced CHF unresponsive to diuretic treatment is associated with diuresis restoration and with a significant reduction of B-type natriuretic peptide (BNP) circulating levels. Methods. We prospectively enrolled 10 patients with decompensated CHF (NYHA classes III–IV). Five patients unresponsive to diuretic treatment underwent a short course of intermittent haemodiafiltration (iHDF), whereas five patients responsive to diuretics were treated with intravenous boluses of furosemide. Renal function was similar between the two groups. Results. Excess body fluids were removed in both groups always resulting in a reduction of pulmonary congestion and peripheral oedema. NYHA class improved in all patients, but one treated by intravenous boluses of furosemide. Only patients treated with iHDF showed a significant reduction of circulating interleukin-8 and monocyte chemoattractant protein-1. After the end of iHDF treatment, patients showed consistent restoration of diuretic responsiveness to significantly lower doses of oral furosemide up to one month of follow-up. Plasma levels of BNP before treatment were significantly higher in the iHDF group, lowering significantly in both groups after treatment. Conclusions. Our results suggest that HDF is an effective treatment for patients with advanced CHF when cytokines have to be cleared and diuretic responsiveness needs to be restored. In our experience, iHDF is a cost-effective option when compared with continuous ultrafiltration methods because it can be performed in a routine dialysis unit without adjunctive costs for machinery or personnel training.

Background: Peroxisome Proliferator-Activated Receptor ! (PPAR! ) is a nuclear receptor that regulates the transcription of genes associated with lipid and glucose metabolism. Recently, it has been shown that PPAR! modulates the activity of T cells, resulting in inhibition of T cell proliferation and IL-2 release. In this study we investigated whether the PPAR! ligand rosiglitazone (R) enhances in vitro the immunosuppressive effects of cyclosporine A (CsA). Methods: CD4 + T cells isolated from peripheral blood mononuclear cells of healthy donors were activated either with mitogens or by one-way mixed lymphocyte reaction. The activated T cells were treated with (1) CsA at low and high concentration (50, 150 ng/ml); (2) R (20 " M); (3) R (20 " M) in combination with CsA at low concentration (50 ng/ml). We studied the effects of the various treatments on cell proliferation (incorporation of [ 3 H] thymidine), the cell-cycle phases (FACS analysis), IL-2 release (ELISA), and IL-2 receptor (CD25) expression (FACS analysis). Results: R used alone reduced T cell proliferation and CD25 expression. Low-dose CsA combined with R was significantly more powerful than either high-dose CsA alone or R alone in suppressing IL-2 release, arresting the T cell cycle, and blocking the growth of activated T cells. Conclusion: PPAR! ligand R potentiates in vitro the inhibitory action of CsA on activated T helper cells. The combined use of PPAR! ligands and low-dose CsA represents a rationale therapeutic approach aimed to prevent CsA nephrotoxicity while maintaining adequate immunosuppression. © 2007 Elsevier B.V. All rights reserved.

Costimulatory pathways (Cluster of differentiation 28, tumor necrosis factor-related, adhesion and T Cell Ig- and mucin-domain molecules) regulating the interactions between receptors on the T cells and their ligands expressed on several cell types, have a key role in controlling many immunological and non immunological processes. Indeed, accumulating evidence indicate that these molecules are involved in the pathogenesis of numerous conditions, such as allograft rejection, atherosclerosis, rheumatoid arthritis, psoriasis and renal diseases, including glomerulonephritis. Primary or secondary (i.e., associated with infections, drugs or systemic diseases, such as systemic lupus erythematosus, diabetes, etc.) glomerulonephritis represent a group of heterogeneous diseases with different pathogenic mechanisms. Since costimulatory molecules, in particular CD80 and CD40, have been found to be expressed on podocytes in the course of different experimental and clinical glomerulonephritis, costimulation has been thought as a new therapeutic target for patients with glomerular diseases. However, although experimental data suggested that the blockade of costimulatory pathways is effective and safe in the prevention and treatment of glomerular diseases, clinical trials reported contrasting results. So, at this moment, there is not a strong evidence for the general use of costimulatory blockade as an alternative treatment strategy in patients with primary or secondary glomerulonephritis. Here, we critically discuss the current data and the main issues regarding the development of this innovative therapeutic approach.

Background. In experimental extracapillary glomerulonephritis (EG) podocytes migrate, proliferate and change phenotype, and play a pivotal role in crescent formation. Hepatocyte Growth Factor (HGF) is an injury-induced effector of tissue repair that causes cell migration, growth and transdifferentiation via its receptor Met. Methods. In 11 patients with EG we measured serum levels of HGF and investigated whether serum induces the release of HGF by Peripheral Blood Mononuclear Cells (PBMC). In renal biopsies we studied the expression of Met. In cultured podocytes we studied Met expression, migration, growth and morphological changes induced by recombinant (r) HGF. Results. In patients with EG average serum levels of HGF (0.73 ng/ml) were higher than in normal volunteers (N, 0.10 ng/ml, p

This paper summarizes the role of the Inter-Regional Reference Center (RC) of the North Italy Transplant program (NITp), in coordinating a donor procurement and organ transplantation network, with a special focus on the strategies to minimize immunological risk and complications after transplantation. In the NITp, patients enrolled on the renal transplantation (RT) waiting list are typed for HLA-A,B,DRB1 antigens with a genomic method. They are periodically screened for the presence of lymphocytotoxic antibodies in their serum by the RC and their suitability to receive the transplant is checked periodically. Cadaver kidney allocation is ruled by a computerized algorithm, named NITK3, established in 1997, which aims at ensuring quality, equity, transparency and traceability during all the phases of the allocation decision-making process. NITK3 has been set up by the NITp Working Group on the basis of biological, medical and administrative criteria and it is periodically reviewed after the analysis of transplant results. In this paper, we show the results of a preliminary analysis of RTs performed from 1998 to 2002 in nine out of sixteen centers of the NITp area, which demonstrates the general quality of the NITp program in terms of patients and graft survival and the special attention to the patients at higher immunological risk.

This paper summarizes the role of the Inter-Regional Reference Center (RC) of the North Italy Transplant program (NITp), in coordinating a donor procurement and organ transplantation network, with a special focus on the strategies to minimize immunological risk and complications after transplantation. In the NITp, patients enrolled on the renal transplantation (RT) waiting list are typed for HLA-A,B,DRB1 antigens with a genomic method. They are periodically screened for the presence of lymphocytotoxic antibodies in their serum by the RC and their suitability to receive the transplant is checked periodically. Cadaver kidney allocation is ruled by a computerized algorithm, named NITK3, established in 1997, which aims at ensuring quality, equity, transparency and traceability during all the phases of the allocation decision-making process. NITK3 has been set up by the NITp Working Group on the basis of biological, medical and administrative criteria and it is periodically reviewed after the analysis of transplant results. In this paper, we show the results of a preliminary analysis of RTs performed from 1998 to 2002 in nine out of sixteen centers of the NITp area, which demonstrates the general quality of the NITp program in terms of patients and graft survival and the special attention to the patients at higher immunological risk.

The proto-oncogene product Ron is the receptor for macrophage stimulating protein, a scatter factor that stimulates cell proliferation, prevents apoptosis, and induces an invasive cell phenotype. We investigated the expression of Ron, Ki-67 (proliferation index), p53. and bcl-2 (proapoptotic and antiapoptotic proteins, respectively) in 50 renal tumors (19 clear cell carcinomas. 18 oncocytomas, 7 papillary cell carcinomas, 5 chromophobe cell carcinomas, and I carcinoma with sarcomatoid areas). In addition, we studied Ron in normal kidney and in the renal carcinoma cell line Caki-1. Immunostaining and Western blot showed Ron in normal kidney and in all oncocytomas but never in renal cell carcinomas or in Caki-1. In addition, Western blot showed that Ron was expressed in phosphorylated. i.e., active. form. Bcl-2 was strongly expressed in oncocytomas, whereas Ki-67 and p53 were much less expressed in oncocytomas than in carcinomas. These results indicate in Ron a marker that differentiates oncocytoma from the other renal epithelial tumors. We therefore think that Ron may prove to be a new tool for a sound and precise diagnosis of oncocytoma, a benign tumor that cannot always be distinguished from carcinomas at histologic examination. The overexpression of bcl-2, but not p53 in oncocytoma, suggests that the MSP/Ron system sustains the growth of oncocytoma by opposing apoptosis.

A 59-year-old man was admitted with dyspnoea and vomiting. A blood count showed anaemia, thrombocytopenia and lymphocytosis (lymphocyte count 21 3 9 10/l). He had severe renal failure (serum creatinine 1284 8 lmol/l) with oliguria. Haemodialysis was promptly started. Flow cytometry immunophenotyping detected a clonal B-cell population (CD20, CD5, CD23, CD3 , CD10 , FMC7 , CD79a, CD79b , CD38 , ZAP70 with membrane kappa light chain restriction at low density) indicative of B-lineage chronic lymphocytic leukaemia (B-CLL). Computerized tomography (CT) scanning of the abdomen and pelvis revealed extensive lymphadenopathy, splenomegaly (spleen length 15 cm) and a striking increase in kidney size (length of right and left kidneys 15 and 14 cm, respectively) (top left); kidney biopsy showed extensive infiltration of the interstitium, tubules, glomeruli and vessels by lymphocytes of the same clone as was found in peripheral blood, with the proliferation fraction, evaluated by Ki67 expression, being

Peritonitis causes mesothelial detachment that may result in persistent peritoneal denudation and fibrosis. We investigated whether hepatocyte growth factor (HGF), a scatter factor that induces detachment from substrate and fibroblastic transformation of several cell types, is produced during peritonitis and is active on mesothelial cells. We studied 18 patients on peritoneal dialysis, 9 uncomplicated, 9 with peritonitis. HGF was measured in serum, peritoneal fluid, and supernatant of peripheral blood mononuclear cells and peritoneal mononuclear cells. Primary culture of human peritoneal mesothelial cells and the human mesothelial cell line MeT-5A were conditioned with recombinant HGF, serum, and peritoneal fluid. HGF levels were significantly higher in serum and peritoneal fluid of peritonitic than uncomplicated patients. Mononuclear cells of peritonitic patients produced more HGF than cells of uncomplicated patients. Recombinant HGF, serum, and peritoneal fluid of peritonitic patients caused mesothelial cell growth, detachment, transformation from epithelial to fibroblast-like shape, overexpression of vimentin, and synthesis of type I and III collagen. In conclusion, HGF released during peritonitis causes a change in mesothelial cell phenotype and function. HGF may affect the healing process facilitating repair through mesothelial cell growth, but may contribute to peritoneal fibrosis inducing cell detachment with mesothelial denudation and collagen synthesis.

Renal dysfunction is one of the most common and threatening complications in heart transplant recipients. Even if ciclosporin seems to play a central role in inducing renal damage, other factors may concur or predispose to renal injury. In order to identify factors responsible for renal dysfunction, we retrospectively studied a cohort of 114 cardiac transplant recipients during a follow-up period of at least 3 years. The patients had a normal renal function before and 0.5 months after heart transplantation. Doubling of baseline serum creatinine or attainment of serum creatinine steadily above 176.8 µmol/l (2.0 mg/dl) was used as criterion to define the end-point renal dysfunction. A series of clinical and laboratory variables were obtained from the patients’ charts at different time intervals, and their prognostic value for the occurrence of renal dysfunction was calculated by Cox proportional hazards models. 23 out of 114 patients reached the end point after a median time period of 21 months. High serum triglyceride, alanine aminotransferase, alkaline phosphatase, ciclosporin, urea, glucose, and hemoglobin levels were shown to be associated with the development of renal dysfunction. Four variables, i.e., triglyceride, ciclosporin, urea, and alkaline phosphatase, had an independent prognostic value. Our results confirm a role for ciclosporin in inducing renal dysfunction and identify hyperlipidemia and an increased plasma urea level as risk factors for renal dysfunction in heart transplant recipients.

Hemodialysis stimulates hepatocyte growth factor release. Studies were performed in 26 patients on regular dialysis treatment with cuprophane (CU), polymethylmetacrilate (PMMA) or cuprammonium (CAM) dialyzers. Controls were six patients with chronic renal failure but not on regular dialysis treatment (CRF) and six healthy subjects (N). Blood was collected at the start (T0), and at 15 (T15) and 240 (T240) minutes of dialysis to measure the serum hepatocyte growth factor (HGF) concentration and to study HGF production by peripheral blood mononuclear cells (PBMC) in vitro. The form of HGF (that is, inactive/monomeric, active/dimeric) present in the serum was analyzed by immunoblotting. In addition, the ability of serum to stimulate proliferation of tubular cells (HK-2) and HGF release by PBMC and fibroblasts (MRC-5) was investigated. At T0, serum HGF levels were identical to that of the controls. In patients treated with CU, serum HGF rose from 0.24 ng/ml at T0 to 7.44 ng/ml at T15, and remained high at T240. PBMC collected at T15 and T240 released significantly more HGF in vitro than those collected at T0. Serum at T15 stimulated proliferation of HK-2 cells and the release of HGF by PBMC and MRC-5 cells. The PMMA and CAM dialyzers had similar effects as the CU. These results indicate that dialysis induces a striking rise in serum HGF and a prompt circulation of factor(s) stimulating HGF release. Dialysis-activated PBMC release HGF.

Inflammatory effects of peritoneal dialysis: Evidence of systemic monocyte activation. We evaluated in peritonitis-free patients undergoing continuous ambulatory peritoneal dialysis (CAPD) the release of both interleukin-6 (IL-6) and β-2-microglobulin (β2m) by cultured peripheral blood mononuclear cells (PBMC), as well as the levels of serum amyloid A (SAA), that is, the main hepatic acute phase protein during inflammation. The same measurements were obtained in hemodialysis (HD) patients, uremic non-dialyzed patients (ESRD) and healthy controls (CON). In CAPD, IL-6 production from PBMC was markedly increased in comparison to the control value (600.7 ± 104.3 vs. 14.2 ± 3.6 pg/3 × 106 PBMC/24 hr, P < 0.005). Similarly, a striking enhancement of the PBMC release of β2m was detected in CAPD with respect to CON (10.1 ± 2.6 vs. 0.063 ± 0.013 µg/3 × 106 PBMC/24 hr, P < 0.001). Also, the SAA levels were significantly greater in CAPD patients (21.3 ± 8.7 µg/dl) than in controls (3.14 ± 0.17 µg/dl, P < 0.05). Analogous increases of both IL-6 and β2m cell releases, as well as of SAA levels, were observed in HD patients. No difference concerning the three parameters was detected between CON and ESRD. In conclusion, CAPD induces per se PBMC activation with an enhanced release of both IL-6 and β2m; this is associated to higher levels of SAA. These systemic inflammatory effects are comparable to those observed in HD patients indicating that CAPD is similar to HD in terms of biocompatibility of the treatment.

A 57-year-old woman was admitted for nausea, vomiting and bdominal pain. She had an adult dominant polycystic kidney isease (ADPKD), associated with multiple liver cysts with normal epatic function. The kidneys had been removed ten years earier, when she underwent kidney transplantation. At admission enal function was normal, but severe liver injury was proven by ew-onset ascites, increased bilirubin level (2.1 mg/dl), reduced lbumin concentration (2.6 g/dl) and prolonged prothrombin nternational normalised ratio (INR 1.7). The patient reported she ad been involved in a road accident two weeks earlier. Magnetic esonance imaging (MRI) showed massive polycystic liver disease PCLD) (Fig. 1, Panel A, star indicates the transplanted kidney) with aemorrhagic cysts, probably due to the recent trauma (Fig. 1, anel B, arrows).

Early allograft calcifications after kidney transplantation (KT) have already been reported, but the clinical implications of this finding are not clear thus far. Patient-related factors such as age, gender, underlying renal disease, and dialytic modality, seem to be irrelevant. It has been postulated that factors promoting the development of metastatic calcifications, including elevated calcium phosphate product and severe secondary hyperparathyroidism, could play a causal role. Here we report a case of a KT patient who developed early kidney calcifications which were associated with severe allograft dysfunction.

The basal production of IL-6 by cultured peripheral blood mononuclear cells (PBMC) from patients with IgAN, is markedly higher (A, 109 pg/ml) as compared to that of PBMC of either patients without clinical signs (I, 39 pg/ml) or appropriate controls (C, 44 pg/ml). When PBMC from healthy subjects were incubated in the presence of sera from patients A, the IL-6 production was strongly enhanced. No such an effect was observed by stimulating PBMC with sera from the other two groups of subjects (I, C). In another experiment we observed that the IL-6 production stimulated by serum from patients A could be inhibited by addition of specific monosaccharides. The inhibitory effect was rapidly abolished when the sugar-containing medium was substituted with the original one. Finally molecular components from serum of A were grossly separated by gel column chromatography. Individual fractions were incubated with PBMC of C: fractions with Mr > 30,000 highly stimulated the release of IL-6 (up to 1320 pg/ml); fractions with lower molecular weight were inactive. The data suggest the presence of an IL-6 releasing factor in the serum of IgAN patients. Although the chemical nature of such a factor is not yet established, the observations reported focus our attention to the lectins family. Since this factor seems potentially important in the understanding of the pathogenesis of IgAN, both its isolation and structural/functional characterization deserve further efforts.

A 61-year-old man with a history of a kidney transplant presented with diffuse cutaneous redness and mild pruritus. He had previously been diagnosed with eczema, but no improvement was seen with topical steroids. Physical examination revealed hyperkeratotic plaques involving the feet with onychodystrophy (Fig. 1A). Fig. 1 Physical examination revealed hyperkeratotic plaques involving the feet with onychodystrophy (A). Examination of a superficial shave biopsy revealed a scabies mite within the subcorneal layer (B) Histopathological examination of a superficial shave biopsy revealed a scabies mite within the subcorneal layer (Fig. 1B). A diagnosis of Scabies crustosa (SC) was made. SC is a rare, highly contagious form of Sarcoptes scabiei hominis infestation that can occur in patients with impaired cellular immunity.1–3 Whereas the typical scabies infestation usually involves fewer than 15 adult female mites, patients with SC frequently have thousands to millions of mites.4 SC is characterized by erythema with diffuse scales and crusting, most prominently on acral areas, which may evolve into erythroderma. Pruritis, the hallmark of common scabies, is usually absent or mild.5 This condition may be confused with psoriasis, eczema, seborrheic dermatitis, or bacterial or mycotic infections.6 The patient was placed on contact isolation and successfully treated with three doses of Ivermectin 200 μg/kg and, topically, with permethrin cream 5% every 2 days for 2 weeks.7 Medical staff and family were treated prophylactically with topical permethrin.