Pro- and anti-inflammatory cytokine gene expression in subcutaneous and visceral fat in severe obesity.

BACKGROUND AND AIMS: Pro-inflammatory molecules produced by adipose tissue have been implicated in the risk of cardiovascular (CV) disease in obesity. We investigated the expression profile of 19 pro-inflammatory and seven anti-inflammatory genes in subcutaneous adipose tissue (SAT) and in visceral adipose tissue (VAT) in 44 severely obese individuals who underwent bariatric surgery. METHODS AND RESULTS: SAT and VAT expressed an identical series of pro-inflammatory genes. Among these genes, 12 were significantly more expressed in SAT than in VAT while just one (IL18) was more expressed in VAT. The remaining genes were equally expressed. Among pro-inflammatory cytokines, both IL6 and IL8 were about 20 times more intensively expressed in SAT than in VAT. The expression of nine genes was highly associated in SAT and VAT. Only for three pro-inflammatory cytokines (IL8, IL18, SAA1) in SAT the gene expression in adipose tissue associated with the circulating levels of the corresponding gene products while no such an association was found as for VAT. CONCLUSIONS: The expression of critical pro-inflammatory genes is substantially higher in SAT than in VAT in individuals with morbid obesity. The variability in circulating levels of pro-inflammatory cytokines is, in small part and just for three pro-inflammatory cytokines, explained by underlying gene expression in SAT but not in VAT. These results point to a compartment-specific adipose tissue contribution to inflammation in obesity and indicate that abdominal SAT contributes more than VAT to the pro-inflammatory milieu associated with severe obesity.

[Proposals for the prevention of kidney disease in Italy by the Italian Society of Nephrology (SIN)]. / Prevenzione renale: proposte metodologiche nazionali e regionali della Societa' Italiana di Nefrologia.

Although national epidemiological data on the prevalence of chronic kidney disease in Italy are lacking, local and regional studies report that over 6% of the general population live with an eGFR <60 mL/min/1.73 m2 of body surface. In 2007, the Italian Society of Nephrology (SIN) pointed out the main routes for the widespread recognition of the problem, involving the local agencies (ASLs) of the National Health Service in close collaboration with general practitioners and nephrologists, to ensure a wide range of information and continuous education of the general population on this issue. Special attention should be paid to financial and human resources, the shortage of nephrologists, and the role of the various stakeholders with the aim to counteract the progressive increase of CKD in the Italian population.

Patient mortality after graft failure reduces kidney transplant patient survival only in the long term: an "intention to treat" analysis.

The benefits of kidney transplantation over dialysis on patient survival have been demonstrated without considering the outcomes of patients with graft loss. To determine whether mortality after graft failure reduced the transplantation advantage in patient survival, we retrospectively reviewed the outcomes of 918 first-deceased renal transplant recipients from May 1979 to August 2005. Patient survivals were 88% and 72% at 10 and 20 years; cancer (26%) and cardiovascular disease (25%) were the major causes of death. Graft survivals were 72% and 50% at 10 and 20 years; chronic rejection was the major cause of graft loss (50%). Patient outcomes after return to dialysis were reviewed in 224 of 240 patients. The survivals were 97%, 83%, and 70% at 1, 5, and 10 years, respectively; cardio-cerebrovascular disease (56%), infections (9%), cachexia (9%), and cancer (8%) were the major causes of death. Mortality correlated with patient age at transplantation (P< .001). Re-listed patients (96 of 224) were younger (32+/-10 vs 43+/-11 years; P< .001), had a shorter dialysis period pretransplant (3.2+/-3.1 vs 4.3+/-3.9 years; P< .03), and a better survival at 10 years (98% vs 56%; P< .001). Ten-year mortality for patients who returned to dialysis was 20% higher than for patients with a functioning graft (P< .001). The reduction in overall patient survival was 2.2% at 10 years (P=NS), 5% at 15 years (P=NS), and 14% at 20 years (P< .05). The same results have been demonstrated for patients >50 years at transplantation. In conclusion, the mortality rate after return to dialysis did not influence the long-term benefits of kidney transplantation.

[Antimicrobial agents for preventing peritonitis in peritoneal dialysis: guideline from the Italian Society of Nephrology]. / Strategie antimicrobiche per la prevenzione delle peritoniti in dialisi peritoneale: Linea Guida.

BACKGROUND: The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic reviews (SR) of randomized trials (RCT) or RCT data only. The present guideline reports evidence of the use of antimicrobial agents for preventing peritonitis in peritoneal dialysis (PD). METHODS: SR of RCT and RCT on treatments aiming at preventing peritoneal dialysis peritonitis were identified referring to a Cochrane Library and Renal Health Library search (2005 update). Quality of SR and RCT was assessed according to current methodological standards. RESULTS: One SR and 19 RCT were found addressing this issue. Staphylococcus Aureus nasal carriage treatment with mupirocin reduces exit-site and tunnel infections but not peritonitis. Topical gentamicin treatment on the exit site reduces Staphylococcus Aureus infection and peritonitis incidence. Intravenous antibiotics administration prior to catheter placement significantly reduces the risk of early peritonitis but not exit-site and tunnel infections. Oral nistatin associated with antibiotic treatment significantly reduces the incidence of Candida peritonitis. No other prophylaxis measure seems to be effective based on available evidence. CONCLUSION: In patients on peritoneal dialysis current evidence supports the hypothesis that topical mupirocin reduces the risk of Staphylococcus Aureus peritonitis, intravenous antibiotics prior to catheter placement prevent the risk of early peritonitis, and oral nistatin reduces the risk of Candida peritonitis. Further studies are necessary to test the effectiveness of other interventions.

[Catheter-related interventions to prevent peritonitis in peritoneal dialysis: guideline from the Italian Society of Nephrology]. / Strategie correlate al catetere per la prevenzione delle peritoniti in dialisi peritoneale: Linea Guida.

BACKGROUND: The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic reviews (SR) of randomized trials (RCT) or RCT data only. The present guideline report evidence of catheter-related interventions to prevent peritonitis in peritoneal dialysis (PD). METHODS: SR of RCT and RCT of catheter-related interventions to prevent peritonitis in PD were identified referring to a Cochrane Library and Renal Health Library search (2005 update). RESULTS: Two SR and 17 RCT were found addressing this issue. Methodological quality of available RCT was suboptimal according to current methodological standards. The use of the Y-set systems with disinfectant and the twin-bag systems was associated with a significantly lower risk of peritonitis. No other catheter-related interventions were found to be of proven efficacy in preventing the risk of peritonitis and exit-site/tunnel infection in PD patients. CONCLUSION: It is still unknown whether any particular PD catheter design or implantation technique are effective to prevent peritonitis in patients on peritoneal dialysis. Further studies are necessary to test the effectiveness of new interventions.

[Treating peritonitis in peritoneal dialysis: guideline from the Italian Society of Nephrology]. / Terapia iniziale della peritonite in dialisi peritoneale: Linea Guida.

BACKGROUND: The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic reviews (SR) of randomized trials (RCT) or RCT data only. The present guideline reports evidence of interventions to treat peritonitis in peritoneal dialysis (PD). METHODS: SR of RCT and RCT on treatments for peritoneal dialysis peritonitis were identified referring to a Cochrane Library and Renal Health Library search (2005 update). Quality of SR and RCT was assessed according to current methodological standards. RESULTS: Thirty-six RCT were found addressing the intervention issue. Vancomycin or first generation cephalosporins may be used for treating peritoneal dialysis peritonitis due to Gram-positive agents. Third-generation cephalosporins or amino-glycosides may be used for Gram-negative agents peritonitis. Association of first-generation cephalosporins and agents against Gram-negative bacteria via the intraperitoneal route represents the most frequently used approach. Intraperitoneal administration of antibiotic agents is the most effective treatment of peritoneal dialysis peritonitis. Intermittent administration may be preferred to continuous administration of antibiotic agents in peritoneal dialysis peritonitis. CONCLUSION: In peritoneal dialysis peritonitis current evidence supports the hypothesis that intraperitoneal administration of antibiotics agents and intermittent administration may be preferred to other routes of administration and continuous administration. Further studies are necessary to test this hypothesis in selected patient populations.

[The Italian Society of Nephrology Guidelines (3rd Edition): principles and methods]. / I principi ed i metodi della III edizione delle Linee Guida della Società Italiana di Nefrologia (2005-2006).

Scientific Societies at both a local and international level are making big effort to prepare their clinical practice guidelines. The Italian Society of Nephrology has already published in two previous editions a series of guidelines relating to various aspects of management and diagnosis of different renal diseases. In this review we present the criteria of the 3(rd) edition of the Italian Society of Nephrology guidelines. This 3(rd) edition of guidelines will be based on the availability of scientific evidence in different areas of nephrology, dialysis and transplantation. Ten key intervention questions have been identified, based on the availability of systematic reviews of randomized trials or individual randomized address them. Systematic reviews and randomized trials are the optimal study design to address intervention questions. These have been summarized based upon rigid methodological criteria and strictly reflect the evidence basis. The different phases of development and publication of the 3(rd) edition of the Italian Society of Nephrology guidelines are presented.

Atherosclerotic renovascular disease: medical therapy versus medical therapy plus renal artery stenting in preventing renal failure progression: the rationale and study design of a prospective, multicenter and randomized trial (NITER).

BACKGROUND: Many studies suggest a major prevalence of atherosclerotic renovascular disease (ARVD), caused by mono or bilateral renal artery stenosis (RAS). Unfortunately, there is no definite therapy to cure this disease to date; therefore, ARVD is burdened by important clinical complications with high social and economic costs. The last few years have seen important advancements in both medical therapy and in interventional radiology (for example, percutaneous transluminal renal artery stenting (PTRS)). All of them could affect, in some way, the natural history of ARVD, but to date the optimal strategy has not been established. METHODS: The protocol of a prospective, multicenter, randomized trial "Nephropathy Ischemic Therapy (NITER)" is presented. It enrolls patients with stable renal failure (glomerular filtration rate (GFR) >or=30 ml/min) and hypertension, and hemodynamically significant atherosclerotic ostial RAS (>or=70%) diagnosed by duplex Doppler (DD) ultrasonography and confirmed by magnetic resonance angiography (MRA). This study aims to evaluate whether medical therapy plus interventional PTRS is superior to medical therapy alone according to the following combined primary endpoint: death or dialysis initiation or reduction by >20% in estimated GFR after 0.5, 1, and 2 yrs of follow-up and an extended follow-up until the 4th year. Medical therapy means drugs to control hypertension, improve dyslipidemia and optimize platelet anti-aggregant therapy. The sample size is estimated in 50 patients per group to achieve a statistical significance of 0.05 in case of a reduction by 50% in the combined endpoints.

[Successful treatment with liposomal doxorubicin and foscarnet in a patient with widespread Kaposi's sarcoma and human herpes virus 8-related, serious hemophagocytic syndrome, after renal transplantation]. / Efficacia del trattamento con doxorubicina liposomiale e foscarnet in un caso di sarcoma di Kaposi disseminato e grave sindrome emofagocitica herpes virus 8 correlate, nel post-trapianto di rene.

BACKGROUND: It is well known that the human herpes virus 8 (HHV8) is linked to several malignancies such as Kaposi's sarcoma (KS). Moreover, pancytopenia due to hemophagocytic syndrome could be associated with HHV8 infection. In renal transplant recipients affected by KS, the tapering of immunosuppression often leads to KS remission, but also results in graft loss in >50% of cases. Chemotherapy and antiviral therapy have also been used, mainly in the presence of visceral involvement. CASE REPORT: We describe a transplant recipient with widespread cutaneous and visceral KS HHV8 associated, complicated by hemophagocytic syndrome. At transplantation the patient's serology for HHV8 was negative, but thereafter it became positive. The first step in treatment (cyclosporine dose reduction until suspension) failed to improve the clinical course. Therefore, therapy combining liposomal doxorubicin and foscarnet was started. Clearance of HHV8 in the blood and complete resolution of the KS lesions were achieved. Immunosuppression with cyclosporine was resumed. No KS relapse has occurred, blood tests for HHV8 are negative, and graft function is good after a 5-yr follow-up. CONCLUSIONS: Therapy combining liposomal doxorubicin and foscarnet was effective in this renal transplant recipient with KS and HHV8 infection and enabled us to resume immunosuppressive therapy; therefore, reducing the risk of acute/chronic rejection.

Experience with cyclosporine.

Six hundred thirty-eight cadaveric kidney transplant patients between 1983 and 2001 were treated with cyclosporine (CsA) for 87 +/- 58 months. Among 571 patients with follow-up greater than 12 months, the 15-year renal function was investigated to assess the probability of a >30% increase in serum creatinine (sCr) above the month-6 value (baseline) and the impact on graft survival. At 15 years, patient and graft survival rates were 82.7% and 56.1%, respectively, with a 19.5-year half-life (censored for deaths). The main causes of graft loss were chronic rejection (33.0%) and patient death (24%). Cardiovascular disease and neoplasms were the main causes of death. Renal function remained stable in 266 patients (46.6%) with excellent sCr values observed even after a 15-year treatment period. An increased sCr was observed in 305 patients (53.4%) with a 15-year probability of 74%. In 178 patients (59.3%) it was self-limited; their grafts are still functioning well. One hundred three patients (32.8%) lost their graft which was more likely when the sCr had increased >45%. Twenty-four patients (7.9%) died with a functioning graft. Multivariate analysis showed the progression of graft deterioration to be related to proteinuria (P<.0001), a late acute rejection episode (P<.002), or the extent of sCr increase (P<.008). In conclusion, the long-term use of CsA has allowed us to achieve excellent long-term patient and transplant survival rates. Our data indicate a high 15-year probability of an increased sCr, but the rate of progression is slow.

[Guidelines of the Italian Society of Nephrology. Peritoneal dialysis Guidelines]. / Linee Guida della Societa' Italiana di Nefrologia. Linee Guida per la dialisi peritoneale (DP).

The adequate dosage of peritoneal dialysis (PD) has been defined (using unrandomized and uncontrolled studies) asKt/V = 2, with a total (peritoneal + renal) creatinine clearance = 60 mL/min. The recent prospective, randomized ADEMEX study, suggests targets of 1.8 and 54 mL/min respectively. Dialysis must also be adequate to control fluid removal, phosphate levels, nutritional status, and hypertension. The targets for automated PD (APD) should be either 10% more than CAPD or similar, depending on the time of blood sample collection either immediately at the end of the automated exchanges or 6 to 8 hours after. A peritoneal equilibration test should be done 1 to 2 months after the start of PD, yearly, and when peritoneal permeability or ultrafiltration changes occurr. Residual renal function must be protected as long as possible by avoiding nephrotoxic drugs and excessive dehydration. Every effort must be taken in the attempt to maintain a good nutritional status and to diagnose as soon as possible any changes toward malnutrition. Hypertension has a high prevalence in PD patients and has negative effects on both cardiovascular status and patient survival. However, anti-hypertensive therapy should avoid hypotension, mainly in older patients, who are more at risk for cerebrovascular accident. Hyperparathiroidism must be controlled by diet, phosphate binders, and calcitriol supplement, but attention must be paid to avoid cardiac and vascular calcifications. Peritonitis and exit-site infection should be prevented by all means available. In the case of infection, empiric antibiotic therapy should be started as soon as possible and then adapted according to the antibiogram.

Hepatocyte growth factor/scatter factor released during peritonitis is active on mesothelial cells.

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.

Direct effect of the correction of acidosis on plasma parathyroid hormone concentrations, calcium and phosphate in hemodialysis patients: a prospective study.

BACKGROUND: Metabolic acidosis contributes to renal osteodystrophy and together with hyperphosphatemia, hypocalcemia and altered vitamin D metabolism may result in increased levels of intact parathyroid hormone (iPTH) and metastatic calcifications. However, the impact of the correction of metabolic acidosis on iPTH levels and calcium-phosphate metabolism is still controversial. STUDY DESIGN: The effects of the correction of metabolic acidosis on serum concentrations of iPTH, calcium (Ca), phosphate (PO(4)) and alkaline phosphatase were prospectively studied. Twelve uremic patients on maintenance hemodialysis (HD) for 49 months (median; range 6-243 months) with serum bicarbonate levels < or =20 mmol/l were studied before and after 3 months of oral sodium bicarbonate supplementation. Predialysis serum bicarbonate, arterial pH, ionized calcium, plasma sodium, plasma potassium, serum creatinine, hemoglobin, K(t)/V, postdialysis body weight, predialysis systolic and diastolic blood pressure were also evaluated before and after correction. RESULTS: Serum bicarbonate levels and arterial pH increased respectively from 19.3 +/- 0.6 to 24.4 +/- 1.2 mmol/l (p < 0.0001) and 7.34 +/- 0.03 to 7.40 +/- 0.02 (p < 0.001). iPTH levels decreased significantly from 399 +/- 475 to 305 +/- 353 pg/ml (p = 0.026). No changes in total serum Ca, plasma PO(4), serum akaline phosphatase, K(t)/V, serum creatinine, hemoglobin, body weight, predialysis systolic and diastolic blood pressures were observed. iCa decreased significantly. CONCLUSIONS: Our study demonstrates that the correction of metabolic acidosis in chronic HD patients reduces iPTH concentrations in HD patients with secondary hyperparathyroidism possibly by a direct effect on iPTH secretion.

Adequacy of dialysis reduces the doses of recombinant erythropoietin independently from the use of biocompatible membranes in haemodialysis patients.

BACKGROUND: The effect of the adequacy of dialysis on the response to recombinant human erythropoietin (rHuEpo) therapy is still incompletely understood because of many confounding factors such as iron deficiency, biocompatibility of dialysis membranes, and dialysis modality that can interfere. METHODS: We investigated the relationship between Kt/V and the weekly dose of rHuEpo in 68 stable haemodialysis (HD) patients (age 65+/-15 years) treated with bicarbonate HD and unsubstituted cellulose membranes for 6-343 months (median 67 months). Inclusion criteria were HD for at least 6 months, subcutaneous rHuEpo for at least 4 months, transferrin saturation (TSAT) > or = 20%, serum ferritin > or = 100 ng/ml, and haematocrit (Hct) level targeted to 35% for at least 3 months. Exclusion criteria included HBsAg and HIV positivity, need for blood transfusions or evidence of blood loss in the 3 months before the study, and acute or chronic infections. Hct and haemoglobin (Hb) levels were evaluated weekly for 4 weeks; TSAT, serum ferritin, Kt/V, PCRn, serum albumin (sAlb), and weekly dose of rHuEpo were evaluated at the end of observation. No change in dialysis or therapy prescription was made during the study. RESULTS: The results for the whole group of patients were: Hct 35 +/- 1.2%, Hb 12.1 +/- 0.6 g/dl, TSAT 29 +/- 10%, serum ferritin 204 +/- 98 ng/ml, sAlb 4.1 +/- 0.3 g/dl, Kt/V 1.33 +/-0.19, PCRn 1.11+/- 0.28 g/kg/day, weekly dose of rHuEpo 123 +/- 76 U/kg. Hct did not correlate with Kt/V, whereas rHuEpo dose and Kt/V were inversely correlated (r = -0.49; P < 0.0001). Multiple regression analysis with rHuEpo as dependent variable confirmed Kt/V as the only significant variable (P < 0.002). Division of the patients into two groups according to Kt/V (group A, Kt/V < or = 1.2; group B, Kt/V > or = 1.4), showed no differences in Hct levels between the two groups, while weekly rHuEpo dose was significantly lower in group B than in group A (group B, 86 +/- 33 U/kg; group A, 183 +/- 95 U/kg, P < 0.0001). CONCLUSIONS: In iron-replete HD patients treated with rHuEpo in the maintenance phase, Kt/V exerts a significant sparing effect on rHuEpo requirement independent of the use of biocompatible synthetic membranes. By optimizing rHuEpo responsiveness, an adequate dialysis treatment can contribute to the reduction of the costs of rHuEpo therapy.