Further decompensation in cirrhosis: Results of a large multicenter cohort study supporting Baveno VII statements.

BACKGROUND AND AIMS: The prognostic weight of further decompensation in cirrhosis is still unclear. We investigated the incidence of further decompensation and its effect on mortality in patients with cirrhosis. APPROACH AND RESULTS: Multicenter cohort study. The cumulative incidence of further decompensation (development of a second event or complication of a decompensating event) was assessed using competing risks analysis in 2028 patients. A 4-state model was built: first decompensation, further decompensation, liver transplant, and death. A cause-specific Cox model was used to assess the adjusted effect of further decompensation on mortality. Sensitivity analyses were performed for patients included before or after 1999. In a mean follow-up of 43 months, 1192 patients developed further decompensation and 649 died. Corresponding 5-year cumulative incidences were 52% and 35%, respectively. The cumulative incidences of death and liver transplant after further decompensation were 55% and 9.7%, respectively. The most common further decompensating event was ascites/complications of ascites. Five-year probabilities of state occupation were 24% alive with first decompensation, 21% alive with further decompensation, 7% alive with a liver transplant, 16% dead after first decompensation without further decompensation, 31% dead after further decompensation, and <1% dead after liver transplant. The HR for death after further decompensation, adjusted for known prognostic indicators, was 1.46 (95% CI: 1.23-1.71) ( p <0.001). The significant impact of further decompensation on survival was confirmed in patients included before or after 1999. CONCLUSIONS: In cirrhosis, further decompensation occurs in ~60% of patients, significantly increases mortality, and should be considered a more advanced stage of decompensated cirrhosis.

Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology.

BACKGROUND & AIMS: Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model. METHODS: In total, 776 patients who underwent elective TIPS (TIPS cohort) and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses. RESULTS: In the TIPS/non-TIPS cohorts, the etiology of liver disease was viral in 402/188, alcoholic in 185/130, and non-alcoholic steatohepatitis in 65/33; mean follow-up±SD was 25±9/19±21 months; and the number of deaths at 3-6-12 months was 57-102-142/31-47-99, respectively. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in the non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used to update the MELD. CONCLUSIONS: In this validation study, the performance of the MELD score was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for an update to the MELD score are proposed. LAY SUMMARY: While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model.

Real-life effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in hepatitis C patients with previous DAA failure.

BACKGROUND & AIMS: Sofosbuvir/velpatasivr/voxilaprevir (SOF/VEL/VOX) is approved for retreatment of patients with HCV and a previous failure on direct-acting antivirals (DAAs), however real-life data are limited. The aim of this study was to assess the effectiveness and safety of SOF/VEL/VOX in a real-life setting. METHODS: All consecutive patients with HCV receiving SOF/VEL/VOX between May-October 2018 in 27 centers in Northern Italy were enrolled. Bridging fibrosis (F3) and cirrhosis (F4) were diagnosed by liver stiffness measurement: >10 and >13 kPa respectively. Sustained virological response (SVR) was defined as undetectable HCV-RNA 4 (SVR4) or 12 (SVR12) weeks after the end-of-treatment. RESULTS: A total of 179 patients were included: median age 57 (18-88) years, 74% males, median HCV-RNA 1,081,817 (482-25,590,000) IU/ml. Fibrosis stage was F0-F2 in 32%, F3 in 21%, F4 in 44%. HCV genotype was 1 in 58% (1b 33%, 1a 24%, 1nc 1%), 2 in 10%, 3 in 23% and 4 in 9%; 82% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Patients received SOF/VEL/VOX for 12 weeks, ribavirin was added in 22% of treatment schedules. Undetectable HCV-RNA was achieved by 74% of patients at week 4 and by 99% at week 12. Overall, 162/179 (91%) patients by intention to treat analysis and 162/169 (96%) by per protocol analysis achieved SVR12, respectively; treatment failures included 6 relapsers and 1 virological non-responder. Cirrhosis (p = 0.005) and hepatocellular carcinoma (p = 0.02) were the only predictors of treatment failure. Most frequent adverse events included fatigue (6%), hyperbilirubinemia (6%) and anemia (4%). CONCLUSIONS: SOF/VEL/VOX is an effective and safe retreatment for patients with HCV who have failed on a previous DAA course in a real-life setting. LAY SUMMARY: This is the largest European real-life study evaluating effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in a large cohort of consecutive patients with hepatitis C virus infection and a prior direct-acting antiviral failure, who were treated within the NAVIGATORE Lombardia and Veneto Networks, in Italy. This study demonstrated excellent effectiveness (98% and 96% sustained virological response rates at week 4 and 12, respectively) and an optimal safety profile of SOF/VEL/VOX. Cirrhosis and hepatocellular carcinoma onset were the only features associated with treatment failure.

Saccharomyces boulardii for the prevention of antibiotic-associated diarrhea in adult hospitalized patients: a single-center, randomized, double-blind, placebo-controlled trial.

OBJECTIVES: Antibiotic-associated diarrhea (AAD) and Clostridium difficile-associated diarrhea (CDAD) are common complications of antibiotic use. Probiotics were effective in preventing AAD and CDAD in several randomized controlled trials. This study was aimed at testing the effect of Saccharomyces boulardii on the occurrence of AAD and CDAD in hospitalized patients. METHODS: A single-center, randomized, double-blind, placebo-controlled, parallel-group trial was performed. Patients being prescribed antibiotics or on antibiotic therapy for <48 h were eligible. Exclusion criteria were ongoing diarrhea, recent assumption of probiotics, lack of informed consent, inability to ingest capsules, and severe pancreatitis. Patients received a capsule containing S. boulardii or an indistinguishable placebo twice daily within 48 h of beginning antibiotic therapy, continued treatment for 7 days after antibiotic withdrawal, and were followed for 12 weeks after ending antibiotic treatment. RESULTS: Of 562 consecutive eligible patients, 275 patients aged 79.2 ± 9.8 years (134 on placebo) were randomized and 204 aged 78.4 ± 10.0 years (98 on placebo) completed the follow-up. AAD developed in 13.3% (13/98) of the patients receiving placebo and in 15.1% (16/106) of those receiving S. boulardii (odds ratio for S. boulardii vs. placebo, 1.16; 95% confidence interval (CI), 0.53-2.56). Five cases of CDAD occurred, 2 in the placebo group (2.0%) and 3 in the probiotic group (2.8%; odds ratio for S. boulardii vs. placebo, 1.40; 95% CI, 0.23-8.55). There was no difference in mortality rates (12.7% vs. 15.6%, P=0.60). CONCLUSIONS: In elderly hospitalized patients, S. boulardii was not effective in preventing the development of AAD.

Real-world experience with obeticholic acid in patients with primary biliary cholangitis.

BACKGROUND & AIMS: Obeticholic acid (OCA) is the second-line treatment approved for patients with primary biliary cholangitis (PBC) and an inadequate response or intolerance to ursodeoxycholic acid. We aimed to evaluate the effectiveness and safety of OCA under real-world conditions. METHODS: Patients were recruited into the Italian PBC Registry, a multicentre, observational cohort study that monitors patients with PBC at national level. The primary endpoint was the biochemical response according to Poise criteria; the secondary endpoint was the biochemical response according to normal range criteria, defined as normal levels of bilirubin, alkaline phosphatase (ALP), and alanine aminotransferase (ALT) at 12 months. Safety and tolerability were also assessed. RESULTS: We analysed 191 patients until at least 12 months of follow-up. Median age was 57 years, 94% female, 61 (32%) had cirrhosis, 28 (15%) had histologically proven overlap with autoimmune hepatitis (PBC-AIH). At 12 months, significant median reductions of ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%) were observed. Response rates were 42.9% according to Poise criteria, and 11% by normal range criteria. Patients with cirrhosis had lower response than patients without cirrhosis (29.5% vs. 49.2%, p = 0.01), owing to a higher rate of OCA discontinuation (30% vs. 12%, p = 0.004), although with similar ALP reduction (29.4% vs. 34%, p = 0.53). Overlap PBC-AIH had a similar response to pure PBC (46.4% vs. 42.3%, p = 0.68), with higher ALT reduction at 6 months (-38% vs. -29%, p = 0.04). Thirty-three patients (17%) prematurely discontinued OCA because of adverse events, of whom 11 experienced serious adverse events. Treatment-induced pruritus was the leading cause of OCA discontinuation (67%). CONCLUSIONS: Effectiveness and safety of OCA under real-world conditions mirror those in the Poise trial. Patients with cirrhosis had lower tolerability. Overlap PBC-AIH showed higher ALT reduction at 6 months compared with patients with pure PBC. LAY SUMMARY: Obeticholic acid (OCA) was shown to be effective in more than one-third of patients not responding to ursodeoxycholic acid in a real-world context in Italy. Patients with cirrhosis had more side effects with OCA, and this led to suspension of the drug in one-third of patients. OCA was also effective in patients who had overlap between autoimmune hepatitis and primary biliary cholangitis.

Decompensated chronic heart failure: increased liver stiffness measured by means of transient elastography.

PURPOSE: To analyze transient elastography-measured liver stiffness in patients with acute decompensated heart failure to describe variations in liver stiffness measurements and assess their relationship with the patients' clinical course and laboratory data. MATERIALS AND METHODS: This study was approved by the local institutional review board, and all of the subjects gave verbal informed consent. Twenty-seven hospitalized patients with heart failure with no signs of liver disease (mean age, 79 years ± 12 [standard deviation]; 12 men [mean age, 78 years ± 11], 15 women [mean age, 80 years ± 12]) underwent liver stiffness and N-terminal proß brain natriuretic peptide (NTproßBNP) assessments at admission, and 24 patients underwent stiffness measurements at discharge. (Three patients had failed measurement at admission; two of whom did not undergo measurement at discharge and one patient who died had only an admission value obtained.) The predefined stiffness cutoff values were greater than 7.65 kPa for substantial fibrosis and greater than 13.01 kPa for cirrhosis. The control subjects were 21 patients unaffected by heart failure or liver disease. The two groups were compared by using two-tailed Wilcoxon, Mann-Whitney, or t tests, as appropriate. RESULTS: Among the patients with heart failure, median liver stiffness at admission was 8.80 kPa (interquartile range, 5.92-11.90 kPa), greater than 7.65 kPa in 14 (58%) cases and greater than 13.01 kPa in five (21%). During hospitalization, liver stiffness decreased in 18 patients (including all five patients with baseline measurement > 13.01 kPa) and increased in five. Median liver stiffness (P < .003) and NTproßBNP (P < .001) levels both significantly decreased during hospitalization. Liver stiffness was less than 7.65 kPa in all control patients and did not significantly change during hospitalization (P = .261). CONCLUSION: Most patients with acute decompensated heart failure have high liver stiffness values which, like NTproßBNP levels, tend to decrease with clinical improvement. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100013/-/DC1.

Coronavirus Disease 2019 in Autoimmune Hepatitis: A Lesson From Immunosuppressed Patients.

Chronic immunosuppression is associated with increased and more severe viral infections. However, little is known about the association between immunosuppression and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Our aim was to describe the clinical course of patients with immunosuppressed autoimmune hepatitis (AIH) during coronavirus disease 2019 (COVID-19) infection in Italy. Our study is a case series of patients with AIH treated with immunosuppression, who tested positive for SARS-CoV-2 in March 2020 during the outbreak of COVID-19. Ten patients from seven different hospitals in Italy were diagnosed with COVID-19 during the outbreak of SARS-CoV-2 in March 2020. Seven subjects were female (70%), and age ranged from 27 to 73 years. Before the onset of SARS-CoV-2 infection, all patients were taking immunosuppressive therapy for AIH, and eight of them were on biochemical remission. Two other patients had recent acute onset of their AIH, and consequently started high-dose steroids, as per induction protocol. All patients had a respiratory syndrome and a positive nasal swab for SARS-CoV-2. Five patients developed a computed tomography-confirmed COVID-19 pneumonia. Six subjects received a combination of antiretroviral and antimalarial drugs. In seven patients, the dosage of immunosuppressive medication was changed. Liver enzymes were repeated during SARS-CoV-2 infection in all hospitalized cases; they remained within the normal range in all cases, and improved in the two acute cases treated with high-dose steroids. The clinical outcome was comparable to the reported cases occurring in non-immunosuppressed subjects. Conclusion: Patients under immunosuppressive therapy for AIH developing COVID-19 show a disease course presumptively similar to that reported in the non-immunosuppressed population. These data might aid in medical decisions when dealing with SARS-CoV-2 infection in immunocompromised patients.

Renal safety in 3264 HCV patients treated with DAA-based regimens: Results from a large Italian real-life study.

BACKGROUND: Sofosbuvir (SOF)-based regimens have been associated with renal function worsening in HCV patients with estimated glomerular filtration rate (eGFR) ≤ 45 ml/min, but further investigations are lacking. AIM: To assess renal safety in a large cohort of DAA-treated HCV patients with any chronic kidney disease (CKD). METHODS: All HCV patients treated with DAA in Lombardy (December 2014-November 2017) with available kidney function tests during and off-treatment were included. RESULTS: Among 3264 patients [65% males, 67% cirrhotics, eGFR 88 (9-264) ml/min], CKD stage was 3 in 9.5% and 4/5 in 0.7%. 79% and 73% patients received SOF and RBV, respectively. During DAA, eGFR declined in CKD-1 (p < 0.0001) and CKD-2 (p = 0.0002) patients, with corresponding rates of CKD stage reduction of 25% and 8%. Conversely, eGFR improved in lower CKD stages (p < 0.0001 in CKD-3a, p = 0.0007 in CKD-3b, p = 0.024 in CKD-4/5), with 33-45% rates of CKD improvement. Changes in eGFR and CKD distribution persisted at SVR. Baseline independent predictors of CKD worsening at EOT and SVR were age (p < 0.0001), higher baseline CKD stages (p < 0.0001) and AH (p = 0.010 and p < 0.0001, respectively). CONCLUSIONS: During DAA, eGFR significantly declined in patients with preserved renal function and improved in those with lower CKD stages, without reverting upon drug discontinuation.

Microbial Preparations (Probiotics) for the Prevention of Clostridium difficile Infection in Adults and Children: An Individual Patient Data Meta-analysis of 6,851 Participants.

OBJECTIVETo determine whether probiotic prophylaxes reduce the odds of Clostridium difficile infection (CDI) in adults and children.DESIGNIndividual participant data (IPD) meta-analysis of randomized controlled trials (RCTs), adjusting for risk factors.METHODSWe searched 6 databases and 11 grey literature sources from inception to April 2016. We identified 32 RCTs (n=8,713); among them, 18 RCTs provided IPD (n=6,851 participants) comparing probiotic prophylaxis to placebo or no treatment (standard care). One reviewer prepared the IPD, and 2 reviewers extracted data, rated study quality, and graded evidence quality.RESULTSProbiotics reduced CDI odds in the unadjusted model (n=6,645; odds ratio [OR] 0.37; 95% confidence interval [CI], 0.25-0.55) and the adjusted model (n=5,074; OR, 0.35; 95% CI, 0.23-0.55). Using 2 or more antibiotics increased the odds of CDI (OR, 2.20; 95% CI, 1.11-4.37), whereas age, sex, hospitalization status, and high-risk antibiotic exposure did not. Adjusted subgroup analyses suggested that, compared to no probiotics, multispecies probiotics were more beneficial than single-species probiotics, as was using probiotics in clinical settings where the CDI risk is ≥5%. Of 18 studies, 14 reported adverse events. In 11 of these 14 studies, the adverse events were retained in the adjusted model. Odds for serious adverse events were similar for both groups in the unadjusted analyses (n=4,990; OR, 1.06; 95% CI, 0.89-1.26) and adjusted analyses (n=4,718; OR, 1.06; 95% CI, 0.89-1.28). Missing outcome data for CDI ranged from 0% to 25.8%. Our analyses were robust to a sensitivity analysis for missingness.CONCLUSIONSModerate quality (ie, certainty) evidence suggests that probiotic prophylaxis may be a useful and safe CDI prevention strategy, particularly among participants taking 2 or more antibiotics and in hospital settings where the risk of CDI is ≥5%.TRIAL REGISTRATIONPROSPERO 2015 identifier: CRD42015015701Infect Control Hosp Epidemiol 2018;771-781.

Treating anemia at different stages of renal disease.

Cardiovascular disease is the leading cause of the poor long-term survival of patients with chronic kidney disease (CKD). Anemia, which is a frequent and early complication of CKD, not only impairs patients' quality of life, but also is an independent risk factor for adverse cardiovascular outcomes. This may be due to its impact on cardiac function leading to the development of left ventricular hypertrophy. Starting from the clear association between higher hemoglobin levels and better outcomes found in observational surveys, a number of interventional studies have been designed to verify whether correcting anemia fully improves patient outcomes. The results have not indicated any major effect, although the majority of the studies were not primarily designed to test the effect of anemia correction on mortality. This is especially true in the case of CKD patients not undergoing dialysis. Many of these studies have also suffered from relatively short follow-up periods and from the fact that their statistical power was reduced because the difference in achieved hemoglobin levels between the experimental and control groups was often less than expected. Further studies aimed at better investigating the complex mechanisms underlying responsiveness to erythropoiesis-stimulating agents will probably help to explain the disagreement between observational studies and randomized clinical trials.

Pure red-cell aplasia "epidemic"--mystery completely revealed?

Starting in 1998, the number of pure red-cell aplasia (PRCA) cases in patients treated with recombinant human erythropoietin (rHuEPO) increased dramatically. Most cases were observed in patients treated with epoetin alfa produced outside the United States. The peak was observed in 2002; since then, the PRCA incidence has declined. Many factors are likely to have contributed to this up-surge. The molecular structure of the various epoetins and patient characteristics do not seem to play a major role. The route of administration holds some importance, because most PRCA patients received rHuEPO subcutaneously. The peak of PRCA cases overlapped with the removal of human serum albumin from the Eprex formulation (Janssen-Pharmaceutica NV, Beerse, Belgium), for which polysorbate 80 and glycine were substituted. Polysorbate 80 may have increased the immunogenicity of Eprex by eliciting the formation of epoetin-containing micelles or by interacting with leachates released by the uncoated rubber stoppers of prefilled syringes. Compared with the previous formulation, the polysorbate 80 formulation has lower stability, making it more susceptible to stress conditions such as insufficient attention to the cold chain. This situation could facilitate protein denaturation or aggregate formation. Uncoated rubber stoppers were replaced with coated stoppers, and the cold chain was reinforced; the Eprex formulation has remained unchanged. Even though the incidence of PRCA returned to very low levels, discriminating the cause-effect relationship of a single action is difficult, given that all occurred with a similar chronology, and that PRCA develops after a relatively long exposure period. Careful observation of future trends of new PRCA cases is thus mandatory.

Effectiveness of sodium and conductivity kinetic models in predicting end-dialysis plasma water sodium concentration: preliminary results of a single-center experience.

The attainment of a neutral sodium balance represents a major objective in hemodialysis patients. It requires that at the end of each dialysis session, total body water volume (V(f)) and total plasma water sodium concentration (Na(pwf)) are constant. Whereas to achieve a constant V(f) it is sufficient that ultrafiltration equals the interdialytic increase in body weight, it is impossible to predict the value of Na(pwf) and calculate the dialysate sodium concentration needed to obtain it without making use of kinetic mathematical models. The effectiveness of both sodium and conductivity kinetic models in predicting Na(pwf) has already been validated in previous clinical studies. However, applying the sodium kinetic model appears to be poorly feasible in the everyday clinical practice, due to the need for blood samples at the start of each dialysis session for the determination of predialysis plasma water sodium concentration. The conductivity kinetic model appears to be more easily applicable, because no blood samples or laboratory tests are needed to determine plasma water conductivity (C(pw)) and ionic dialysance (ID), used in place of plasma water sodium concentration and sodium dialysance, respectively. We applied the 2 models in 69 chronic hemodialysis patients using the Diascan Module for the automatic determination of C(pw) and ID, and using the latter as an estimate of sodium dialysance in the sodium kinetic model. The conductivity kinetic model was shown to be more accurate and precise in predicting Na(pwf) as compared with the sodium kinetic model. Both accuracy and imprecision of the 2 models were not significantly affected by the method used to estimate total body water volume. These findings confirm the conductivity kinetic model as being an effective and easily applicable instrument for the achievement of a neutral sodium balance in chronic hemodialysis patients.

Dialysis adequacy and response to erythropoiesis-stimulating agents: what is the evidence base?

Despite an increase in the use and average dose of erythropoiesis-stimulating agents (ESA) over the past 15 years, a substantial percentage of patients still do not achieve hemoglobin targets recommended by international guidelines. A clear relationship among hemoglobin or hematocrit levels, ESA dose, and increase in dialysis dose has been pointed out by a number of prospective or retrospective studies. This is particularly true in patients receiving inadequate dialysis. Increasing attention also has been paid to the relationship between dialysis, increased inflammatory stimulus, and ESA response because dialysate contamination and low-compatible treatments may increase cytokine production and consequently inhibit erythropoiesis. The biocompatibility of dialysis membranes and flux are other important factors. However, in highly selected, adequately dialyzed patients without iron or vitamin depletion, the effect of these treatment modalities on anemia seems to be smaller than expected. The role of on-line treatments still is controversial given that it is still difficult to discriminate between the effect of on-line hemodiafiltration per se from that of an increased dialysis dose. Very preliminary results obtained with short or long nocturnal daily hemodialysis on anemia correction are encouraging.

Nephrology: main advances in the last 40 years.

Modern nephrology has become one of the liveliest and most productive branches of medicine. Once seen as a temporary means of rescue from uremic coma, hemodialysis (HD) has allowed thousands of people with irreversible uremia to survive for many years, and evolving treatment modalities have led to a significant increase in efficacy and tolerability. At the same time, two other forms of renal replacement therapy (RRT) have been developed: peritoneal dialysis (PD) and renal transplantation. The number of end-stage renal disease (ESRD) patients requiring RRT has increased dramatically throughout the world for a number of reasons: the improved survival of patients affected by other diseases, a real increase in the incidence of chronic kidney disease (CKD) mainly due to the burden of 'metabolic syndrome', and the significant broadening of RRT acceptance criteria. This last factor means that RRT has become available to increasing numbers of elderly patients, diabetics and patients with other severe comorbidities, among whom the leading cause of death is cardiovascular disease (CVD). However, nephrology is not just a case of substituting the function of failing kidneys; it also covers the treatment of glomerular diseases, slowing down CKD progression and managing the related comorbidities, all of which have substantially improved over the last 40 yrs.

ACE inhibitors and angiotensin II receptor blockers in IgA nephropathy with mild proteinuria: the ACEARB study.

Few studies have investigated IgA nephropathy patients presenting with 'favorable' clinical features at onset, such as normal renal function, proteinuria<1 g/24 hours and the absence of hypertension, and no controlled clinical trials have tested the effects of treatment in such patients who may nevertheless develop end-stage renal disease. It is therefore important to find a well-tolerated and economic therapy capable of decreasing their risk of high proteinuria and blood pressure levels. The aim of this multicenter open-label randomized clinical trial is to test whether blocking the renin-angiotensin system (RAS) decreases the risk of progression in patients aged 3-60 years with biopsy-proven benign IgA glomerulonephritis, proteinuria levels of 0.3-0.9 g/24 hours, and normal renal function and blood pressure. The RAS is blocked by first using a single drug class (angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker), and then combining the 2 classes as soon as the 1-drug blockade has become ineffective. We plan to enroll 378 patients over the next 3 years and randomize them to receive ramipril 5 mg/day (3 mg/m2 in children) (group A), irbesartan 300 mg/day (175 mg/m 2 in children) (group B) or supportive therapy (group C); if an increase in proteinuria of at least 50% from baseline is detected after 6 months of treatment, the other RAS inhibitor will be added. The observation period will be at least 5 years (except in the case of the development of the primary end point).

The relevance of convection in clinical practice: a critical review of the literature.

Convective treatments (high-flux hemodialysis (HD), hemodiafiltration and hemofiltration) are characterized by enhanced removal of middle and large molecular weight solutes compared with conventional low-flux HD. As these molecules are claimed to play an important role in the genesis of many complications of chronic HD, the availability of these techniques represented an intriguing innovation and a possible means to improve the still poor prognosis of HD patients. Here we will critically review the most important published studies comparing convective treatments with low-flux HD on chronic morbidity, preservation of residual renal function, and long-term survival.

Anemia and heart failure in chronic kidney disease.

Cardiovascular disease is mainly responsible for the poor long-term survival observed in chronic kidney disease (CKD) patients on dialytic treatment. Anemia is an early complication of CKD and, by inducing important cardiovascular alterations, first of all left ventricular hypertrophy, it does not only impair quality of life, but has also been shown to be an independent risk factor for adverse cardiovascular outcomes in CKD patients. Clinical studies, although with discordant results, have shown that cardiovascular benefits, mainly in terms of left ventricular hypertrophy regression, may be achieved by a partial correction of hemoglobin levels, however, it still is unclear whether starting anemia correction in a very early phase of CKD or aiming for complete normalization of hemoglobin levels higher than the targets recommended by current guidelines may provide further cardiovascular advantages. Results of ongoing, large-scale, prospective, randomized, clinical trials therefore are awaited with much interest to clarify better which practices of anemia correction may provide the best results on the improvement of cardiovascular status and thus of long-term survival of patients with renal disease.

Clinical benefits of slowing the progression of renal failure.

End-stage renal disease is a social and economic threat worldwide. In this context, any medical intervention that may prevent the progression of chronic kidney disease becomes extremely important. Improving the cardiovascular status is another major objective in the management of this population, because cardiovascular disease is the leading cause of morbidity and mortality among dialysis patients. Moreover, this is only the tip of the iceberg, because many patients die before reaching end-stage renal disease. Today, several interventions are available to delay the progressive loss of renal function and/or prevent the development of cardiovascular disease, but we are still far from being satisfied. These interventions include low protein diets, correction of calcium-phosphate disorders and anemia, blood pressure and proteinuria control, and smoking cessation. Other interventions, such as the administration of lipid-lowering agents, are emerging as particularly promising therapeutic approaches. Recently, growing attention has been paid to polytherapeutic approaches to chronic kidney disease, in order to control different causal factors involved in progression and reduce them as much as possible. However, larger prospective, controlled, randomized clinical trials are needed to demonstrate their actual usefulness. All the interventions are likely to be more effective if performed as early as possible in the course of the disease, because it has been widely demonstrated that early and regular nephrologic care is associated with decreased morbidity and mortality.

Is it the agent or the blood pressure level that matters for renal and vascular protection in chronic nephropathies?

Over the recent years, it has been clearly documented that hypertension and proteinuria are the major factors responsible for progression of chronic kidney disease (CKD). Therefore, a target BP of at least 130/80 mm Hg has been suggested in order to reduce the rate of progression and cardiovascular mortality. Some antihypertensive agents, such as ACE inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and perhaps calcium channel blockers (CCBs), may also be capable of reducing CKD progression because they halt some of the pathogenetic mechanisms involved in renal damage, some of which is unrelated to reduction of proteinuria, per se. Although this specific effect seemed to be partially independent of blood pressure reduction, it remains controversial whether these drugs are really superior to other antihypertensive agents when blood pressure values recommended by guidelines are achieved. This issue is still a matter of debate because in published trials, target and achieved blood pressure values were constantly higher than those recommended today. Nevertheless, available findings seem to indicate that the renoprotective effect of these agents is at least partially independent of a better BP control. The only way to definitely solve this issue would be a new randomized trial. However, the clinical relevance of this trial is debatable, considering that we need all the drugs available to reach these recommended BP values.