Chronic proteinuric nephropathies. II. Outcomes and response to treatment in a prospective cohort of 352 patients: differences between women and men in relation to the ACE gene polymorphism. Gruppo Italiano di Studi Epidemologici in Nefrologia (Gisen)

In the Ramipril Efficacy in Nephropathy study, ramipril decreased the rate of GFR decline (deltaGFR) and progression to end-stage renal disease (ESRD) in 352 patients with proteinuric chronic nephropathies. This study investigated whether in these patients disease outcome and response to treatment were affected by gender or insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene. deltaGFR (0.43 +/- 0.05 versus 0.48 +/- 0.08 ml/min per 1.73 m2) and incidence of ESRD (23 and 22%, respectively) were comparable in male and female patients. However, compared to conventional treatment, ramipril decreased deltaGFR (-52% versus -19%) and progression to ESRD (-74% versus -40%) more effectively in women than in men. Thus, the relative risk (95% confidence interval [CI]) of events (ESRD) between conventional and ramipril treatment was 5.52 (1.59 to 19.17, P = 0.003) in women, but only 1.80 (1.08 to 2.97, P = 0.02) in men. This gender-related effect of ramipril was associated with more reduction in proteinuria (-7.8 +/- 4.2% versus -21.9 +/- 5.7%, P = 0.05) and was still evident even after correction for potentially confounding factors such as baseline GFR, daily sodium intake, ramipril dose, BP control, and concomitant treatment with diuretics or dihydropyridinic calcium channel blockers (adjusted RR [95% CI]: women, 5.07 [1.26 to 20.38], P = 0.02; men, 1.44 [0.85 to 2.44], P = 0.17). Ramipril uniformly decreased deltaGFR and incidence of ESRD in women with either DD (-39% and - 100%) or II + ID (-71% and -82%) genotype, and in men (-25% and -50%) with the DD genotype, but had no beneficial effect in men with the II + ID genotype (+18% and +34%). Thus, the relative risk of events (ESRD) between conventional and ramipril-treated men was higher in subjects with the DD genotype (1.85; 0.69 to 4.94) and lower in those with the II +/- ID genotype (0.71; 0.28 to 1.80). Again, in parallel with deltaGFR and events, proteinuria decreased in women with DD (-23.3 +/-8.0%) or II + ID (-16.0 +/- 9.5%) genotype and in men with the DD genotype (-14.8 +/- 7.0%), but did not change in men with II + ID genotype (+ 1.0 +/- 7.8%). Of note, the ACE genotype-related effect of ramipril was still evident even after correction for the above potentially confounding factors (adjusted RR [95% CI]: DD, 2.52 [0.83 to 7.63], P = 0.10; II + ID, 0.35 [0.12 to 1.01], P = 0.05). Thus, among patients with chronic proteinuric nephropathies, men are at increased risk of progression due to their lower response to ACE inhibitor treatment. ACE inhibition is uniformly renoprotective in women regardless of the ACE polymorphism, and in men with the DD genotype, but is virtually devoid of beneficial effects in men with the II or ID genotype. This information may help to guide therapeutic interventions in clinical practice and to interpret the results of prospective trials in chronic renal disease.     

Protective Effect of Oral Acetylcysteine against the Hepatorenal Toxicity of Carbon Tetrachloride Potentiated by Ethyl Alcohol

Considering the well-documented protection of acetylcysteine (AC) in hepatotoxicity related to acetaminophen, we studied the preventive potential of AC against mild hepatotoxicity of CCl4, potentiated with ethyl alcohol (ETH) and the role of tissue glutathione. Rats fed a liquid diet with 30% of energy from ETH, had-intraperitoneal CCl4 administered in three injections, at 7-day intervals. AC was ingested at the level for acetaminophen overdose. ETH markedly potentiated the injury induced by CCl4, as evidenced by higher values of serum alanine aminotransferase (ALT), urinary bile acids (BA), serum creatinine, histological score of liver cell necrosis, mortality and by lower body weights and lower liver glutathione, when compared with CCl4 alone. Protective effect of AC consisted of a lesser hepatocytic necrosis, better body weights and higher liver glutathione. We conclude, that AC favorably modifies liver damage induced by CCl4 and potentiated with ETH. There is a preventive role for AC in subjects who combine ETH overuse with exposure to hepatotoxic xenobiotics, whose toxicity is modified by tissue glutathione.     

Rituximab in Steroid-Dependent or Frequently Relapsing Idiopathic Nephrotic Syndrome

The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and with major treatment toxicity. This academic, multicenter, off-on trial (ClinicalTrials.gov #{"type":"clinical-trial","attrs":{"text":"NCT00981838","term_id":"NCT00981838"}}NCT00981838) primarily evaluated the effects of rituximab therapy followed by immunosuppression withdrawal on disease recurrence in 10 children and 20 adults with MCD/MesGN (n=22) or FSGS who had suffered ≥2 recurrences over the previous year and were in steroid-induced remission for ≥1 month. Participants received one dose (n=28) or two doses of rituximab (375 mg/m² intravenously). At 1 year, all patients were in remission: 18 were treatment-free and 15 never relapsed. Compared with the year before rituximab treatment, total relapses decreased from 88 to 22 and the per-patient median number of relapses decreased from 2.5 (interquartile range [IQR], 2–4) to 0.5 (IQR, 0–1; P<0.001) during 1 year of follow-up. Reduction was significant across subgroups (children, adults, MCD/MesGN, and FSGS; P<0.01). After rituximab, the per-patient steroid maintenance median dose decreased from 0.27 mg/kg (IQR, 0.19–0.60) to 0 mg/kg (IQR, 0–0.23) (P<0.001), and the median cumulative dose to achieve relapse remission decreased from 19.5 mg/kg (IQR, 13.0–29.2) to 0.5 mg/kg (IQR, 0–9.4) (P<0.001). Furthermore, the mean estimated GFR increased from 111.3±25.7 to 121.8±29.2 ml/min per 1.73 m² (P=0.01), with the largest increases in children and in FSGS subgroups. The mean height z score slope stabilized in children (P<0.01). Treatment was well tolerated. Rituximab effectively and safely prevented recurrences and reduced the need for immunosuppression in steroid-dependent or frequently relapsing nephrotic syndrome, and halted disease-associated growth deficit in children.Idiopathic nephrotic syndrome (NS) in children and young adults is almost invariably the clinical counterpart of a continuum of glomerular diseases ranging from the relatively frequent minimal change disease (MCD) and the less frequent mesangial proliferative GN (MesGN), which are predominantly observed in children, to the relatively uncommon FSGS that is observed more frequently in adult patients.¹ In a small minority of patients that are generally resistant to immunosuppressive therapies, the disease is due to molecular defects of one of the podocyte genes.² In all of the other cases, it appears to be immune-mediated, but the pathophysiologic process underlying glomerular injury remains poorly understood.³Independent of the underlying renal pathology, prednisone continues to be the cornerstone treatment at disease onset, achieving remission within 4 weeks in approximately 90% of children with MCD and in 20%–60% of those with FSGS.^4,5 However, 60%–70% of patients relapse after steroid tapering or withdrawal, and most require repeat courses of prednisone to achieve remission of recurrent episodes and/or the addition of other immunosuppressive medications, such as calcineurin inhibitors, mycophenolate mofetil, or alkylating agents, to reduce the number of relapses and prevent major side effects of steroid treatment.⁶ According to their relapse rate, these patients are classically labeled as “steroid-dependent” or “frequently relapsing”. In these patients, serious adverse effects of treatment associate with complications of relapsing episodes of heavy proteinuria. These are the patients in most urgent need of more effective and safer treatment.The possibility of a specific and, hopefully, safer approach to patients with steroid-dependent or frequently relapsing NS emerged in 2004 when the B cell–depleting mAb rituximab was reported to induce remission of proteinuria in a child with frequently relapsing NS secondary to MCD who had received this medication to cure a supervened idiopathic thrombocytopenic purpura.⁷ Subsequent uncontrolled observations found some effect of rituximab in patients with steroid-dependent or frequently relapsing MCD,^8–11 suggesting that B-cell immunity could play a key role in the pathophysiology of the disease. Controlled studies in support of this hypothesis, however, have been both scanty and almost confined to children^12,13 or to patients with MCD who were evaluated in the context of a retrospective, observational design.¹⁴ Indeed, less attention was given to adults and patients with FSGS given difficulties in designing adequately powered trials.Here, we designed a longitudinal, off-on study (ClinicalTrials.gov #{"type":"clinical-trial","attrs":{"text":"NCT00981838","term_id":"NCT00981838"}}NCT00981838) to evaluate the efficacy of rituximab in reducing the incidence of relapses and need for steroid and other immunosuppressive medications in children and adults with steroid-dependent or frequently relapsing NS due to MCD, MesGN, or FSGS. To minimize the side effects and costs of rituximab, we abandoned the standard four-dose protocol originally implemented for the treatment of B-cell lymphomas,¹⁵ and adopted a new B cell–driven regimen we found to achieve remission of NS in patients with idiopathic membranous nephropathy (IMN) as effectively as the standard protocol, but with fewer side effects and less costs.¹⁶     

Gender effects on cardiac valvular function in hyperprolactinaemic patients receiving cabergoline: a retrospective study

Background Ergot‐derived dopamine agonists are associated with increased risk of valvular dysfunction in Parkinson’s disease. The risk of valvular disease associated with lower doses of cabergoline used to treat prolactinomas remains controversial. Objective To determine whether there is an association of cabergoline and valvular function in patients with hyperprolactinaemia according to gender. Design Case‐record retrospective study. Setting Outpatient neuroendocrine clinical centre at a tertiary care hospital. Study participants One hundred patients (48 men and 52 women) with hyperprolactinaemia who had an echocardiogram while receiving cabergoline for at least 6 months. Controls One hundred controls (48 men and 52 women) selected from Massachusetts general hospital (MGH) database of echocardiograms without clinically significant findings, matched to patients for age, gender, body mass index (BMI) and hypertension. Main outcome measure Echocardiogram. Results There were no significant differences in valvular function in patients compared with controls. However, women patients had a higher prevalence of mild tricuspid regurgitation (TR) than female controls (15·4%vs. 1·9%, P = 0.03). Among men only, patients had more trace TR than controls (68·8%vs. 45·8%, P = 0.02). The mild valvular regurgitation in patients was not clinically significant and did not correlate with dose, duration or cumulative dose. Conclusions Overall cabergoline was not associated with valvulopathy. However, subdivided by gender, hyperprolactinaemic men and women had higher prevalence of trace or mild TR, respectively, compared with gender matched controls. There may be gender differences in valvular dysfunction associated with cabergoline. Longer term, larger studies are necessary to evaluate definitively an effect of cabergoline on valvular function in hyperprolactinaemic patients.     

Socioeconomic status and maternal cigarette smoking before, during and after a pregnancy

Abstract: Research suggests that cigarette use declines when women find out they are pregnant, increasing again after the birth. Pregnancy may provide many women with a substantial impetus to stopping smoking. Also, rates of smoking cessation and reduction may be class-related, with the highest socioeconomic-status groups manifesting higher rates of reduction. Using data from the Mater Hospital-University of Queensland Study of Pregnancy, we report family income related to rates of smoking before, during and after a pregnancy. Before becoming pregnant, 45.9 per cent of women in the sample were smokers. This declined to 34.7 per cent of women at their first clinic visit. Rates of heavy smoking (20 or more cigarettes per day) had returned to earlier levels by the six-month (after birth) follow-up. Women in the lowest family-income group had the highest rates of cigarette use before, during and after their pregnancy. Of the lowest family-income group, 8.4 per cent were heavy smokers before, during and after their pregnancy, compared with 2.8 per cent of women in the highest family-income group. Smoking cessation rates were highest in the highest family-income group (those who smoked least), but relapse rates after the birth were similar for all income groups. Arresting rates of smoking relapse by pregnant women should be seen as a major public health priority     

Xenotransplantation in the 21st century.

Xenotransplantation, i.e. transplantation across species, is increasingly being viewed a potential solution to the problem of severe shortage of transplant donors. Clinical application of xenotransplantation is, however, limited in large part by the pre-eminent hurdle of the immune response of the recipient against the graft. This immunologic reaction is mediated initially by natural xenoreactive antibodies, complement and natural killer cells, and later by elicited humoral and cellular immune responses that ultimately lead to graft failure. Progress in understanding the cellular and molecular basis of xenograft rejection has characterized the past few years. Additional hurdles to xenotransplantation include physiologic incompatibility of the transplant and the risk of infections. The recent development of novel strategies to overcome xenograft rejection has brought about great optimism that xenotransplantation may be attainable in the near future.     

Morphometrical analysis of glomerular changes induced by cyclosporine in the rat

Functional and morphologic techniques were used to study the renal changes induced by a long-term exposure of normal rats to cyclosporine A (CsA), as well as their potential reversibility. CsA treatment for 3 months resulted in a significant (P less than 0.01) reduction of glomerular filtration rate (GFR) as compared with vehicle-treated animals. Histological examination of the kidneys showed mild glomerular damage characterized by ischemic lesions, increased mesangial matrix, and intracapillary hypercellularity in the CsA-treated group, but not in the vehicle-treated group. Proximal tubular abnormalities and limited areas of interstitial fibrosis were also present in the CsA group. A complete reconstruction of glomerular corpuscle was used to evaluate the consequence of CsA-induced renal ischemia on capillary tuft volume. The results showed that in rats administered CsA for 3 months glomerular volume distribution was shifted toward small glomeruli. Prolongation of CsA administration for 5 months did not result in a further decrease in GFR, and was associated with the appearance of a subset of glomeruli that became larger than normal. We have also investigated whether, once established, CsA-induced renal injury is reversible. In rats that were administered CsA for 3 months and then treatment discontinued for 2 months, GFR returned to pretreatment values and partial reversibility of morphologic changes was observed. Morphometric analysis showed that 2 months after withdrawal of CsA, glomerular volume distribution was almost comparable to that observed in vehicle-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies of fish consumption as source of methylmercury should consider fish-meal-fed farmed fish and other animal foods

The co-occurrence of fish MeHg and omega-3 fatty acids in wild species can indeed be optimized by choosing certain species. Farmed finfish and shellfish that are fed fish-meal, however, can bioconcentrate both MeHg (in muscle) and organohalogen pollutants passed on in the fat components [Dorea, J.G., 2006. Fish meal in animal feed and human exposure to persistent bioaccumulative and toxic substances. J. Food Prot. 69, 2777-2785); when fish-meal is used to feed farm animals it may offer the worst of both worlds: saturated fat (with organohalogen pollutants) and MeHg. It is time to address the dietary sources of Hg derived from animals raised on fish-meal that may contribute to increase tissue Hg concentrations.