Aberrant glycosylation in IgA nephropathy (IgAN)

Aberrant glycosylation in IgA nephropathy (IgAN). Immunoglobulin A nephropathy (IgAN) patients exhibit circulating IgA1 with reduced galactose (Gal) and/or sialic acid (Neu5Ac) and increased exposure of N-acetylgalactosamine (GalNAc). These IgA glycoforms fix complement and in mesangial cells regulate integrin expression, enhance nitric oxide synthase (NOS) activity, decrease endothelial growth factor synthesis, meanwhile depressing proliferation and increasing apoptotis. Drugs can be targeted to the effects enhanced by aberrantly glycosylated IgA1 on mesangial cells. Recent data suggest that aberrant IgA1 glycosylation may modulate clinical expression and progression of IgAN

IgA nephropathy at two score and one

On May 26–28, 2009, an international symposium on IgA nephropathy was convened in Stresa, Italy, as a Satellite Symposium of the World Congress of Nephrology held in Milan. This meeting was attended by a large number of scientists and clinicians working in the field of IgA nephropathy. The oral and poster presentations (over 70) ranged from very fundamental structural biology to clinical management. This article attempts to summarize the main findings of the meeting and to put forth some new perspectives and hypotheses regarding human IgA nephropathy on the 41st anniversary of its original description by Berger and Hinglais in 1968

outcome of childhood onset full house nephropathy

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A possible role for nitric oxide in modulating the functional cyclosporine toxicity by arginine

A possible role for nitric oxide in modulating the functional cyclosporine toxicity by arginine. The renal damage consequent to cyclosporine A (CsA) administration ranges from hemodynamic alterations to irreversible chronic lesions. The initial vasoconstriction depends upon the imbalance between the various modulators of the renal vascular tone, among which the most powerful are endothelins and nitric oxide (NO). CsA could play a crucial role by inhibiting the Ca++/calmodulin-mediated activation of the constitutive NO synthase (NOS) isoform, which converts L-arginine (L-Arg) into NO and citrulline, with a 1:1 stoichiometry. To investigate the possibility of modulating CsA nephrotoxicity with L-Arg we studied six groups (G) of Lewis rats treated with daily gavage up to eight weeks: G1, CsA 40 mg/kg; G2, G1 plus L-Arg 300 mg/kg; G3, G2 plus the competitive inhibitor of NOS, NG-nitro-L-Arg (L-NNA); G4, L-Arg alone; G5, L-NNA alone; and G6, controls receiving vehicle alone. After eight weeks L-Arg treated rats were protected against the toxic effects of CsA [creatinine (Cr) values, G2, 0.62 ± 0.05 mg/dl vs. G1, 0.99 ± 0.16 mg/dl, P < 0.001; proteinuria (P), G2, 7.2 ± 1.02 mg/day vs. G1, 15.1 ± 1.9 mg/day, P < 0.01]. The administration of L-NNA abolished the protective effect of L-Arg (G3, Cr 1.23 ± 0.16 mg/dl; P 16.9 = 2.3; P < 0.02 and P < 0.005, respectively vs. G2). The levels of Cr in G2 rats were superimposable to control groups. The NOS activity, evaluated by measuring [3H]citrulline formation from [3H]L-Arg in kidney homogenates, was blocked by L-NNA in G5 (0.019 ± 0.009 pmol/min/mg proteins vs. G6 0.047 ± 0.002, P < 0.01). NOS activity was significantly increased versus controls in G1 (0.110 ± 0.032, P < 0.01) and G2 (0.088 ± 0.009, P < 0.02), while L-NNA reversed this phenomenon (G3, 0.052 ± 0.03). The expression of mRNA encoding for cNOS and iNOS was only slightly increased in CsA-treated rats. We suggest that CsA treatment increases NOS activity in the kidney by a mechanism which does not require a de novo synthesis of the enzyme. Such an increase, that may be devoted to counterbalance the vasoconstrictive effects of the drug, is unable to reduce the toxic effect of CsA in the absence of exogenous L-Arg. Administration of L-Arg is likely to reduce CsA nephrotoxicity by accomplishing the higher request of activated NOS for its substrate, thus potentiating NO synthesis in the kidney.

Considerations on equity in management of end-stage kidney disease in low- and middle-income countries

Achievement of equity in health requires development of a health system in which everyone has a fair opportunity to attain their full health potential. The current, large country-level variation in the reported incidence and prevalence of treated end-stage kidney disease indicates the existence of system-level inequities. Equitable implementation of kidney replacement therapy (KRT) programs must address issues of availability, affordability, and acceptability. The major structural factors that impact equity in KRT in different countries are the organization of health systems, overall health care spending, funding and delivery models, and nature of KRT prioritization (transplantation, hemodialysis or peritoneal dialysis, and conservative care). Implementation of KRT programs has the potential to exacerbate inequity unless equity is deliberately addressed. In this review, we summarize discussions on equitable provision of KRT in low- and middle-income countries and suggest areas for future research

Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN) : a double-blind, randomised, placebo-controlled phase 2b trial

Background IgA nephropathy is thought to be associated with mucosal immune system dysfunction, which manifests as renal IgA deposition that leads to impairment and end-stage renal disease in 20-40% of patients within 10-20 years. In this trial (NEFIGAN) we aimed to assess safety and efficacy of a novel targeted-release formulation of budesonide (TRF-budesonide), designed to deliver the drug to the distal ileum in patients with IgA nephropathy. Methods We did a randomised, double-blind, placebo-controlled phase 2b trial, comprised of 6-month run-in, 9-month treatment, and 3-month follow-up phases at 62 nephrology clinics across ten European countries. We recruited patients aged at least 18 years with biopsy-confirmed primary IgA nephropathy and persistent proteinuria despite optimised renin-angiotensin system (RAS) blockade. We randomly allocated patients with a computer algorithm, with a fixed block size of three, in a 1:1:1 ratio to 16 mg/day TRF-budesonide, 8 mg/day TRF-budesonide, or placebo, stratified by baseline urine protein creatinine ratio (UPCR). Patients self-administered masked capsules, once daily, 1 h before breakfast during the treatment phase. All patients continued optimised RAS blockade treatment throughout the trial. Our primary outcome was mean change from baseline in UPCR for the 9-month treatment phase, which was assessed in the full analysis set, defined as all randomised patients who took at least one dose of trial medication and had at least one post-dose efficacy measurement. Safety was assessed in all patients who received the intervention. This trial is registered with ClinicalTrials.gov, number NCT01738035. Findings Between Dec 11, 2012, and June 25, 2015, 150 randomised patients were treated (safety set) and 149 patients were eligible for the full analysis set. Overall, at 9 months TRF-budesonide (16 mg/day plus 8 mg/day) was associated with a 24.4% (SEM 7.7%) decrease from baseline in mean UPCR (change in UPCR vs placebo 0.74; 95% CI 0.59-0.94; p=0.0066). At 9 months, mean UPCR had decreased by 27.3% in 48 patients who received 16 mg/day (0.71; 0.53-0.94; p=0.0092) and 21.5% in the 51 patients who received 8 mg/day (0.76; 0.58-1.01; p=0.0290); 50 patients who received placebo had an increase in mean UPCR of 2.7%. The effect was sustained throughout followup. Incidence of adverse events was similar in all groups (43 [88%] of 49 in the TRF-budesonide 16 mg/day group, 48 [94%] of 51 in the TRF-budesonide 8 mg/day, and 42 [84%] of 50 controls). Two of 13 serious adverse events were possibly associated with TRF-budesonide-deep vein thrombosis (16 mg/day) and unexplained deterioration in renal function in follow-up (patients were tapered from 16 mg/day to 8 mg/day over 2 weeks and follow-up was assessed 4 weeks later). Interpretation TRF-budesonide 16 mg/day, added to optimised RAS blockade, reduced proteinuria in patients with IgA nephropathy. This effect is indicative of a reduced risk of future progression to end-stage renal disease. TRF-budesonide could become the first specific treatment for IgA nephropathy targeting intestinal mucosal immunity upstream of disease manifestation.Peer reviewe