Paola Mesiano

Genome-wide association study identifies susceptibility loci for IgA nephropathy

We carried out a genome-wide association study of IgA nephropathy, a major cause of kidney failure worldwide. We studied 1,194 cases and 902 controls of Chinese Han ancestry, with targeted follow up in Chinese and European cohorts comprising 1,950 cases and 1,920 controls. We identified three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance (P values for association between 1.59 × 10−26 and 4.84 × 10−9 and minor allele odds ratios of 0.63–0.80). These five loci explain 4–7% of the disease variance and up to a tenfold variation in interindividual risk. Many of the alleles that protect against IgA nephropathy impart increased risk for other autoimmune or infectious diseases, and IgA nephropathy risk allele frequencies closely parallel the variation in disease prevalence among Asian, European and African populations, suggesting complex selective pressures.

Effect of a plasma sodium biofeedback system applied to HFR on the intradialytic cardiovascular stability. Results from a randomized controlled study

Background Intradialytic hypotension (IDH) is still a major clinical problem for haemodialysis (HD) patients. Haemodiafiltration (HDF) has been shown to be able to reduce the incidence of IDH. Methods Fifty patients were enrolled in a prospective, randomized, crossover international study focussed on a variant of traditional HDF, haemofiltration with endogenous reinfusion (HFR). After a 1-month run-in period on HFR, the patients were randomized to two treatments of 2 months duration: HFR (Period A) or HFR-Aequilibrium (Period B), followed by a 1-month HFR wash-out period and then switched to the other treatment. HFR-Aequilibrium (HFR-Aeq) is an evolution of the haemofiltration with endogenous reinfusion (HFR) dialysis therapy, with dialysate sodium concentration and ultrafiltration rate profiles elaborated by an automated procedure. The primary end point was the frequency of IDH. Results Symptomatic hypotension episodes were significantly lower on HFR-Aeq versus HFR (23 ± 3 versus 31 ± 4% of sessions, respectively, P l= l0.03), as was the per cent of clinical interventions (17 ± 3% of sessions with almost one intervention on HFR-Aeq versus 22 ± 2% on HFR, P <0.01). In a post-hoc analysis, the effect of HFR-Aeq was greater on more unstable patients (35 ± 3% of sessions with hypotension on HFR-Aeq versus 71 ± 3% on HFR, P <0.001). No clinical or biochemical signs of Na/water overload were registered during the treatment with HFR-Aeq. Conclusions HFR-Aeq, a profiled dialysis supported by the Natrium sensor for the pre-dialysis Na+ measure, can significantly reduce the burden of IDH. This could have an important impact in every day dialysis practice.

Rituximab therapy for IgA-vasculitis with nephritis: a case series and review of the literature.

Henoch–Schonlein purpura, also called IgA-vasculitis, is a systemic small vessels vasculitis with immunoglobulin A1-dominant immune deposits. The optimal treatment remains controversial. Because IgA-vasculitis is characterized by leukocyte infiltration of the blood vessel walls along with immunoglobulin A deposition, and because glucocorticosteroids inhibit inflammatory processes, early administration of glucocorticosteroids has been postulated to be effective, but this indication remains controversial. Immunosuppressive agents (azathioprine, cyclophosphamide, cyclosporine, mycophenolate) have been used in combination with glucocorticosteroids without definitive evidence of effectiveness. The efficacy of rituximab in adult IgA-vasculitis has been reported in few cases. We described a monocentric experience on the use of rituximab in adult IgA-vasculitis with biopsy-proven nephritis. The patients achieved a complete remission of nephritis and syndromic manifestations, and no patients experienced adverse reactions. These data have been compared with the limited literature nowadays available.

Vascular Injury by Arterial Hypertension in Anti-Phospholipid AntibodySyndrome

Antiphospholipid Syndrome (APS) is defined as the presence of recurrent arterial or venous thrombosis and/or pregnancy morbidity and persistently elevated levels of antiphospholipid antibodies (aPLs) [1]. APS is classified as being primary if autoimmunity is negative, and secondary when it occurs in the course of an autoimmune disease, most often systemic lupus erythematosus [2]. In the original description of the syndrome made by Hughes, arterial hypertension was a common feature that was often associated with livedo reticularis [3]. Thrombosis in vessels of all sizes of the renal vasculature may be responsible for a wide range of renal diseases including systemic hypertension, renal artery stenosis, renal infarction, APS nephropathy, thrombotic microangiopathy and renal vein thrombosis [4]. The prevalence of hypertension (which ranges from mild to severe) in APS is significantly higher in the presence of renal involvement (57.1% versus 22.6% in Sinicos cohort [5]), and the kidney may be considered both the ‘culprit’ and the ‘victim’ of hypertension in APS, as occurs in other forms of hypertension. We present a case of primary APS with multiple organ involvement, kidney disease and newly diagnosed arterial hypertension, and we discuss the possible mechanisms and management of hypertension in the course of this rare disease.

IgG4-related kidney disease: The effects of a Rituximab-based immunosuppressive therapy

IgG4-related disease (IgG4-RD) is a recently recognized disorder, characterized by elevated serum IgG4 concentrations, dense tissue infiltration of IgG4-positive plasma cells and storiform fibrosis. Treatment is usually based on steroids, however, relapses and long-term adverse effects are frequent. We prospectively studied 5 consecutive patients with histologically-proven IgG4-RD and renal involvement, treated with an extended Rituximab protocol combined with steroids. Two doses of intravenous cyclophosphamide were added in 4 patients. Five patients with IgG-RD were investigated: three had tubulointerstitial nephritis (TIN), while two had retroperitoneal fibrosis (RPF). In the patients with TIN, renal biospy was repeated after 1 year. In the patients with TIN, estimated glomerular filtration rate (eGFR) at 12 months increased from 9 to 24 ml/min per 1.73 m2; IgG/IgG4 decreased from 3,236/665 to 706/51 mg/dl; C3/C4 increased from 49/6 to 99/27 mg/dl; CD20+ B-cells decreased from 8.7% to 0.5%; Regulatory T-cells decreased from 7.2% to 2.5%. These functional and immunologic changes persisted at 24 months and in two patients at 36 months. A repeat renal biopsy in the patients with TIN showed a dramatic decrease in interstitial plasma cell infiltrate with normalization of IgG4/IgG positive plasma cells. The patients with RPF showed a huge regression of retroperitoneal tissue. In this sample of patients with aggressive IgG4-RD and renal involvement, treatment aimed at depleting B cells and decreasing antibody and cytokine production was associated with a substantial, persistent increase in eGFR, and a definite improvement in immunologic, radiologic and histological parameters.

Rituximab as a front-line therapy for adult-onset minimal change disease with nephrotic syndrome

Minimal change disease (MCD) accounts for 15% of adult nephrotic syndrome (NS) cases. Adult-MCD patients may have more severe clinical features than pediatric patients. In children, Rituximab (RTX) has been used since 2006 to treat frequently relapsing NS. In adults, data about the efficacy of RTX for MCD are limited. We report our experience on the use of RTX in adult biopsy-proven MCD. Our series includes 6 adult patients (2 males and 4 females), age 45–73 years, treated with RTX (4 weekly doses of 375 mg/m2). Proteinuria decreased from 11,2 (23–4.8) g/24 hours to 0.6 (0–2) g/24 hours after 6 months, and to 0.4 (0–1, 4) g/24 h in the 4 pts with the longer follow-up. Creatinine decreased from 1.95 (0.5–5) mg/dl to 0.88 (0.6–1.3) mg/l. Five patients achieved a complete renal remission, while in 1 pt proteinuria decreased by 75%. RTX successfully depleted CD19 lymphocytes in 100% of pts for at least 6 months. No clinically relevant adverse events have been observed. This case series shows a remarkable efficacy of RTX in treatment of MCD. RTX can be an attractive alternative both in recurrent forms and in induction-therapy of MCD. RTX may be preferentially used in patients at a high risk of development of the adverse effects of corticosteroids and should be considered as an alternative option in patients with recurrent NS. Additional data are needed to inform clinical practice on how best to use RTX in this patient population, so that definitive randomized trials can be planned.