Clinical usefulness of autoantibodies to M-type phospholipase A2 receptor (PLA2R) for monitoring disease activity in idiopathic membranous nephropathy (IMN).

Autoantibodies to M-type phospholipase A2 receptor (PLA2R) are specific markers of idiopathic membranous nephropathy (IMN). They can differentiate IMN from other glomerular diseases and primary from secondary forms of MN. Preliminary data suggest that anti-PLA2R antibody titer correlates with disease activity but more solid evidence is needed. To evaluate the performance of anti-PLA2R antibody for monitoring nephropathy activity, 149 anti-PLA2R antibody measurements were performed during the follow-up of 42 biopsy proven IMN consecutive patients. Patients were enrolled either at time of diagnosis (33 cases, inception cohort) or after diagnosis (9 patients, non-inception cohort). Anti-PLA2R detection was performed using the highly sensitive transfected cell-based indirect immunofluorescence (IIFT). Over the follow-up there was a linear time-trend of decreasing proteinuria (P<0.001), increasing serum albumin (P<0.001) and decreasing PLA2R antibody levels (P=0.002). There was a statistically significant association between changes in PLA2R antibody levels and the clinical course of PLA2R-positive IMN. The positive PLA2R serum antibody status was linearly associated with increasing proteinuria and decreasing serum albumin over time, compared with negative antibody status. Moreover, the strong correlation between the clinical conditions and PLA2R antibody levels allowed the prediction of prevalence distribution of patients with active disease, partial and complete remission. Over the course of the follow-up, the probability of halving proteinuria increased 6.5 times after disappearance of PLA2R antibodies. Our data suggest that the serial evaluation of anti-PLA2R antibodies could help in optimal timing and duration of the immunosuppressive therapy, reducing over(under)-treatment and associated side-effects.

TREX1 C-terminal frameshift mutations in the systemic variant of retinal vasculopathy with cerebral leukodystrophy.

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an adult-onset disorder caused by C-terminal heterozygous frameshift (fs) mutations in the human 3'-5' DNA exonuclease TREX1. Hereditary systemic angiopathy (HSA) is considered a variant of RVCL with systemic involvement of unknown genetic cause, described in a unique family so far. Here we describe the second case of RVCL with systemic involvement, characterized by cerebral calcifications and pseudotumoral lesions, retinopathy, osteonecrosis, renal and hepatic failure. The genetic screening of TREX1 in this patient revealed the novel heterozygous T270fs mutation on the C-terminal region. On the same gene, we found the V235fs mutation, formerly shown in RVCL, in one patient previously reported with HSA. These mutations lead to important alterations of the C-terminal of the protein, with the loss of the transmembrane helix (T270fs) and the insertion of a premature stop codon, resulting in a truncated protein (V235fs). Functional analysis of T270fs-mutated fibroblasts showed a prevalent localization of the protein in the cytosol, rather than in the perinuclear region. RVCL with systemic involvement is an extremely rare condition, whose diagnosis is complex due to multiorgan manifestations, unusual radiological and histopathological findings, not easily attributable to a single disease. It should be suspected in young adults with systemic microangiopathy involving retina, liver, kidney, bones and brain. Here we confirm the causative role played by TREX1 autosomal dominant fs mutations disrupting the C-terminal of the protein, providing a model for the study of stroke in young adults.

Severe reversible acute renal failure in idiopathic nephrotic syndrome.

BACKGROUND: Only few cases of acute renal failure (ARF) requiring dialysis have been reported in patients with idiopathic nephrotic syndrome (NS). This study aims to better define the clinical outcome and treatment of this condition. METHODS: A pilot enquiry regarding the occurrence of ARF requiring dialysis in patients with NS and biopsy proven minimal changes (MC) or focal segmental glomerulosclerosis (FSGS) was conducted among 5 nephrology centers. RESULTS: From 1996-2006, 6 patients with idiopathic NS (4 MC, 2 FSGS) developed ARF requiring dialysis early after onset of NS. At presentation all but 1 patient had elevated blood pressure. Patients were treated with dialysis from 7-40 days. All achieved complete or partial remission after 4-8 weeks of steroids. Recovery of renal function paralleled with the reduction of proteinuria. At renal biopsy proximal tubules showed a large amount of protein droplets, flattening of epithelial cells, and focal detachment of cells from the basal membrane. After a follow-up of 24-60 months, 5 patients had a relapse. Of these 4 were responsive to steroids, while one progressed to dialysis after an episode of hemolytic uremic syndrome related to cyclosporine treatment. ARF did not recur. CONCLUSION: ARF requiring dialysis is a rare and unexpected complication of idiopathic NS occurring in most cases early after presentation. These patients are sensitive to steroids that should be administered as promptly as possible in view of the potential noxious effect of protein overload on proximal tubular cells.