A Genetic Risk Score Distinguishes Different Types of Autoantibody-Mediated Membranous Nephropathy

INTRODUCTION: Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults and is characterized by detectable autoantibodies against glomerular antigens, most commonly phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domain containing 7A (THSD7A). In Europeans, genetic variation in at least five loci, PLA2R1, HLA-DRB1, HLA-DQA1, IRF4, and NFKB1, affects the risk of disease. Here, we investigated the genetic risk differences between different autoantibody states. METHODS: 1,409 MN individuals were genotyped genome-wide with a dense SNV array. The genetic risk score (GRS) was calculated utilizing the previously identified European MN loci, and results were compared with 4,929 healthy controls and 422 individuals with steroid-sensitive nephrotic syndrome. RESULTS: GRS was calculated in the 759 MN individuals in whom antibody status was known. The GRS for MN was elevated in the anti-PLA2R1 antibody-positive (N = 372) compared with both the unaffected control (N = 4,929) and anti-THSD7A-positive (N = 31) groups (p < 0.0001 for both comparisons), suggesting that this GRS reflects anti-PLA2R1 MN. Among PLA2R1-positive patients, GRS was inversely correlated with age of disease onset (p = 0.009). Further, the GRS in the dual antibody-negative group (N = 355) was intermediate between controls and the PLA2R1-positive group (p < 0.0001). CONCLUSION: We demonstrate that the genetic risk factors for PLA2R1- and THSD7A-antibody-associated MN are different. A higher GRS is associated with younger age of onset of disease. Further, a proportion of antibody-negative MN cases have an elevated GRS similar to PLA2R1-positive disease. This suggests that in some individuals with negative serology the disease is driven by autoimmunity against PLA2R1

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10-12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10-14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10-103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10-49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10-93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10-23 and OR = 3.39, P = 5.2 × 10-82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk

Successful treatment of PLA2R1-antibody positive membranous nephropathy with ocrelizumab

Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. The disease is induced by antibodies, which are directed against the podocyte protein phospholipase

Hazard ratios with 95% confidence intervals and p values as estimated by univariate (A) and multivariate (B) Cox regression analysis.

<p>The explanatory variable PLA₂R-Ab levels was ln-transformed prior to analysis. Effects of age and PLA₂R-Ab levels are significant at α = 0.05. The corresponding hazard ratios indicate increasing risks for development of nephrotic range proteinuria with increasing age and PLA₂R-Ab levels (high PLA₂R-Ab levels).</p

Proteinuria during the study follow-up.

<p>Proteinuria significantly increased in PLA₂R-Ab positive patients (solid line) but remained low in PLA₂R-Ab negative patients (dashed line). The bars show the SD-values of proteinuria for PLA₂R-Ab positive patients (up) and PLA₂R-Ab negative patients (down). “N” gives the number of patients for whom data were available at these specific times of follow-up. “*” shows a statistically significant difference (p<0.05) between the single time point and the start of the study. “§” shows a statistically significant difference (p<0.05) between PLA₂R-Ab positive patients and PLA₂R-Ab negative patients.</p

Flow chart of patients included in the study and their follow-up.

<p>Of the 33 patients included in the study 16 were PLA₂R-Ab positive and 17 were PLA₂R-Ab negative at the start of the study. Nephrotic proteinuria developed in 13 PLA₂R-Ab positive and five PLA₂R-Ab negative patients. Immunosuppressive treatment was used in 13 PLA₂R-Ab positive patients and two PLA₂R-Ab negative patients. At the end of the follow-up eight patients were still PLA₂R-Ab positive, two of them had a remission of proteinuria (both partial remission) and five of them had a significant increase in serum creatinine. PLA₂R-Ab were negative in 25 patients at the end of the follow-up, 24 of them had a remission of proteinuria (16 complete remission, eight partial remission) and one of them had a significant increase in serum creatinine. CR = complete remission; PR = partial remission; NR = no remission. ^a = Significantly more PLA₂R-Ab positive patients developed nephrotic-range proteinuria compared to PLA₂R-Ab negative patients (Fisher’s exact test: p<0.005). ^b = Significantly more PLA₂R-Ab positive patients received immunosuppressive therapy compared to PLA₂R-Ab negative patients (Fisher’s exact test: p<0.001). ^c = Significantly less patients who were still positive for PLA₂R-Ab at the end of the study follow-up reached remission of proteinuria compared to patients who were negative for PLA₂R-Ab at the end of the follow-up (Fisher’s exact test: p<0.001). ^d = Significantly more patients who were still positive for PLA₂R-Ab at the end of the study follow-up had a significant increase of serum creatinine compared to patients who were negative for PLA₂R-Ab at the end of the follow-up (Fisher’s exact test: p = 0.001).</p

Clinical baseline characteristics of the patients at the time of inclusion in the study.

<p>At the time of inclusion in the study 16 (48%) patients had detectable PLA₂R-Ab in the serum. Proteinuria at inclusion in the study was higher in PLA₂R-Ab positive patients compared to PLA₂R-Ab negative patients but this difference did not reach statistical significance. Serum creatinine and age were not different between PLA₂R-Ab positive and PLA₂R-Ab negative patients. Significantly more PLA₂R-Ab positive patients received immunosuppressive treatment during the follow-up time.</p><p>Clinical baseline characteristics of the patients at the time of inclusion in the study.</p

Rituximab Treatment for Relapsing Minimal Change Disease and Focal Segmental Glomerulosclerosis: A Systematic Review

Background: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) remain a therapeutic challenge, since steroids and other immunosuppressive agents exhibit an unfavorable adverse event spectrum. The aim of this review was to systematically summarize and analyze data from preexisting studies reporting the outcome of rituximab (RTX) treatment in these patients. Methods: Study data on adult patients with either steroid-dependent or frequently relapsing MCD/FSGS were identified by a PubMed and Embase search. The number of relapses was calculated and the use of imnnunosuppressive co-medication prior to and after RTX treatment was quantified. Results: We identified 14 studies including 86 patients with frequently relapsing and steroid-dependent MCD or FSGS. Treatment with RTX reduced the number of relapses per year from 1.3 (0-9) relapses prior to treatment compared to 0 (0-2) after therapy (p < 0.001). Proteinuria decreased from 2.43 (0-15) g/day to 0 (0-4.89) g/day (p < 0.001), while serum albumin increased from 2.9 (1.2-4.6) at baseline to 4.0 (1.8-5.09) g/I after RTX (p = 0.001). The use of immunosuppression used at the time of RTX administration was also reduced after RTX therapy (p < 0.001). Baseline serum albumin was lower (p = 0.018), whereas the number of imnnunosuppressants prior to RTX was higher (p = 0.018) in patients with relapse after RTX. Condusions: The published data suggest that RTX is effective in reducing the number of relapses and sparing immunosuppression in frequently relapsing and steroid-dependent nephrotic syndrome due to MCD and FSGS. These promising findings have to be confirmed in controlled and prospective studies. (C) 2014 S. Karger AG, Base