Albumin determined by bromocresol green leads to erroneous results in routine evaluation of patients with chronic kidney disease

Objectives: Measurement of plasma albumin is pivotal for clinical decision-making in patients with chronic kidney disease (CKD). Routinely used methods as bromocresol green (BCG) and bromocresol purple (BCP) can suffer from aselectivity, but the impact of aselectivity on the accuracy of plasma albumin results of CKD-patients is still unknown. Therefore, we evaluated the performance of BCG-, BCP- and JCTLM-endorsed immunological methods in patients with various stages of CKD. Methods:We evaluated the performance of commonly used albumin methods in patients with CKD stages G1 through G5, the latter divided in two groups based on whether they received hemodialysis treatment. In total, 163 patient plasma samples were measured at 14 laboratories, on six different BCG and BCP-platforms, and four different immunological platforms. The results were compared with an ERM-DA-470k-corrected nephelometric assay. The implications on outcome is evaluated by the proportion of patient results &lt;38g/L for the diagnosis of protein energy wasting. Results:Albumin results determined with BCP- and immunological methods showed the best agreement with the target value (92.7 and 86.2%, respectively vs. 66.7% for BCG, namely due to overestimation). The relative agreement of each method with the target value was platform-dependent, with larger variability in agreement between platforms noted for BCG and immunological methods (3.2-4.6 and 2.6-5.3%) as opposed to BCP (0.7-1.5%). The stage of CKD had similar effects on the variability in agreement for the three method-groups (0.6-1.8% vs. 0.7-1.5% vs. 0.4-1.6%). The differences between methods cause discrepancies in clinical decision-making, as structurally fewer patients were diagnosed with protein energy wasting upon using BCG-based albumin results. Conclusions: Our study shows that BCP is fit for the intended use to measure plasma albumin levels in CKD patients from all stages, including patients on hemodialysis. In contrast, most BCG-based platforms falsely overestimate the plasma albumin concentration.</p

The anti-PLA2R antibody in membranous nephropathy:what we know and what remains a decade after its discovery

Contains fulltext : 215542.pdf (publisher's version ) (Closed access)The discovery in 2009 of the M-type phospholipase A2 receptor (PLA2R) as the primary target in membranous nephropathy (MN) greatly advanced basic and clinical research. Primary MN is now considered a renal-limited autoimmune disease, with antibodies against PLA2R (aPLA2Rab) identified in 70-80 % of patients of various ethnic groups. Although the use of aPLA2Rab as a diagnostic and prognostic biomarker is now widely accepted, many questions related to the development of the auto-immune response, the role of IgG subclasses and antigenic epitopes, and the pathways to podocyte injury remain unresolved. PLA2R-associated MN most likely develops governed by factors such as genetic susceptibility, loss of tolerance, alterations in antigen expression with a role for environmental factors like air pollution, smoking, and infections. More detailed knowledge of genetic factors, the relevant B- and T-cell epitopes, and the mechanisms of podocyte injury is needed to identify patients at risk for disease progression and to develop optimized, targeted treatment strategies. In this review we highlight unresolved issues, addressing initiation of antibody formation, the timeline of antibody production, the role of IgG subclass, and the pathogenicity of the antibodies in concert with complement to produce glomerular pathology and proteinuria

Anti-PLA2R1 Antibodies as Prognostic Biomarker in Membranous Nephropathy

International audienc

The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy

Corticoides; Ciclofosfamida; Nefropatia membranosa primàriaCorticosteroides; Ciclofosfamida; Nefropatía membranosa primariaCorticosteroids; Cyclophosphamide; Primary membranous nephropathyA cyclical corticosteroid-cyclophosphamide regimen is recommended for patients with primary membranous nephropathy at high risk of progression. We hypothesized that sequential therapy with tacrolimus and rituximab is superior to cyclical alternating treatment with corticosteroids and cyclophosphamide in inducing persistent remission in these patients. This was tested in a randomized, open-label controlled trial of 86 patients with primary membranous nephropathy and persistent nephrotic syndrome after six-months observation and assigned 43 each to receive six-month cyclical treatment with corticosteroid and cyclophosphamide or sequential treatment with tacrolimus (full-dose for six months and tapering for another three months) and rituximab (one gram at month six). The primary outcome was complete or partial remission of nephrotic syndrome at 24 months. This composite outcome occurred in 36 patients (83.7%) in the corticosteroid-cyclophosphamide group and in 25 patients (58.1%) in the tacrolimus-rituximab group (relative risk 1.44; 95% confidence interval 1.08 to 1.92). Complete remission at 24 months occurred in 26 patients (60%) in the corticosteroid-cyclophosphamide group and in 11 patients (26%) in the tacrolimus-rituximab group (2.36; 1.34 to 4.16). Anti-PLA2R titers showed a significant decrease in both groups but the proportion of anti-PLA2R-positive patients who achieved immunological response (depletion of anti-PLA2R antibodies) was significantly higher at three and six months in the corticosteroid-cyclophosphamide group (77% and 92%, respectively), as compared to the tacrolimus-rituximab group (45% and 70%, respectively). Relapses occurred in one patient in the corticosteroid-cyclophosphamide group, and three patients in the tacrolimus-rituximab group. Serious adverse events were similar in both groups. Thus, treatment with corticosteroid-cyclophosphamide induced remission in a significantly greater number of patients with primary membranous nephropathy than tacrolimus-rituximab

Synthetic ACTH in High Risk Patients with Idiopathic Membranous Nephropathy: A Prospective, Open Label Cohort Study

<div><p>New therapeutic agents are warranted in idiopathic membranous nephropathy. Synthetic ACTH may be advantageous with reported remission rates up to 85% and few side effects. We conducted a prospective open label cohort study from 2008 till 2010 (<a href="https://clinicaltrials.gov/ct2/show/NCT00694863" target="_blank">NCT00694863</a>). We prospectively selected patients with idiopathic membranous nephropathy and high risk for progression (defined as βeta-2-microglobulin (β2m) excretion of >500 ng/min). For comparison, we selected matched historical controls treated with cyclophosphamide. The prospectively selected patients received intramuscular injections of synthetic ACTH during 9 months (maximal dose 1 mg twice a week). The primary endpoints concerned the feasibility and incidence of remissions as a primary event. Secondary endpoints included side effects of treatment and the incidence of remissions and relapses at long-term follow-up. Twenty patients (15 men) were included (age 54±14 years, serum creatinine 104 μmol/l [IQR 90–113], urine protein:creatinine ratio 8.7 g/10 mmol creatinine [IQR 4.3–11.1]). Seventeen patients (85%) completed treatment. 97% of injections were administered correctly. Cumulative remission rate was 55% (complete remission in 4 patients, partial remission 7 patients). In a group of historical controls treated with cyclophosphamide and steroids, 19 of 20 patients (95%) developed a remission (complete remission in 13 patients, partial remission in 6 patients) (p<0.01). The main limitation of our study is its small size and the use of a historical control group. We show that treatment with intramuscular injections of synthetic ACTH is feasible. Our data suggest that synthetic ACTH is less effective than cyclophosphamide in inducing a remission in high risk patients with idiopathic membranous nephropathy. The use of synthetic ACTH was also associated with many adverse events. Therefore, we advise against synthetic ACTH as standard treatment in membranous nephropathy.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT00694863" target="_blank">NCT00694863</a></p></div

Kaplan-Meier plot for cumulative incidence of remission.

<p>Legend: Number of patients at risk for a remission at each time point are given below the figure. Log-rank test p = 0.005. ACTH = synthetic ACTH, CP = cyclophosphamide.</p

Adverse events with ACTH treatment.

<p>AE = adverse events, SAE = serious adverse events.</p><p>Adverse events with ACTH treatment.</p

Flowchart of treatment and events during follow-up in the ACTH group.

<p>Legend: ACTH = synthetic ACTH, CR = complete remission, PR = partial remission, PNS = persisting nephrotic syndrome, RF = renal failure, 2^nd treatment = alternative immunosuppressive treatment</p

Baseline characteristics.

<p>Values are expressed as number (percent), means ± SD and median [interquartile ranges]. ACTH = synthetic ACTH, eGFR = estimated glomerular filtration rate (by MDRD 4 equation), PCR = protein:creatinine ratio, β2m excretion = urinary beta2-microglobulin excretion, α1m excretion = urinary alfa1-microglobulin excretion, min = minute, T0 = start of ACTH treatment.</p><p>* The interval between the end of previous treatment and start of the current treatment was respectively 20, 38, 80 and 162 months in the ACTH group.</p><p>** In the CP treated group this interval was 27 months in one patient and 257 months in the other patient.</p><p>Baseline characteristics.</p

Kaplan-Meier plot for relapse free survival.

<p>Legend: Number of patients at each time point are given below the figure. Log-rank test p = 0.020. ACTH = ACTH, CP = cyclophosphamide.</p