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

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

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

Adverse events with ACTH treatment.

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

Genotypes in iMN patients with clinical remission versus patients with renal failure.

<p>*N = 45 for renal failure.</p><p>*P-value for minor allele frequencies-comparison (Mann-Whitney U).</p

<i>TRPC6</i> variants in patients with iMN (n = 101).

<p>Chr  =  chromosome; position  =  basepair position based on UCSC genome browser version Human Feb. 2009 (GRCh37/hg19) assembly; name  =  rs identifier; ref  =  genomic reference allele; all  =  alleles; CEU AF  =  allele frequencies variant allele in control population. Control population consists of Caucasian population from 1000 Genomes project (release 10 - March 2012), complemented with data form 292 geographically matched controls for variants marked with **; ∧ =  not reported in 1000 Genomes project; AF patient  =  patient minor allele frequencies; p-value  =  comparison allele frequencies controls and patients; AF PLA2R  =  minor allele frequencies in PLA2R positive patients (n = 62); p-value*  =  comparison allele frequencies controls and PLA2R positive patients; genomic level  =  NC_000002.11; ref cDNA  =  reference allele cDNA (given that TRPC6 is on the negative strand); cDNA  =  NM_004621.5; prot. level  =  NP_004612.2; CCD  =  coiled-coiled domain; TMD  =  transmembrane domain.</p

TRPC6 topology.

<p>Structure of the TRPC6 monomer. TRPC6 belongs to the large family of TRP channels, which contain six transmembrane domains, one pore-forming region and large intracellular N- and C-tails. Four subunits are required to assemble a functional channel. In the pococyte, TRPC6 is part of the slit diaphragm multiprotein complex. TRP: transient receptor potential, ANK: Ankyrin repeat, cc: coiled–coiled domain, CIRB: CaM/IP3R-binding domain.</p

Primers used to sequence the 13 exons of <i>TRPC6</i>.

<p>F, forward; R, reverse.</p