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Original Report: Patient-Oriented, Translational Research
Am J Nephrol 2012;36:58–67
DOI: 10.1159/000339287
Treatment of Resistant Glomerular
Diseases with Adrenocorticotropic
Hormone Gel: A Prospective Trial
Andrew S. Bomback
a
Pietro A. Canetta
a
Laurence H. Beck Jr.
b
Rivka Ayalon
b
Jai Radhakrishnan
a
Gerald B. Appel
a
a Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, N.Y. , and
b Section of Nephrology, Department of Medicine, Boston University School of Medicine, Boston, Mass. , USA
phropathy. Two resistant MN subjects achieved partial re-
mission on ACTH therapy, although 3 achieved immunolog-
ic remission of disease (PLA
2
R antibody disappeared by 4
months of therapy). One subject with resistant FSGS achieved
complete remission on ACTH; one subject with resistant
MCD achieved partial remission but relapsed within 4 weeks
of stopping ACTH. Two subjects with resistant IgA nephrop-
athy demonstrated 1 50% reductions in proteinuria while on
ACTH, with proteinuria consistently ! 1 g/g by 6 months.
Three of 15 subjects reported significant steroid-like adverse
effects with ACTH, including weight gain and hyperglyce-
mia, prompting early termination of therapy without any
clinical response. Conclusions: ACTH gel is a promising
treatment for resistant glomerular diseases and should be
studied further in controlled trials against currently available
therapies for resistant disease.
Copyright © 2012 S. Karger AG, Bas el
Introduction
Patients with idiopathic glomerular diseases often re-
quire immunosuppression to achieve remissions of dis-
ease, defined by resolution of proteinuria with stable or
improving renal function. Unfortunately, many patients
Key Words
Membranous nephropathy Minimal change disease
Focal segmental glomerulosclerosis IgA nephropathy
A b s t r a c t
B a c k g r o u n d : Adrenocorticotropic hormone (ACTH) has
shown promising results in glomerular diseases resistant to
conventional therapies, but the reported data have solely
been from retrospective, observational studies. Methods: In
this prospective, open-label study (NCT01129284), 15 sub-
jects with resistant glomerular diseases were treated with
ACTH gel (80 units subcutaneously twice weekly) for 6
months. Resistant membranous nephropathy (MN), minimal
change disease (MCD), and focal segmental glomeruloscle-
rosis (FSGS) were defined as failure to achieve sustained re-
mission of proteinuria off immunosuppressive therapy with
at least 2 treatment regimens; resistant IgA nephropathy was
defined as 1 1 g/g urine protein:creatinine ratio despite max-
imally tolerated RAAS blockade. Remission was defined as
stable or improved renal function with 6 50% reduction in
proteinuria to ! 0.5 g/g (complete remission) or 0.5–3.5 g/g
(partial remission). Results: The study included 5 subjects
with resistant idiopathic MN, 5 subjects with resistant MCD
(n = 2)/FSGS (n = 3), and 5 subjects with resistant IgA ne-
Recei ved: February 28, 2012
Accepted: May 2, 2012
Published onlin e: June 19, 2012
Nephrolo
gy
American Journal of
Andrew S. Bomback, MD, MPH
Department of Med icine, Division of Nephrology
Columbia University Medical Center
622 West 168t h Street, PH 4-124, New York, NY 10032 (USA)
Tel. +1 212 305 0320, E-Ma il asb68
@ columbia.edu
© 2012 S. Ka rger AG, Basel
0250–8095/12/0361–0058$38.00/0
Accessible online at:
www.karger.com/ajn
ACTH for Resistant Glomerular Diseases Am J Nephrol 2012;36:58–67
59
do not respond to first- or second-line treatment choices
or relapse once immunosuppression has been reduced or
discontinued. For example, while up to 90% of adults
with minimal change disease (MCD) will respond to ini-
tial therapy with prednisone, approximately 40% of these
same patients will relapse within 6 months and require
further immunosuppression
[1] . First-line therapies for
diseases such as idiopathic membranous nephropathy
(MN) and focal segmental glomerulosclerosis (FSGS)
produce substantially lower initial response rates and are
marked by similarly high relapse rates
[2–5] . Thus, physi-
cians who treat these patients commonly employ second-,
third- and even fourth-line therapies in attempting to
achieve a sustained remission. New treatment options are
always in demand.
In the last two decades, adrenocorticotropic hormone
(ACTH) has re-emerged as a potential treatment option
for patients with idiopathic nephrotic syndrome, with
benefit shown in a variety of disease states ranging from
idiopathic MN and FSGS to diabetic nephropathy and
hereditary nephritis. The mechanism of action by which
ACTH ameliorates proteinuria remains unclear. Pro-
posed mechanisms include stimulation of endogenous
steroid production, activation of melanocortin receptors
on inflammatory cells (including B cells, T cells, and an-
tigen-presenting cells), and direct binding to melanocor-
tin receptors on the podocyte.
Virtually all of the experience using ACTH for ne-
phrotic syndrome comes from retrospective, observa-
tional case series of heterogeneous patient populations,
including patients who received ACTH as first-line ther-
apy and patients who were treated after failing 2, 3, or 4
prior immunomodulatory regimens
[6–10] . To date, only
one prospective study of ACTH has been reported, a ran-
domized trial comparing ACTH and cyclophosphamide
as initial therapy in 32 patients with idiopathic MN
[11] .
Given this lack of prospective data, particularly among
patients with resistant glomerular diseases, the popula-
tion in which ACTH is almost exclusively used in the
United States
[9] , we performed a prospective, open-la -
bel study of ACTH in patients with resistant forms of
the most common idiopathic glomerular diseases: MN,
FSGS, MCD and IgA nephropathy.
M e t h o d s
S u b j e c t s
This open-label, nonblinded, efficacy and safety study of
ACTH gel (H.P. Acthar Gel, repository corticotropin injection,
Questcor Pharmaceuticals, Inc., Hayward, Calif., USA), a long-
acting formulation of full-sequence ACTH(1–39) that includes
other pro-opiomelanocortin peptides, consisted of 15 subjects
with resistant glomerular diseases: 5 subjects with resistant MN,
5 subjects with MCD or FSGS, and 5 subjects with resistant IgA
nephropathy. Resistant MN was defined as failure to achieve sus-
tained remission with at least 2 prior immunosuppressive regi-
mens, resistant MCD/FSGS was defined as failure to achieve sus-
tained remission with corticosteroids and at least 1 other immu-
nosuppressive regimen, and resistant IgA nephropathy was
defined as 1 g/g urine protein:creatinine ratio despite stable and
maximally tolerated doses of renin-angiotensin-aldosterone sys-
tem (RAAS) blockade. Exclusion criteria were age ^ 18 years, e s-
timated GFR ! 30 ml/min/1.73 m
2
, use of rituximab or other
monoclonal antibody within 6 months of the trial, use of cyclo-
phosphamide within 3 months of the trial, ongoing pregnancy or
breastfeed ing, refusa l to use birth control if ch ildbearing age, ot h-
er renal diseases (e.g. diabetes, renal vascular disease) that would
interfere with interpretation of study results, and known contra-
indications to the use of ACTH gel (scleroderma, osteoporosis,
system ic fu ngal infect ions, ocu lar herp es simplex, recent surgery,
history of or the presence of a peptic ulcer, congestive heart fail-
ure, uncontrolled hypertension, and allergies to pork or pork
products). All subjects signed an informed consent prior to en-
rollment. The study was approved by the Institutional Review
Board of Columbia University Medical Center and registered on
clinicaltrials.gov (NCT01129284).
Treatment Regimen and Evaluations
Subjects were treated with ACTH gel for 24 weeks, dosed at 40
units twice weekly subcutaneously for 2 weeks, then 80 units
twice weekly subcutaneously afterwards. Twice weekly treat-
ments were given at the study site for weeks 1 through 3, during
which time subjects received instructions for home administra-
tion. Medication could be injected in the arm, abdomen, or thigh.
Starting at week 4, subjects were given one treatment at the study
site and administered the other treatment at home, maintaining
the same t wice weekly dosing schedule. Subjects who did not wish
to self-administer the treatment were given the option to receive
all treatments at the study center. The twice weekly injections
were spaced out 72–96 h apart. No changes were made to subjects’
RAAS-blocking medications or cholesterol-lowering medica-
tions during the treatment period unless clinically indicated (e.g.
hyperkalemia). Subjects who were on calcineurin inhibitors were
weaned off this therapy during the first 12 weeks of ACTH ther-
apy.
Laboratory measurements were performed week ly for the first
4 weeks of the study period, and then every 4 weeks thereafter
until the conclusion of the study. These measurements included
basic metabolic panel, complete blood count, hepatic function
panel, lipid prof ile, spot uri ne protein:creatini ne ratio, serum cor-
tisol (reference range 5.0–25.0 g/dl), and serum ACTH (refer-
ence range 7–69 pg/ml). Blood and urine samples were collected
immediately prior to ACTH injections. Baseline proteinuria was
calculated by the average of the first 3 weeks’ urine protein:creati-
nine ratio (U PCR) values. Stored serum s amples from the subjects
with MN were sent, after completion of the trial, to Boston Uni-
versity for antibody testing against the M-type phospholipase A
2
receptor (PLA
2
R) to serve as a serologic marker of disease activ-
ity. The details of this immunoassay have been described else-
where
[12 ] .
Bomback /Canetta /BeckJr. /Aya lon /
Radhakrishnan
/Ap pe l
Am J Nephrol 2012;36:58–67
60
O u t c o m e s
The primary outcome for subjects with nephrotic syndrome
was remission st atus at the completion of ACTH therapy. Complete
remission was def ined as stable or improved renal function (creati-
nine ^ 125% of baseline) with final UPCR ! 0.500 g/g. Partial re-
mission was defined as stable or improved renal function with
6 50% reduction in UPCR to 0.500–3.500 g/g. All subjects failing
to meet these criteria were deemed nonresponders. The primary
outcome for subjects with IgA nephropathy was percent reduction
in proteinuria from baseline at the completion of ACTH therapy.
Se con dar y outc omes in cluded cha nge in s erum a lbu mi n, c han ge i n
total cholesterol a nd LDL cholesterol, and adverse effect s of therapy.
Statistical Analysis
Given the small number of subjects and the pilot design of this
study, no formal statistical analysis was performed. Instead, the
data are presented descriptively.
R e s u l t s
Fifteen subjects were included in this open-label pilot
study of ACTH gel for resistant glomerular diseases ( ta-
ble1 ). The five subjects with MN all had impaired renal
function at baseline (serum creatinine range 1.6–2.9 mg/
dl). The most commonly failed prior therapies in this
group were mycophenolate mofetil (MMF, n = 4) and cal-
cineurin inhibitors (n = 3). Two subjects had previously
been treated with cyclophosphamide. The 5 subjects with
resistant FSGS or MCD had preserved renal function at
baseline (serum creatinine range 0.6–1.2 mg/dl) and, per
protocol, all had failed a traditional course of oral corti-
costeroids. All of these subjects failed at least one course
of calcineurin inhibitor therapy, and 3 had previously
been on MMF without sustained remission. No subject in
this group had previously been treated with cyclophos-
phamide. The five subjects with IgA nephropathy includ-
ed 2 subjects with preserved kidney function (eGFR 1 60
ml/min/1.73 m
2
) and 3 subjects with impaired kidney
function; all were on stable doses of RAAS blockade. The
3 subjects with IgA nephropathy and reduced eGFR had
previously been treated with a 6-month course of corti-
costeroids without response.
Two of the 5 subjects with MN achieved partial remis-
sion over the 6-month course of ACTH therapy ( fig. 1 ;
Table 1. Baseline characteristics of study participants
Age Race/
ethnicity
Sex Months
from
Previous immunosuppressive therapy Pre-ACTH
Screat
Pre-ACTH eGFR
ml/min/1.73 m2
Pre-ACTH
UPCR
diagnosis mg/dl g/g
MN
Subject 1 68 white male 78 steroids, cyclosporine, tacrolimus 1.6 44 6.70
Subject 2 50 Af-Am female 108 MMF, tacrolimus, cyclosporine,
rituximab
2.0 33 3.05
Subject 3 68 Asian male 49 steroids, MMF, cyclophosphamide 2.2 34 3.80
Subject 4 58 white male 58 cyclosporine, MMF 1.7 43 2.23
Subject 5 71 white male 12 MMF, cyclophosphamide 2.9a 21
a 12.46
FSGS/MCD
Subject 6 29 Hispanic female 120 steroids, MMF, rituximab, tacrolimus 0.7 117 4.76
Subject 7 30 white female 57 steroids, tacrolimus 0.6 123 3.16
Subject 8 41 white male 87 steroids, tacrolimus, cyclosporine,
MMF
1.2 75 1.94
Subject 9 35 white male 99 steroids, cyclosporine 0.8 116 1.96
Subject 10 66 white male 128 steroids, cyclosporine, MMF 1.0 78 1.65
IgA nephropathy
Subject 11 37 Hispanic female 10 steroids 1.7 38 1.95
Subject 12 46 white male 31 steroids, MMF 2.4 31 1.59
Subject 13 55 Asian female 1 none 0.8 83 0.61b
Subject 14 36 Asian male 84 steroids 2.7 29 4.12
Subject 15 35 Asian male 7 none 1.0 97 1.51
Af-Am = African-American; eGFR = estimated glomerular filtration rate (CKD EPI formula); S
creat
= serum creatinine.
a At screening visit, subject 5’s serum creatinine was 2.1 and eGFR was 31 ml/min/1.73 m2.
b At screening visit, subject 13’s UPCR was 1.543 mg/g.
ACTH for Resistant Glomerular Diseases Am J Nephrol 2012;36:58–67
61
table2 ). Subject 4, whose creatinine levels fell from 1.7 to
1.2 mg/dl, albumin levels rose from 2.9 to 4.0 g/dl and
UPCR fell from 2.23 to 0.84 g/g, proceeded to have a sig-
nificant decline in proteinuria after ACTH was with-
drawn, achieving complete remission of proteinuria
within 3 months of stopping ACTH. He continues to
demonstrate sustained complete remission 12 months af-
ter his last dose of ACTH, with creatinine stable at 1.3 mg/
d l a nd UP CR 0.07 g/g . A nt ib od ie s t o t he PL A
2
R were con-
sistently negative for this subject. Subject 5 experienced
both clinical and immunologic remission of disease while
on ACTH: creatinine fell from 2.9 to 1.4 mg/dl, albumin
rose from 2.1 to 3.4 g/dl, and UPCR fell from 12.46 to 3.14
g/g, while antibodies to the PLA
2
R went from strongly
positive to negative. Surveillance laboratories done 10
months after stopping ACTH showed that, clinically, this
remission was maintained (UPCR was 0.87 g/g) despite
reappearance of anti-PLA
2
R antibodies. Testing for anti-
bodies to the PLA
2
R suggested that subjects 2 and 3
achieved an immunologic remission of disease (antibod-
ies went from strongly positive to negative) during treat-
ment with ACTH despite no apparent improvement in
clinical parameters. Subject 2 remains PLA
2
R antibody
negative more than one year from her last dose of ACTH
with proteinuria ranging from 3.0 to 4.5 g/day; subject 3
was lost to long-term follow-up after the study. As a
group, the 5 subjects with MN went from a pre-ACTH
median (range) proteinuria of 3.80 mg/g (2.23–12.46) to
a post-ACTH median (range) proteinuria of 3.79 mg/g
(1.37–10. 50).
One subject with MCD (subject 7) and 1 subject with
FSGS (subject 8) achieved partia l remission of proteinuria
during ACTH therapy ( fig.2 ; table3 ). Subject 7 demon-
strated a drop in UPCR from peak 3.16 to 0.78 g/g with
albumin rising from nadir 3.3 to 3.7 g/dl during treat-
ment; however, UPCR rose to 1 3.50 g/g 4 weeks after
stopping ACTH. Subject 8 demonstrated a drop in UPCR
f rom pe ak 3. 27 to 0.43 g/g wi th album in ri si ng fr om na di r
3.2 to 3.9 g/dl during treatment. At 8 months since dis-
continuation of ACTH, his UPCR was 0.68 g/g. Subjects
6 (MCD) and 9 (FSGS), per protocol, were weaned off
calcineurin inhibitor therapy during the first 3 months
of their ACTH treatment regimens; both subjects saw
marked rises in proteinuria with declining serum albu-
min level, and both subjects remain calcineurin inhibi-
0
2
4
6
8
10
12 UPCR pre-ACTH (g/g)
14
Subject 1 Subject 2 Subject 3 Subject 4 Subject 5
UPCR post-ACTH (g/g)
0
2
4
6
8
10
UPCR pre-ACTH (g/g)
12
Subject 6 Subject 7 Subject 8 Subject 9 Subject 10
UPCR post-ACTH (g/g)
0
1
2
3
4
UPCR pre-ACTH (g/g)
5
Subject 11 Subject 12 Subject 13 Subject 14 Subject 15
UPCR post-ACTH (g/g)
F i g . 1 . Changes in UPCR over a 6-month ACTH treatment period
in subjects with MN. Detailed laboratory values over this time
period are presented in table2. Subjects 1 and 2 withdrew early
from the study.
F i g . 2 . Changes in UPCR over a 6-month ACTH treatment period
in subjects with MCD or FSGS. Detailed laboratory values over
this time period are presented in table3.
F i g . 3 . Changes in UPCR over a 6-month ACTH treat ment period
in subje cts with Ig A ne phr opa thy. Det ai led la bor ato ry value s ov er
this time period are presented in table4. Subject 14 withdrew ear-
ly from the study.
Bomback /Canetta /BeckJr. /Aya lon /
Radhakrishnan
/Ap pe l
Am J Nephrol 2012;36:58–67
62
tor-dependent approximately 1 year after therapy. As a
group, the 5 subjects with MCD or FSGS went from a pre-
ACTH median (range) proteinuria of 1.96 mg/g (1.65–
4.76) to a post-ACTH median (range) proteinuria of 1.93
mg/g (0.43–11.35).
All but 1 subject with IgA nephropathy showed reduc-
tions in proteinuria during ACTH therapy ( fig.3 ; table4 ).
All subjects were on stable RAAS-blocking medications
for at least 6 months prior to enrollment, at highest doses
tolerated by blood pressure and/or serum potassium
(losartan 25 mg daily for subject 11, losartan 100 mg dai-
ly for subject 12, ramipril 10 mg daily + spironolactone 25
mg daily for subject 13, irbesartan 75 mg daily for subject
14, and enalapril 5 mg daily for subject 15). Subjects 12
and 13 demonstrated the largest reductions in UPCR
from 1.59 to 0.57 g/g (64%) and 0.61 to 0.21 g/g (66%), re-
spectively. These reductions have been sustained at 11
and 9 months, respectively, from last ACTH dose. Subject
11, whose UPCR fell from 1.95 to 1.22 g/g (38%) during
ACTH therapy, was unable to sustain this reduction in
proteinuria in the setting of discontinuing her RAAS-
blocking regimen to plan a pregnancy. Subject 15, whose
UPCR fell from 1.51 to 0.85 g/g during treatment, has
shown further declines in proteinuria (last UPCR 0.28
Table 2. Detailed results from 5 subjects with resistant MN
Baseline Week 4 Week 8 Week 12 Week 16 Week 20 Week 24
Subject 1
Scr, mg/dl 1.6 1.5 1.5 1.4 – – –
Salb, g/dl 3.2 3.0 2.5 2.6 – – –
UPCR, g/g 6.70 9.11 8.71 10.50 – – –
Cholesterol, mg/dl 148 171 177 151 – – –
Cortisol, g/dl 11.7 14.1 8.3 9.7 – – –
ACTH, pg/ml 11 13 15 8 – – –
Subject 2
Scr, mg/dl 2 1.8 1.9 1.7 1.8 – –
Salb, g/dl 4.1 3.6 3.3 3.4 3.7 – –
UPCR, g/g 3.05 2.88 3.58 3.79 3.75 – –
Cholesterol, mg/dl 196 166 169 196 – – –
Cortisol, g/dl 13.4 10.1 10.9 9.9 – – –
ACTH, pg/ml 15 15 17 19 – – –
Subject 3
Scr, mg/dl 2.2 2.1 1.9 1.9 1.8 1.8 1.9
Salb, g/dl 3.1 3.1 3.0 3.2 3.2 3.5 3.7
UPCR, g/g 3.80 3.59 3.36 3.28 4.00 3.56 3.88
Cholesterol, mg/dl 332 345 309 341 330 353 241
Cortisol, g/dl 16.7 9.3 9.9 11.0 7.6 11.6 15.5
ACTH, pg/ml 37 22 16 23 28 29 31
Subject 4
Scr, mg/dl 1.7 1.6 1.3 1.3 1.3 1.2 1.2
Salb, g/dl 2.9 3.0 3.7 3.5 4.0 3.9 4.0
UPCR, g/g 2.23 0.62 1.05 1.37 0.71 0.25 0.84
Cholesterol, mg/dl 243 241 261 232 229 213 236
Cortisol, g/dl 9.5 10.4 9.9 8.3 7.5 11.7 6.8
ACTH, pg/ml 4 11 8 10 8 7 8
Subject 5
Scr, mg/dl 2.9 2.1 1.8 1.4 1.5 1.4 1.4
Salb, g/dl 2.1 2.1 2.5 2.9 3.5 3.2 3.4
UPCR, g/g 12.46 12.60 6.29 7.21 4.92 4.06 3.14
Cholesterol, mg/dl 201 216 218 225 158 146 157
Cortisol, g/dl 12.6 9.8 11.3 8.7 11.4 8.4 6.8
ACTH, pg/ml 14 15 19 16 14 10 12
Cholesterol = Total cholesterol; Scr = serum creatinine; Salb = serum albumin.
ACTH for Resistant Glomerular Diseases Am J Nephrol 2012;36:58–67
63
g/g) at 7 months’ follow-up since discontinuing ACTH.
As a group, the 5 subjects with IgA nephropathy went
from a pre-ACTH median (range) proteinuria of 1.59
mg/g (0.61–4.12) to a post-ACTH median (range) pro-
teinuria of 0.85 mg/g (0.21–3.51).
An independent effect of ACTH on total cholesterol
and LDL levels was not apparent. Improvements in these
lipid parameters mirrored improvements in proteinuria
in those subjects who demonstrated a response to therapy
but were unchanged for those subjects who did not re-
spond ( tables 2–4 ). No significant changes in serum cor-
tisol or ACTH levels, drawn immediately prior to ACTH
injections, were detected in any subject during the treat-
ment period.
Three subjects discontinued therapy early due to ad-
verse events. Subjects 1 and 2, both with MN and previ-
ous diagnoses of diet-controlled diabetes, had worsened
glycemic control prompting initiation of oral hypoglyce-
mic therapy. Subject 1 withdrew at 12 weeks, and subject
2 withdrew at 16 weeks. Neither had demonstrated any
Table 3. Detailed results from 5 subjects with resistant MCD or FSGS
Baseline Week 4 Week 8 Week 12 Week 16 Week 20 Week 24
Subject 6
Scr, mg/dl 0.7 0.6 0.6 0.6 0.5 0.6 0.6
Salb, g/dl 2.5 2.6 2.5 2.7 2.8 2.4 2.4
UPCR, g/g 4.76 2.29 2.13 3.32 3.28 5.30 11.35
Cholesterol, mg/dl 453 384 432 443 527 – 332*
Cortisol, g/dl 19.2 7.3 3.5 7.4 5.5 5.4 5.7
ACTH, pg/ml 47 14 13 12 10 13 12
Subject 7
Scr, mg/dl 0.6 0.6 0.7 0.6 0.6 0.6 0.5
Salb, g/dl 3.4 3.3 4.0 3.6 3.7 3.8 3.7
UPCR, g/g 3.16 1.69 1.22 2.64 1.21 1.51 0.78
Cholesterol, mg/dl 289 234 244 210 228 219 210
Cortisol, g/dl 20.0 10.4 11.3 13.0 7.6 7.7 11.6
ACTH, pg/ml 15 9 6 9 7 10 6
Subject 8
Scr, mg/dl 1.2 1.2 1.3 1.2 1.3 1.5 1.4
Salb, g/dl 3.7 3.8 3.4 3.2 3.8 4.0 3.9
UPCR, g/g 1.94 1.68 1.98 3.27 0.51 0.30 0.43
Cholesterol, mg/dl 223 188 166 166 168 163 165
Cortisol, g/dl 5.5 6.1 7.6 5.5 6.5 8.4 9.8
ACTH, pg/ml 7 9 8 15 8 9 –
Subject 9
Scr, mg/dl 0.8 0.7 0.8 0.8 1.0 0.9 1.0
Salb, g/dl 2.8 2.7 2.7 2.6 2.4 2.4 2.3
UPCR, g/g 1.96 2.58 4.00 3.12 2.43 3.85 4.08
Cholesterol, mg/dl 166 183 193 167 – 216 231
Cortisol, g/dl 11.8 10.4 9.4 7.6 13.8 – 9.8
ACTH, pg/ml 32 34 32 37 36 29 34
Subject 10
Scr, mg/dl 1.0 0.9 1.0 1.2 0.9 0.9 1.0
Salb, g/dl 3.6 3.4 3.4 3.8 3.7 3.6 3.8
UPCR, g/g 1.65 2.19 1.65 2.62 1.43 1.72 1.93
Cholesterol, mg/dl 174 156 148 181 – 155 190
Cortisol, g/dl 16.4 10.3 8.0 12.8 12.0 19.0 17.5
ACTH, pg/ml 11 9 11 9 11 9 17
Cholesterol = Total cholesterol; Scr = serum creatinine; Salb = serum albumin.
* Subject 6 was started on atorvastatin after the week-16 visit.
Bomback /Canetta /BeckJr. /Aya lon /
Radhakrishnan
/Ap pe l
Am J Nephrol 2012;36:58–67
64
evidence of response to ACTH therapy by conventional
laboratory parameters at the time of withdrawal (al-
though subject 2’s serum showed disappearance of anti-
bodies to the PLA
2
R over the 16 weeks of treatment). Both
su bject s rema in dep end ent on o ral hy po glycemic t herapy
1 1 year from their last dose of ACTH. Subject 14 com-
plained of weight gain and Cushingoid facies by week 8,
accompanied by an average increased in blood pressure
of 20/10 mm Hg during this time. He had experienced
similar side effects with prednisone in the past. At week
12, with evidence of worsening kidney function, he was
withdrawn from the study. Four other subjects com-
plained of insomnia during the first month of therapy,
typically on the night of injections; these symptoms abat-
ed by month 2 for these subjects. Subjects 4 and 10 re-
ported increased pigmentation of their skin, which re-
solved within 4 weeks of discontinuing the drug. No sub-
ject developed a significant infection during the study
period.
Table 4. Detailed results from 5 subjects with resistant IgA nephropathy
Baseline Week 4 Week 8 Week 12 Week 16 Week 20 Week 24
Subject 11
Scr, mg/dl 1.7 1.7 1.8 1.9 2.0 1.8 1.7
Salb, g/dl 3.7 4.0 4.1 3.7 4.0 4.1 4.4
UPCR, g/g 1.95 1.76 1.45 1.54 1.57 1.38 1.22
Cholesterol, mg/dl 175 168 175 190 191 222 194
Cortisol, g/dl 11.7 4.6 6.7 8.7 5.3 5.0 15.0
ACTH, pg/ml 11.0 9.0 12.0 14.0 13.0 10.0 20.0
Subject 12
Scr, mg/dl 2.4 2.4 2.2 2.5 2.2 2.0 2.1
Salb, g/dl 4.0 4.0 3.7 4.3 4.3 3.9 4.1
UPCR, g/g 1.59 1.50 1.08 0.84 0.94 0.79 0.57
Cholesterol, mg/dl 171 164 156 174 165 166 154
Cortisol, g/dl 12.6 11.4 8.9 – 10.3 10.3 9.1
ACTH, pg/ml 14 23 14 – 17 16 26
Subject 13
Scr, mg/dl 0.8 0.8 0.8 0.8 1.0 0.8 0.8
Salb, g/dl 4.1 4.1 4.2 4.1 4.6 4.3 4.5
UPCR, g/g 0.61 1.16 0.40 0.29 0.14 0.14 0.21
Cholesterol, mg/dl 153 187 201 175 198 162 188
Cortisol, g/dl 16.7 15.3 19.9 10.3 20.3 17.3 11.2
ACTH, pg/ml 12 8 15 15 11 17 11
Subject 14
Scr, mg/dl 2.7 2.8 3.1 3.4 – – –
Salb, g/dl 4.0 3.8 3.8 3.4 – – –
UPCR, g/g 4.12 5.34 5.21 3.51 – – –
Cholesterol, mg/dl 215 191 209 209 – – –
Cortisol, g/dl 8.5 7.1 8.3 – – – –
ACTH, pg/ml 13 12 17 – – – –
Subject 15
Scr, mg/dl 1.0 1.1 1.0 1.1 1.1 1.1 1.2
Salb, g/dl 4.3 4.4 4.4 4.4 4.6 – 4.4
UPCR, g/g 1.51 1.74 1.32 0.84 1.03 0.85 0.85
Cholesterol, mg/dl 192 216 242 240 220 185 183
Cortisol, g/dl 16.3 14.0 10.4 16.5 13.2 8.0 12.5
ACTH, pg/ml 15 17 17 20 20 22 30
Cholesterol = Total cholesterol; Scr = serum creatinine; Salb = serum albumin.
ACTH for Resistant Glomerular Diseases Am J Nephrol 2012;36:58–67
65
Discussion
We present here the first prospective study data using
ACTH for resistant glomerular diseases. In this open-la-
bel, efficacy and safety study, we treated 15 subjects with
resistant MN, MCD, FSGS, or IgA nephropathy with
ACTH gel, 80 units twice weekly, for 6 months. Two of 5
resistant MN subjects, 2 of 5 resistant MCD/FSGS sub-
jects, and 3 of 5 resistant IgA nephropathy subjects
showed significant reductions i n proteinuria to remission
levels during the treatment period, and all but 1 subject
have sustained these remissions up to 1 year after discon-
tinuing therapy. Three subjects discontinued therapy
early due to Cush ingoid side effects, including exacerba-
tion of diabetes and weight gain. These results support
the use of ACTH gel therapy for some patients with resis-
ta nt glomeru lar disease s and, nota bly, show that an ef fect
of therapy can be seen in patients with reduced kidney
function and/or prolonged course of disease.
The data from this prospective trial add to a growing
body of literature on using ACTH for nephrotic syn-
drome that, to date, is based almost entirely on observa-
tional, retrospective case series
[6, 7, 9] . Only one previ-
ous report, from Ponticelli et al.
[11] , provides data from
a prospective study of ACTH, in which 16 subjects with
MN treated with a synthetic analogue of ACTH demon-
strated similar remission rates (14 of 16 remissions, or
87.5%) as 16 subjects with MN treated with alternating
months of steroids and cyclophosphamide (12 of 16 re-
missions, or 75%). In this study, however, ACTH was used
as a first-line immunomodulatory therapy and thus
would be expected to have a better response rate than
would be seen if used in resistant patients. A case series
published by our group reported 21 cases of idiopathic
nephrotic syndrome treated with ACTH gel outside of
research settings (i.e. by prescription), of which 18 were
considered to have resistant nephrotic syndrome, having
failed a mean 2.3 immunosuppressive regimens prior to
ACTH gel therapy (9 patients had failed at least 3 prior
therapies). Overall, 11 of 21 patients (52%) achieved a
complete or partial remission, with 4 (19%) in complete
remission. Of the 11 patients who achieved complete or
partial remission, 9 had idiopathic MN, 1 had FSGS, and
1 had IgA nephropathy
[9] . The response rates presented
here of 40–60%, depending on diagnosis, appear to con-
firm the signal seen in this previous, retrospective series.
The literature to date on the benefits of ACTH for ne-
phrotic syndrome has also been almost exclusively based
on patients with MN. Our study, therefore, provides im-
por ta nt da ta on us in g AC TH in p at ien ts wi th MCD, FS GS ,
and IgA nephropathy. Indeed, prior to this current study,
the results of ACTH treatment have been reported for
only 2 patients with FSGS
[7, 9] , 3 patients with MCD [7,
9]
, and 1 patient with IgA nephropathy [9] . We chose to
combine MCD and FSGS into one treatment group. Al-
though the courses of MCD and FSGS can be quite differ-
ent on initial presentation, particularly regarding re-
sponse to immunosuppressive therapy, treatment pat-
terns converge in the setting of steroid resistance, which
(along with failure of a second-line therapy) was a prereq-
uisite for enrollment in this study. We defined resistant
IgA nephropathy as proteinuria 1 1 g/day despite effective
inhibition of the RAAS; this proteinuria cutoff has been
shown to be a strong predictor of progression to renal fail-
ure
[13 ] and previous studies have shown that use of R AAS
blockade to achieve goal proteinuria ! 1 g/day leads to sig-
nificantly better outcomes
[14 ] . Our patients, thus, have
essentially failed the standard-of-care for IgA nephropa-
thy and are at increased risk for disease progression, as
demonstrated by signficantly reduced eGFR in 3 of the 5
subjects. The benefits of ACTH therapy in this IgA popu-
lation should be compared not against RAAS blockade
therapy, which has been studied in nonresistant popula-
tions
[14 ] , but rather against steroid therapy, which has
been studied in comparable patient populations
[15 , 16] .
These resu lts should be interpreted in light of the study
population of resistant patients. In all of the glomerular
diseases included in this study, failure of first-line ther-
apy increases the probability for failure of second-line
therapy, failure of second-line therapy increases the prob-
ability for failure of third-line therapy, and so forth. The
response rates of 2/5 or 3/5 patients are impressive for
such a population and place ACTH alongside other third-
or fourth-line therapies, such as rituximab and MMF, in
terms of expected benefits and strength of supportive
data
[17 –2 2] . In addition, by restricting the use of ACTH
in this study to patients with previous treatment resis-
tance, we have reduced the possibility of spontaneous re-
mission of disease confounding interpretation of clinical
improvements, which can happen in up to one-third of
patients with MN and a much smaller percentage of pa-
tients with IgA nephropathy. Our study also gives some
guidance on when and how the drug should be used, sug-
gesting that prolonged duration of disease and moderate
renal dysfunction are not contraindications, and that
treatment responses may take up to 3 or 4 months to
manifest. The small sample presented here does not pro-
vide any evidence supporting the use of ACTH for calci-
neurin inhibitor-dependent patients, unlike previous re-
ports using rituximab
[23] .
Bomback /Canetta /BeckJr. /Aya lon /
Radhakrishnan
/Ap pe l
Am J Nephrol 2012;36:58–67
66
The data from this study are limited, however, by the
small subject sample, the lack of a control group, and the
relatively short-term follow-up. This open-label pilot
study was not intended and clearly not powered to test
hypotheses. These data do demonstrate treatment re-
sponses as well as provide safety profiles for patients with
glomerular diseases who could be candidates for ACTH
therapy. These data should be viewed, in our opinion, as
stronger than retrospective and observational data previ-
ously reported by our group and others
[6–10] , but not as
robust as those provided by Ponticelli et al. in their ran-
domized trial of synthetic ACTH
[11] nor by those data
that will emerge from the ongoing randomized trial
of ACTH gel in resistant MN (NCT01386554). Those sub-
jects who began treatment with low urine protein:crea -
tinine ratio values (i.e. ! 2.0 g/g) conceivably may have
already achieved a partial remission of disease prior to
ACTH therapy, which would increase their likelihood of
showing a response to ACTH. Finally, the relatively short
duration of follow-up in these subjects does not provide
sufficient data on the sustainability of the responses doc-
umented here. In previous reports with synthetic ACTH
from Europe, a number of subjects who have responded
to therapy have required one or more additional courses
of ACTH for relapsing disease before achieving a sus-
tained remission
[7] .
In conclusion, we present here the first prospective
data on using ACTH as therapy for resistant glomerular
diseases. In a small sample of patients with MN, FSGS,
MCD, and IgA nephropathy who had not previously re-
sponded to conventional therapies, ACTH yielded a 40–
60% response rate depending on diagnosis. For all but
one subject, remission of proteinuria was sustained up to
1 year from cessation of therapy. Despite a 20% rate of
Cushingoid side effects, the drug was otherwise well tol-
erated with no significant infections. We believe that
these data support the further investigation of ACTH as
third- or fourth-line immunosuppressive therapy for pa-
tients with resistant glomerular diseases.
Acknowledgements
We are grateful to Angela Cha, Irma Orbe, and Melanie Foley
for their assistance with conduct of this study at the Clinical Re-
se ar ch O ff ic es o f the D iv isi on o f Ne phr olo gy at C olu mbia U niv er-
sity. These data were originally presented in abstract form at the
2011 American Society of Nephrology Renal Week.
Disclosure Statement
This study was supported by an investigator initiated study
grant from Questcor Pharmaceuticals, the manufacturer of
ACTH gel, and by the Center for Glomerular Diseases at Colum-
bia University. The investigators were responsible for study de-
sign, implementation, data analysis, and manuscript preparation.
Drs. Bomback, Beck, and Appel have received consulting hono-
raria from Questcor Pharmaceuticals. Drs. Canetta, Ayalon, and
Radhakrishnan have no relevant disclosures.
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