The document discusses the resurgence of adrenocorticotropic hormone (ACTH) as a potential treatment for proteinuric nephropathies, a condition that has historically seen limited effective therapies. Evidence suggests that ACTH can reduce proteinuria and may be beneficial in cases resistant to steroids, with mechanisms of action involving immunomodulation and direct effects on renal cells. However, further large-scale studies are needed to fully assess its efficacy and safety in diverse patient populations.

1. Adrenocorticotropichormone(ACTH):Aforgotten
toolinthetreatmentofproteinuricnephropathies

2. Review Article
Adrenocorticotropic hormone (ACTH): A forgotten
tool in the treatment of proteinuric nephropathies
Abhijit Taraphder*
Senior Consultant, Department of Nephrology, Apollo Gleneagles Hospitals, Flat E 301, Emerald Isle, 4, D L Khan Road, Kolkata 700025, West
Bengal, India
a r t i c l e i n f o
Article history:
Received 8 December 2012
Accepted 2 January 2013
Available online 20 January 2013
Keywords:
ACTH
Proteinuria
MCRs
Steroidogenesis
Immunomodulation
a b s t r a c t
Any new treatment option in proteinuric nephropathies is faced with several challenges
namely doubtful efficacy, unfavourable side effects and prohibitive cost. In 1950s and
1960s, ACTH was widely used for the treatment of childhood nephrotic syndrome. With the
availability of “better” therapeutic options, ACTH was dumped into oblivion. Recently there
has been a renewed interest in ACTH. After the discovery of melanocortin receptors
(MCRs), it is now known, these receptors are widely distributed in various organs including
the kidneys. ACTH remains the preferred agonist of all the MCRs. Either through ste-
roidogenesis, or other mechanism like immunomodulation, ACTH exerts its action in the
kidneys to reduce proteinuria in proteinuric nephropathies. Both preclinical and clinical
evidences are accumulating which speak in favour of a potential therapeutic role of ACTH
in these disorders. ACTH might also be useful in inducing remission in steroid-resistant
nephropathies, like immune-complex mediated glomerular diseases and podocyto-
pathies. Large multicentre studies with ACTH are to be initiated, before a definite con-
clusion can be arrived at.
Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
1. Introduction
Treatment of idiopathic glomerular diseases often faces sev-
eral challenges, namely low initial response, relapse of the
disease during/after reduction or withdrawal of the therapy
and untoward side effects or prohibitive cost of the medicines.
These have led to a research for second, third or fourth line
therapies to attain sustained remission, at the same time
avoiding complications. In an attempt to achieve the same,
the usual practice is to find something which is more modern,
at the same time more expensive.
In the last two decades, attention has been drawn to ad-
renocorticotropic hormone (ACTH), which was once used
extensively for the treatment of idiopathic nephrotic
syndrome in children, but subsequently dumped into oblivion
for nearly half of a century.1
ACTH has reemerged as a po-
tential treatment option in a variety of glomerular diseases,
including those which have initially shown a less than sat-
isfactory response to the usual therapies in idiopathic neph-
rotic syndrome.2
2. Physiology of ACTH
ACTH, or corticotropin is a polypeptide hormone, consisting
of 39 amino acids (ACTH1e39). It is produced in the anterior
lobe of the pituitary gland, by proteolytic cleavage of the
precursor peptide pre-pro-opiomelanocortin (pre-POMC),
* Tel.: þ91 (0) 9433390853.
E-mail address: taraphder@rediffmail.com.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/apme
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 5 e1 8
0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.apme.2013.01.005

3. when stimulated by corticotropin releasing hormone secreted
from the hypothalamus. ACTH in turn stimulates the adrenal
cortex to produce cortisol in response to stress, and serves as
a major component of the HPA axis.
In addition to steroidogenesis, ACTH also acts as a physio-
logical agonist of the melanocortin system.3
This system
comprises of multiple components, including five class A G-
protein coupled melanocortin receptors (MCRs), namely
MCIReMC5R. The five MCRs each have a distinct tissue dis-
tribution, and when acted upon by specific agonists exert
varying biological activities (Table 1). All five MCRs have
a strong affinity for ACTH, and all of them are expressed in
kidney cells. Hence kidney remains an important target for
the effects of ACTH.
ACTH stimulates lipolysis, has insulinotropic action4
(mediated through corticotropin like intermediate peptide,
CLIP, also known as ACTH18e39 fragment), and possesses
immunomodulatory functions.
3. Natural versus synthetic ACTH
At present, 2 products that contain ACTH, are commercially
available. The first one is ACTH gel, isolated from porcine
pituitary extracts. It contains the intact ACTH1e39, but in
addition, also contains some POMC derived peptides having
biological activity. The second product is a synthetic ACTH
analogue (tetracopeptide), which consists of the first 24 amino
acids of the native hormone (ACTH1e24). The insulinotropic
effect of the intact hormone resides in the C-terminal of ACTH
and is omitted from the synthetic analogue.4
4. ACTH in renal diseases
4.1. Evidence derived from animal experiments
ACTH has shown to improve renal inflammation and apop-
tosis in experimental animals.5
Pretreatment with ACTH gel
could attenuate tumour necrosis factor induced acute kidney
injury in rats. Renal histological injury was also prevented. In
subtotally nephrectomized rats (a standard model of focal and
segmental glomerulosclerosis, i.e. FSGS) ACTH gel has been
found to have a direct protective effect on podocytes. A five
week alternate day course of ACTH gel not only improved
proteinuria (by 50%), but also improved renal plasma flow and
serum creatinine levels. Histologically, glomerulosclerosis,
renal inflammation, tubular atrophy, interstitial fibrosis, and
tubular epithelialemesenchymal transdifferentiation all
showed improvement.6
The point which needs to be men-
tioned is, glucocorticoid therapy exacerbated proteinuria and
glomerulosclerosis in this model.7
Hence there has to be
glucocorticoid-independent mechanism(s) through which
ACTH exerts its renoprotective effect. It is proposed, ACTH has
considerable role in preventing podocyte injury and amelio-
ration of podocyte markers.
4.2. Clinical evidence
Most of the experience using ACTH for the treatment of idio-
pathic nephrotic syndrome is derived from retrospective
observational case series of heterogenous patient popula-
tion.8,9
These included patients who were treated with ACTH
as first line therapy, as also those who were tried with ACTH
after they had failed with first, second or third line agents. As
of today, there are only two studies where ACTH has been
used to treat nephrotic syndrome in a prospective design.
In the first one, an open-label randomized prospective
controlled trial was conducted to assess the safety and effi-
cacy of a 12-month course of synthetic ACTH1e24 therapy in 32
patients of idiopathic membranous nephropathy. The ACTH
therapy was compared with the standard protocol (methyl
prednisolone alternating with a cytotoxic agent) in patients
suffering from biopsy-proven idiopathic membranous ne-
phropathy. Response was found to be comparable: 83% of
those treated with ACTH and 75% of standard regimen expe-
rienced complete or partial remission. Both groups showed
comparable magnitude of dyslipidemia correction.10
In a recently published prospective open-label study, 15
subjects with resistant glomerular disease were treated with
ACTH gel (80 units subcutaneously twice weekly) for 6
months. Resistant minimal change disease, (MCD), focal seg-
mental glomerulosclerosis (FSGS) and idiopathic membra-
nous nephropathy (IMN) were defined as failure to achieve
sustained remission of proteinuria off immunosuppressive
therapy with at least 2 treatment regimens, and resistant IgA
nephropathy was defined as >1 g/g urine protein: creatinine
ratio despite maximally tolerated RAAS blockade. The study
included 5 subjects with resistant MCD/FSGS, 5 subjects with
resistant IMN and 5 subjects with resistant IgA nephropathy.
It was observed that one subject with resistant FSGS achieved
complete remission; one subject with resistant MCD achieved
partial remission, but relapsed within 4 weeks of stopping
ACTH; two subjects with resistant IgA nephropathy
Table 1 e Melanocortin receptors:their bio physiology.
Receptor Main sites of expression Agonist preference Biological effect
MC1R Melanocytes, testes, kidneys, skin glands,
endothelial cells, inflammatory & immune cells
ACTH ¼ aMSH >
bMSH > gMSH
Pigmentation, antipyresis,
immunomodulation
MC2R Adipocytes, kidneys, adrenal glands ACTH Steroidogenesis
MC3R Brain, kidneys, placenta, GI tract, pancreas As in MC1R Modulation of feeding behaviour
MC4R Brain, kidneys, spinal cord As in MC1R Energy homeostasis, sexual behaviour
MC5R Kidneys, exocrine glands, lymph nodes,
leukocytes, adipose tissue, muscle
As in MC1R Immunomodulation, regulation of exocrine
functions
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 5 e1 816

4. demonstrated >50% reduction of proteinuria, and proteinuria
remained below 1 g/g till 6 months. Of the IMN patients, two
achieved partial remission, though immunological remission
(disappearance of PLA2R antibody) could be achieved in 3 pa-
tients by 4 months of therapy.11
Striking antiproteinuric effects of ACTH have also been
observed in patients suffering from hereditary nephritis,
lupus nephritis, and other proliferative nephropathies.9,12
The
comorbidities, like oedema, oliguria and dyslipidemia also
showed signs of improvement.13
5. Side effects of ACTH therapy
By and large, 6 to 12 month treatment with ACTH is well tol-
erated. Commonly encountered adverse effects are skin pig-
mentation, hypertension, hypokalemia and accelerated bone
loss. In a recently published study, 3 of 15 subjects reported
weight gain and hyperglycemia prompting early termination
of therapy.11
Serious allergic reactions to ACTH are rare, but
have been reported in children while being treated for asthma
and allergic conditions.14
6. Possible mechanisms of ACTH action
Initially it was postulated that ACTH acts through adrenal
MC2R-mediated steroidogenesis. Subsequently it was
observed that ACTH induces remission also in some cases of
steroid-resistant nephrotic syndrome. Hence steroid-
independent mechanisms of ACTH are also being considered.
It is thought that ACTH directly activates MCRs expressed
on renal parenchymal cells and trigger downstream effects
which may have renoprotective potential (Table 2). This leads
to initiation of apoptosis, improvement of cell survival, and
reduction of inflammation. The major effect of ACTH on
podocytopathies (MCD & FSGS) and immune complex glo-
merulopathies (e.g. IMN), is mediated through its systemic
immunomodulatory activities like reducing autoantibody
production, maintaining the balance between subsets of
T-cells, and diminishing the release of lymphokines. There are
some evidence that the effects of ACTH may also be mediated
through the central nervous system. The cholinergic anti-
inflammatory pathway may contribute partly to the reno-
protective effects of ACTH. ACTH also tends to restore the
levels of certain apolipoproteins e.g. apolipoprotein E and
apolipoprotein J. It is postulated that these apolipoproteins
neutralize the activity of circulating permeability factors in
patients with proteinuric nephropathies e.g. FSGS.15
7. Concluding remarks
ACTH, once known as a potent agent for the treatment of
paediatric nephrotic syndrome, has started to attract atten-
tion after 50 years of neglect. It does show encouraging results
even in steroid-resistant cases, raising the possibility of
steroid-independent mechanisms. However, most of the
Table 2 e Potential Renoprotective Mechanisms of ACTH.
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 5 e1 8 17

5. findings are gathered from single centre observational studies
with small sample size, limited controls and short-term follow
up. Large multicentre randomized double-blind studies are
required to examine the efficacy of ACTH in both naı¨ve and
steroid-resistant cases of nephrotic syndrome.
Conflicts of interest
The author has none to declare.
Acknowledgement
Author would like to acknowledge Sri Debesh Saha for pre-
paring the manuscript.
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