Adrenocorticotropichormone(ACTH):Aforgottentoolinthetreatmentofproteinuricnephropathies
Review ArticleAdrenocorticotropic hormone (ACTH): A forgottentool in the treatment of proteinuric nephropathiesAbhijit Tar...
when stimulated by corticotropin releasing hormone secretedfrom the hypothalamus. ACTH in turn stimulates the adrenalcorte...
demonstrated >50% reduction of proteinuria, and proteinuriaremained below 1 g/g till 6 months. Of the IMN patients, twoach...
findings are gathered from single centre observational studieswith small sample size, limited controls and short-term follo...
Apollohospital:http://www.apollohospitals.com/Twitter:https://twitter.com/HospitalsApolloYoutube:http://www.youtube.com/ap...
Upcoming SlideShare
Loading in …5
×

Adrenocorticotropic hormone (acth): a forgotten tool in the treatment of proteinuric nephropathies

1,683 views

Published on

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 steroidogenesis, or other mechanism like immunomodulation, ACTH exerts its action in the MCRs 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 podocytopathies. Large multicentre studies with ACTH are to be initiated, before a definite conclusion can be arrived at.

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
1,683
On SlideShare
0
From Embeds
0
Number of Embeds
2
Actions
Shares
0
Downloads
12
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Adrenocorticotropic hormone (acth): a forgotten tool in the treatment of proteinuric nephropathies

  1. 1. Adrenocorticotropichormone(ACTH):Aforgottentoolinthetreatmentofproteinuricnephropathies
  2. 2. Review ArticleAdrenocorticotropic hormone (ACTH): A forgottentool in the treatment of proteinuric nephropathiesAbhijit Taraphder*Senior Consultant, Department of Nephrology, Apollo Gleneagles Hospitals, Flat E 301, Emerald Isle, 4, D L Khan Road, Kolkata 700025, WestBengal, Indiaa r t i c l e i n f oArticle history:Received 8 December 2012Accepted 2 January 2013Available online 20 January 2013Keywords:ACTHProteinuriaMCRsSteroidogenesisImmunomodulationa b s t r a c tAny new treatment option in proteinuric nephropathies is faced with several challengesnamely doubtful efficacy, unfavourable side effects and prohibitive cost. In 1950s and1960s, ACTH was widely used for the treatment of childhood nephrotic syndrome. With theavailability of “better” therapeutic options, ACTH was dumped into oblivion. Recently therehas 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 includingthe kidneys. ACTH remains the preferred agonist of all the MCRs. Either through ste-roidogenesis, or other mechanism like immunomodulation, ACTH exerts its action in thekidneys to reduce proteinuria in proteinuric nephropathies. Both preclinical and clinicalevidences are accumulating which speak in favour of a potential therapeutic role of ACTHin these disorders. ACTH might also be useful in inducing remission in steroid-resistantnephropathies, 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. IntroductionTreatment of idiopathic glomerular diseases often faces sev-eral challenges, namely low initial response, relapse of thedisease during/after reduction or withdrawal of the therapyand untoward side effects or prohibitive cost of the medicines.These have led to a research for second, third or fourth linetherapies to attain sustained remission, at the same timeavoiding 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 usedextensively for the treatment of idiopathic nephroticsyndrome in children, but subsequently dumped into oblivionfor nearly half of a century.1ACTH 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.22. Physiology of ACTHACTH, or corticotropin is a polypeptide hormone, consistingof 39 amino acids (ACTH1e39). It is produced in the anteriorlobe of the pituitary gland, by proteolytic cleavage of theprecursor peptide pre-pro-opiomelanocortin (pre-POMC),* Tel.: þ91 (0) 9433390853.E-mail address: taraphder@rediffmail.com.Available online at www.sciencedirect.comjournal homepage: www.elsevier.com/locate/apmea p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 5 e1 80976-0016/$ 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. 3. when stimulated by corticotropin releasing hormone secretedfrom the hypothalamus. ACTH in turn stimulates the adrenalcortex to produce cortisol in response to stress, and serves asa major component of the HPA axis.In addition to steroidogenesis, ACTH also acts as a physio-logical agonist of the melanocortin system.3This systemcomprises of multiple components, including five class A G-protein coupled melanocortin receptors (MCRs), namelyMCIReMC5R. The five MCRs each have a distinct tissue dis-tribution, and when acted upon by specific agonists exertvarying biological activities (Table 1). All five MCRs havea strong affinity for ACTH, and all of them are expressed inkidney cells. Hence kidney remains an important target forthe effects of ACTH.ACTH stimulates lipolysis, has insulinotropic action4(mediated through corticotropin like intermediate peptide,CLIP, also known as ACTH18e39 fragment), and possessesimmunomodulatory functions.3. Natural versus synthetic ACTHAt present, 2 products that contain ACTH, are commerciallyavailable. The first one is ACTH gel, isolated from porcinepituitary extracts. It contains the intact ACTH1e39, but inaddition, also contains some POMC derived peptides havingbiological activity. The second product is a synthetic ACTHanalogue (tetracopeptide), which consists of the first 24 aminoacids of the native hormone (ACTH1e24). The insulinotropiceffect of the intact hormone resides in the C-terminal of ACTHand is omitted from the synthetic analogue.44. ACTH in renal diseases4.1. Evidence derived from animal experimentsACTH has shown to improve renal inflammation and apop-tosis in experimental animals.5Pretreatment with ACTH gelcould attenuate tumour necrosis factor induced acute kidneyinjury in rats. Renal histological injury was also prevented. Insubtotally nephrectomized rats (a standard model of focal andsegmental glomerulosclerosis, i.e. FSGS) ACTH gel has beenfound to have a direct protective effect on podocytes. A fiveweek alternate day course of ACTH gel not only improvedproteinuria (by 50%), but also improved renal plasma flow andserum creatinine levels. Histologically, glomerulosclerosis,renal inflammation, tubular atrophy, interstitial fibrosis, andtubular epithelialemesenchymal transdifferentiation allshowed improvement.6The point which needs to be men-tioned is, glucocorticoid therapy exacerbated proteinuria andglomerulosclerosis in this model.7Hence there has to beglucocorticoid-independent mechanism(s) through whichACTH exerts its renoprotective effect. It is proposed, ACTH hasconsiderable role in preventing podocyte injury and amelio-ration of podocyte markers.4.2. Clinical evidenceMost of the experience using ACTH for the treatment of idio-pathic nephrotic syndrome is derived from retrospectiveobservational case series of heterogenous patient popula-tion.8,9These included patients who were treated with ACTHas first line therapy, as also those who were tried with ACTHafter they had failed with first, second or third line agents. Asof today, there are only two studies where ACTH has beenused to treat nephrotic syndrome in a prospective design.In the first one, an open-label randomized prospectivecontrolled trial was conducted to assess the safety and effi-cacy of a 12-month course of synthetic ACTH1e24 therapy in 32patients of idiopathic membranous nephropathy. The ACTHtherapy was compared with the standard protocol (methylprednisolone alternating with a cytotoxic agent) in patientssuffering from biopsy-proven idiopathic membranous ne-phropathy. Response was found to be comparable: 83% ofthose treated with ACTH and 75% of standard regimen expe-rienced complete or partial remission. Both groups showedcomparable magnitude of dyslipidemia correction.10In a recently published prospective open-label study, 15subjects with resistant glomerular disease were treated withACTH gel (80 units subcutaneously twice weekly) for 6months. Resistant minimal change disease, (MCD), focal seg-mental glomerulosclerosis (FSGS) and idiopathic membra-nous nephropathy (IMN) were defined as failure to achievesustained remission of proteinuria off immunosuppressivetherapy with at least 2 treatment regimens, and resistant IgAnephropathy was defined as >1 g/g urine protein: creatinineratio despite maximally tolerated RAAS blockade. The studyincluded 5 subjects with resistant MCD/FSGS, 5 subjects withresistant IMN and 5 subjects with resistant IgA nephropathy.It was observed that one subject with resistant FSGS achievedcomplete remission; one subject with resistant MCD achievedpartial remission, but relapsed within 4 weeks of stoppingACTH; two subjects with resistant IgA nephropathyTable 1 e Melanocortin receptors:their bio physiology.Receptor Main sites of expression Agonist preference Biological effectMC1R Melanocytes, testes, kidneys, skin glands,endothelial cells, inflammatory & immune cellsACTH ¼ aMSH >bMSH > gMSHPigmentation, antipyresis,immunomodulationMC2R Adipocytes, kidneys, adrenal glands ACTH SteroidogenesisMC3R Brain, kidneys, placenta, GI tract, pancreas As in MC1R Modulation of feeding behaviourMC4R Brain, kidneys, spinal cord As in MC1R Energy homeostasis, sexual behaviourMC5R Kidneys, exocrine glands, lymph nodes,leukocytes, adipose tissue, muscleAs in MC1R Immunomodulation, regulation of exocrinefunctionsa p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 5 e1 816
  4. 4. demonstrated >50% reduction of proteinuria, and proteinuriaremained below 1 g/g till 6 months. Of the IMN patients, twoachieved partial remission, though immunological remission(disappearance of PLA2R antibody) could be achieved in 3 pa-tients by 4 months of therapy.11Striking antiproteinuric effects of ACTH have also beenobserved in patients suffering from hereditary nephritis,lupus nephritis, and other proliferative nephropathies.9,12Thecomorbidities, like oedema, oliguria and dyslipidemia alsoshowed signs of improvement.135. Side effects of ACTH therapyBy 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 boneloss. In a recently published study, 3 of 15 subjects reportedweight gain and hyperglycemia prompting early terminationof therapy.11Serious allergic reactions to ACTH are rare, buthave been reported in children while being treated for asthmaand allergic conditions.146. Possible mechanisms of ACTH actionInitially it was postulated that ACTH acts through adrenalMC2R-mediated steroidogenesis. Subsequently it wasobserved that ACTH induces remission also in some cases ofsteroid-resistant nephrotic syndrome. Hence steroid-independent mechanisms of ACTH are also being considered.It is thought that ACTH directly activates MCRs expressedon renal parenchymal cells and trigger downstream effectswhich may have renoprotective potential (Table 2). This leadsto initiation of apoptosis, improvement of cell survival, andreduction of inflammation. The major effect of ACTH onpodocytopathies (MCD & FSGS) and immune complex glo-merulopathies (e.g. IMN), is mediated through its systemicimmunomodulatory activities like reducing autoantibodyproduction, maintaining the balance between subsets ofT-cells, and diminishing the release of lymphokines. There aresome evidence that the effects of ACTH may also be mediatedthrough the central nervous system. The cholinergic anti-inflammatory pathway may contribute partly to the reno-protective effects of ACTH. ACTH also tends to restore thelevels of certain apolipoproteins e.g. apolipoprotein E andapolipoprotein J. It is postulated that these apolipoproteinsneutralize the activity of circulating permeability factors inpatients with proteinuric nephropathies e.g. FSGS.157. Concluding remarksACTH, once known as a potent agent for the treatment ofpaediatric nephrotic syndrome, has started to attract atten-tion after 50 years of neglect. It does show encouraging resultseven in steroid-resistant cases, raising the possibility ofsteroid-independent mechanisms. However, most of theTable 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. 5. findings are gathered from single centre observational studieswith small sample size, limited controls and short-term followup. Large multicentre randomized double-blind studies arerequired to examine the efficacy of ACTH in both naı¨ve andsteroid-resistant cases of nephrotic syndrome.Conflicts of interestThe author has none to declare.AcknowledgementAuthor would like to acknowledge Sri Debesh Saha for pre-paring the manuscript.r e f e r e n c e s1. Arneil GC, Wilson HE. A.C.T.H. in nephrosis. Arch Dis Child.1953;28:372e380.2. Berg AL, Arnadottir M. ACTH revisited e potentialimplications for patients with renal disease. Nephrol DialTransplant. 2000;15:940e942.3. Cone RD. Studies on the physiological functions of themelanocortin system. Endocr Rev. 2006;27:736e749.4. Beloff-Chain A, Morton J, Dunmore S, Taylor GW, Morris HR.Evidence that the insulin secretagogue, beta-cell-tropin, isACTH22-39. Nature. 1983;301:255e258.5. Gong R, Ge Y, Tolbert EM, Zhuang S, Dworkin LD.Renoprotection by adrenocorticotropin in experimental acutekidney injury. J Am Soc Nephrol. 2009;20:510A.6. Gong R, Dworkin LD. ACTH (Acthar Gel) prevents proteinuriaand renal injury in the remnant kidney: evidence for directpodocyte protection. J Am Soc Nephrol. 2010;21:548A.7. Garcia DL, Rennke HG, Brenner BM, Anderson S. Chronicglucocorticoid therapy amplifies glomerular injury in ratswith renal ablation. J Clin Invest. 1987;80:867e874.8. Rauen T, Michaelis A, Floege J, Mertens PR. Case series ofidiopathic membranous nephropathy with long-termbeneficial effects of ACTH peptide 1-24. Clin Nephrol.2009;71:637e642.9. Berg AL, Arnadottir M. ACTH-induced improvement in thenephrotic syndrome in patients with a variety of diagnoses.Nephrol Dial Transplant. 2004;19:1305e1307.10. Ponticelli C, Passerini P, Salvadori M, et al. A randomized pilottrial comparing methylprednisolone plus a cytotoxic agentversus synthetic adrenocorticotropic hormone in idiopathicmembranous nephropathy. Am J Kidney Dis. 2006;47:233e240.11. Bomback AS, Canetta PA, Beck Jr LH, Ayalon R,Radhakrishnan J, Appel GB. Treatment of resistantglomerular diseases with adrenocorticotropic hormone gel:a prospective trial. Am J Nephrol. 2012;36:58e67.12. Bomback AS, Tumlin JA, Baranski J, et al. Treatment ofnephrotic syndrome with adrenocorticotropic hormone(ACTH) gel. Drug Des Dev Ther. 2011;5:147e153.13. Berg AL, Nilsson-Ehle P, Arnadottir M. Beneficial effects ofACTH on the serum lipoprotein profile and glomerularfunction in patients with membranous nephropathy. KidneyInt. 1999;56:1534e1543.14. Rosenblum AH, Rosenblum P. Anaphylactic reactions toadrenocorticotropic hormone in children. J Pediatr.1964;64:387e395.15. Gong R. The renaissance of corticotropin therapy inproteinuric nephropathies. Nat Rev Nephrol. 2012;8:122e128.a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 1 5 e1 818
  6. 6. Apollohospital:http://www.apollohospitals.com/Twitter:https://twitter.com/HospitalsApolloYoutube:http://www.youtube.com/apollohospitalsindiaFacebook:http://www.facebook.com/TheApolloHospitalsSlideshare:http://www.slideshare.net/Apollo_HospitalsLinkedin:http://www.linkedin.com/company/apollo-hospitalsBlog:Blog:http://www.letstalkhealth.in/

×