Combining Spironolactone with ACEi and/or ARB in the Treatment of Diabetic Patients with Nephropathy

This paper explores the literature on the effectiveness of combining spironolactone with ACEi and/or ARB in the treatment of a diabetic patient with nephropathy. It discusses the systemic action of these agents and recommends double blockage enhanced by using a mixture of both ACE inhibitor and ARB as a single dosage.

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Introduction
Treatment of diabetic patients diagnosed with nephropathy has been tactical following
the progression of renal failure. One of the challenges that have affected the treatment of
nephropathy among diabetic patients is the aldosterone escape phenomenon that increases the
level of aldosterone within the body plasma. Many different drugs are sued in treatment of
nephropathy among diabetic patients currently used. Most of these drugs have been infective
calling for more treatment methods. One of the improved treatments is the mixture of more than
two drugs to increase effectiveness. Mixture of spironolactone with either ACE inhibitors or
ARB agent has shown effective results in the treatment of nephropathy. Under short term
treatment, the mixturehas proved effective though with time the level of aldosterone increases
due to aldosterone escape. The literature presents the systemic action of these agents and
recommends double blockage enhanced by using a mixture of both ACE inhibitor and ARB as a
single dosage. This paper, therefore, explores the literature on the effectiveness of combining
spironolactone with ACEi and/or ARB in the treatment of a diabetic patient with nephropathy.
Literature review
Diabetic nephropathy
Diabetic nephropathy refers to the presence and persistence of proteinuria that is greater
than 0.5 g/day. The clinical proteinuria patient excretes albumin that is >200-300 μg /min. The
risk of proteinuria is known for the development of proliferative retinopathy. This, therefore,
necessitates the need for reduction of proteinuria in the body of a diabetic patient. In addition,
Chaszczewska-Markowska, Sagan, and Bogunia-Kubik indicate that high level of proteinuria in

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the body result in nephropathy condition of pathological changes that are a risk for the bodyi.
This is due to the occurrence of an end of renal failure that has been known to occur in 75% of
diabetic patients with nephropathy. Uses of drugs that reduce proteinuria are one of the primary
treatments for patients with diabetic nephropathy.ii
Aldosterone is a key product within the body that contributes to renal and cardiovascular
disease in the body of diabetic patients. Using those drugs that block aldosterone is key for
treating patients with nephropathy. For effective action of the aldosterone, renin-angiopoietin-
aldosterone system (RAAS) is formed within the body. Angiotensin II is known to cause the
action of RAAS in the body of diabetic patients. According to Tylicki, Lizakowski, and
Rutkowski, treatment of a diabetic patient with an ACE inhibitor or ARB reduces plasma
aldosteroneiii. This further inhibits the formation of the RAAS within the body thus increasing
the chances of survival. However, Bhaskar Mahin Ginila and Soundararajan indicate that
aldosterone may return to the initial state at the pretreatment stage in aldosterone escape
phenomenon. This causes the treatment of nephropathy unsuccessfuliv. The overall result of the
untreated is an increased level of proteinuria in the blood of the patient and increases the rate of
renal failure in the patient.
i Chaszczewska-Markowska M, Sagan M, Bogunia-Kubik K. The renin-angiotensin-aldosterone
system (RAAS)—physiology and molecular mechanisms of functioning. Postepy Hig Med
Dosw. 2016; 70:917–927. DOI: 10.5604/17322693.1218180.
ii Tylicki L, Lizakowski S, Rutkowski B. Renin-angiotensin-aldosterone system blockade for
nephroprotection: current evidence and future directions. Journal of Nephrol. 2012; 25(6):900–
910. DOI: 10.5301/jn.5000134.

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The action of spironolactone on diabetic patients
As explained by Morishita and Kusano, diabetic nephropathy is known to be the common
atributed to end-stage renal disease. The renal damage at this point is majorly caused by
aldosterone that induces fibrosis, inflammation and necrosis within the kidney systemsv.
Furthermore, albuminuria is the major cause of progressive renal disease in many patients
diabetes type 2. Reducing the amount of albuminuria in patients reduces the progression of
nephropathy in diabetic patients. According to Liu, Xu, Shi, and Zhuang, a mixtureof ARB and
spironolactone which is the anti-aldosterone drug reduces the albuminuria effect. Spironolactone
is effective when reducing the proteinuria in patients and has been confirmed through several
studies. According to Kato and Maruyama et al., the effect of spironolactone is increased when
added to ARB and has worked 80% in patientsvi. Moreover, Makhlough and Kashi et al., confirm
that the deleterious action of aldosterone is partly reduced upon a mixture of spironolactone and
either ACEi or ARB in diabetic nephropathy patients. Struthers and Unger compare the
iii Ujihara N, Babazono T, Haize M, Uchigata Y. Comparison of spironolactone and
trichlormethiazide as add-on therapy to renin–angiotensin blockade for reduction of albuminuria
in diabetic patients. Journal Diabetes Invest. 2013; 4(3):316–319. doi: 10.1111/jdi.12029.
iv Liu N, Xu L, Shi Y, Zhuang S. Podocyte autophagy: a potential therapeutic target to prevent
the progression of diabetic nephropathy. Journal of Diabetes Research. 2017; 2017:3560238.
Available from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420432/

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efficiency of combining spironolactone with ACEi or usage as Monotherapy of spironolactone in
the treatment of diabetic patients.vii
The beneficial effect of mixing spironolactone to antihypertensive treatment in
nephropathy patients
According to Hase and Babazono, adding the spironolactone in the time of treatment of
diabetic patients to ACE inhibitors or ARB adds the cardiovascular benefitviii. The mixture
reduces albuminuria and blood pressure to the patient that has been diagnosed with nephropathy.
This is similar to another study that indicates that addition of an ACE inhibitor increases the
aldosterone blockage benefit to the patient with diabetic nephropathyix.
Mavrakanas, Gariani, and Martin explained that the mixture of the spironolactone with
ACE inhibitor or ARB has proved more effective as it increases Reno-and cardiovascular
v Kato S, Maruyama S, Makino H, Wada J, Ogawa D, Uzu T, Araki H, Koya D, Kanasaki K,
Oiso Y, Goto M, Nishiyama A, Kobori H, Imai E, Ando M, Matsuo S. Anti-albuminuric effects
of spironolactone in patients with type 2 diabetic nephropathy: a multicenter, randomized clinical
trial. Clin Exp Nephrol. 2015; 19(6):1098–1106. DOI: 10.1007/s10157-015-1106-2.
vi Makhlough A, Kashi Z, Akha O, Zaboli E, Yazdanicharati J. Effect of spironolactone on
diabetic nephropathy compared to the mixtureof spironolactone and losartan. Nephro-Urol
Monthly. 2014; 6(1):e12148. Available from
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968951/
vii Struthers AD, Unger T. Physiology of aldosterone and pharmacology of aldosterone blockers.
Eur Heart J. 2011; 13(SB): B27–B30. DOI: 10.1093/eurheartj/sur009.

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protection to the diabetic patient with nephropathyx. This results from short term reduction of
albuminuria and arterial blood pressure. Furthermore, those patients with advance level of
proteinuria show high effectiveness of the mixture as it reduces the presence of albuminuria in
the body. As explained by Bakris, the reduction effect of proteinuria is more effective when ACE
inhibitors are mixed with spironolactone in the treatment of diabetic patient with a rate of 80%.xi
Considering the action of both ACEi and ARB, the reduction of the level of nephropathy
among diabetes patients has also been established. Mixture of spironolactone and ACEi or ARB
has a various impact as highlighted by many different studies. Within this combination,
spironolactone is known to reno-cardiovascular protection when used in treatment. This
viii Hase M, Babazono T, Ujihara N, Uchigata Y. Comparison of spironolactone and
trichlormethiazide as add-on therapy to renin-angiotensin blockade for reduction of albuminuria
in diabetic patients. Journal of Diabetes Invest. 2013; 4(3):316–319. DOI: 10.1111/jdi.12029.
ix Shavit L, Lifschitz MD, Epstein M. Aldosterone blockade and the mineralocorticoid receptor in
the management of chronic kidney disease: current concepts and emerging treatment paradigms.
Kidney Int 2012; 81: 955–968. Available from https://www.ncbi.nlm.nih.gov/pubmed/22336987
x Mavrakanas TA, Gariani K, Martin PY. Mineralocorticoid receptor blockade in addition to
angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment: an
emerging paradigm in diabetic nephropathy: a systematic review. Eur J Intern Med 2014; 25:
173–176. Available from https://www.ncbi.nlm.nih.gov/pubmed/24315413
xi Bakris, G. L. “Recognition, pathogenesis, and treatment of different stages of nephropathy in
patients with type 2 diabetes mellitus,” Mayo Clinic Proceedings, vol. 86, no. 5, pp. 444–456,
2011. View at Publisher

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enhances the treatment especially during the early stages of nephropathy that can be reversed at
this point. Dong and Ting-ting et al, indicates that there are also studies that explore the usage of
both ACEi and ARB as a mixturewith spironolactone when treating diabetic patients with
nephropathyxii. This is due to the double blockade of RAAS as compared to single-agent therapy.
In addition, double blockage according to Weisong and Lihua et al. is short term effects but
under the long-term condition, the effectiveness of the mixture is reduced.xiii
Comparison between systemic review and literature review
According to Soetikno and Arozal et al, systemic action of these drugs mixture is well
researched and presented in literature materialsxiv. Literature shows several researches have been
done to establish the effectiveness of combining various drugs for the treatment of nephropathy
diabetic patients. For instance, Ruggenenti, Cravedi, and Remuzzi explain systemic action of
combining spironolactone with either ACEi and/or ARB when treating a diabetic patient
diagnosed with nephropathyxv. Besides, the effectiveness of the mixtureis also well presented
xii Dong D, Ting-ting F., Ying-shi J., Jin-yu Y., Shan W., & Li Z., Spironolactone alleviates
diabetic nephropathy through promoting autophagy in podocytes. Int Urol Nephrol. 2019;
51(4):755–64.
xiii Weisong W, Lihua L, Zhonghai Z, Junjie G, & Yinghao S, Effect of spironolactone combined
with angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers on chronic
glomerular disease Exp Ther Med. 2013 Dec; 6(6): 1527–1531. DOI: 10.3892/etm.2013.1335

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within the literature identifying the various weakness of this mixturein the reduction of
aldosterone. The literature also provides the study gap that exists when using a mixture of
spironolactone with ARB and or ACEi in treatment of a diabetic patient with nephropathyxvi.
Limitation of a mixture of spironolactone and aldosterone blockers
Despite several studies that show the effectiveness of the mixture of spironolactone and
ACEi and/or ARB in treatment of diabetic patients with nephropathy, continuous use of this
mixtureresult into a high amount of aldosterone in the patient’s plasma. The high level of
aldosterone is resulting in continuous aldosterone escape. According to Mima, this
ineffectiveness of the mixtureduring the treatment has proved the need for more research in the
treatmentxvii. The impact of aldosterone in patients is profound with much research showing that
aldosterone reduces BNP7 action that results in early nephropathy among diabetic patients.
Ruggenenti, Cravedi, and Remuzzi conclude by indicating that application ACEi and ARB is
ineffective when treating diabetic patient’s nephropathyxviii.
xiv Soetikno V, Arozal W, Louisa M, Setiabudy R, The RAAS in the pathogenesis and treatment
of diabetic nephropathy. Nat Rev Nephrol. 2010 Jun; 6(6):319-30. DOI:
10.1038/nrneph.2010.58.
xv Ruggenenti P, Cravedi P, Remuzzi G. New insight into the molecular drug target of diabetic
nephropathy. Int J Endocrinol. 2014; 2014:968681. DOI: 10.1155/2014/968681.
xvi Alireza M, Alireza K, Mahmood S, Reporting Quality Assessment of Randomized Controlled
Trials Published in Nephrology Urology Monthly Journal. Mon. 2015 Jul; 7(4): e28752.
Published online 2015 Jul 1. doi: 10.5812/numonthly.28752

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Future clinical practice
Comparing the systemic action of the nephropathy treatment and literature material
available shows that there is a need to intensify research into the posibility of increasing the
effectiveness of mixture or more treatment options. Songyan et al, explains the need for a more
effective treatment that can prevent aldosterone escape in the chronic treatment of diabetes
patients with nephropathyxix. In addition, there is a need to improve on the already available
drugs for effective treatment and this can be done through research into the perfect mixtureof
drugs or increasing more drug mixture option. More research is needed to determine the reason
for aldosterone escape that makes the drug mixtureineffective as this will help in drug
improvement. Treatment with aldosterone blockers is another option that requires future research
to prove effectiveness in albuminuria improvementxx.
xvii Mima A, Diabetic nephropathy: protective factors and a new therapeutic paradigm. Journal of
Diabetes Complications. 2013 Sep-Oct; 27(5):526-30. DOI: 10.1016/j.jdiacomp.2013.03.003.
xviii Ruggenenti P, Cravedi P, Remuzzi G. New insight into the molecular drug target of diabetic
nephropathy. Int J Endocrinol. 2014; 2014:968681. DOI: 10.1155/2014/968681.
xix Songyan W, Bing, L., Chunguang, L., Wenpeng, C., & Lining, M. Potential Renoprotective
Agents through Inhibiting CTGF/CCN2 in Diabetic Nephropathy. Journal Diabetes Res.
2015:962383.
xx Morishita Y, & Kusano, E. Direct Renin Inhibitor: Aliskiren in Chronic Kidney Disease.
Nephro Urol Mon. PubMed. 2011; 5(1):668–72.

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Conclusion
In conclusion, combining spironolactone with both ACE inhibitor and ARB is the most
effective treatment for a diabetic patient with nephropathy under short term basis. Long term
treatment of the nephropathy among diabetic patients requires additional research to uncover
ways to reduce aldosterone escape. Systemic review shows ways through which nephropathy
develops and how the process can be reversed at early stages. This is mainly through reducing
the proteinuria that leads to renal failure progression. Studies, however, show that the mixture of
spironolactone and two or more aldosterone blockers is currently an effective treatment agent
due to double blockage action when administered to the patient. As shown within the literature,
there is a need for more research to improve the treatment of nephropathy among diabetic
patients as this is a fatal condition.