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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2013  |  Volume : 24  |  Issue : 2  |  Page : 230-234
Autosomal dominant polycystic kidney disease: New insights into treatment

Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO, USA; Laboratory of Kidney Pathology (LR00SP01-Pr Ben Maiz Hedi) Charles Nicolle Hospital, Faculty of Medicine, University of Tunis El Manar, Tunis, Tunisia

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Date of Web Publication26-Mar-2013


Autosomal dominant polycystic kidney disease (ADPKD) is the world's most common inherited kidney disease. An increasing number of animal and human studies have enhanced our understanding of the molecular and cellular pathology of ADPKD. New treatment options are being tested in clinical trials in spite of the failure of mammalian target of rapamycin inhibitor therapy. The main and most effective therapy remains control of hypertension by renin-angiotensin-aldosterone system (RAAS) blockade. This review focuses only on promising therapies, including dual inhibition of RAAS, vasopressin receptor antagonists, increased fluid intake, and blockade of certain receptors of cyclic adenosine monophosphate. Also, the paper reviews what these advances mean to patients and clinicians and elaborates on how these changes can be immediately applied to clinical practice. There is an urgent need for discovery of new therapies targeted toward ADPKD in comparison with therapeutic progress of all other renal diseases.

How to cite this article:
Helal I. Autosomal dominant polycystic kidney disease: New insights into treatment. Saudi J Kidney Dis Transpl 2013;24:230-4

How to cite this URL:
Helal I. Autosomal dominant polycystic kidney disease: New insights into treatment. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2022 May 20];24:230-4. Available from: https://www.sjkdt.org/text.asp?2013/24/2/230/109561

   Introduction Top

Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening single-gene disease. It affects over 600,000 individuals in the United States (US) and 12 million people worldwide. [1],[2] This disease is the fourth leading cause of end-stage renal disease (ESRD) in the US. [3] ADPKD is currently responsible for 2.5% of overall ESRD cases and 2.2% of new ESRD cases each year in the US. [3]

There is currently no treatment that can stop ADPKD from forming cysts in the kidneys, and the condition cannot be cured. Hence, treatment for ADPKD aims to control the condition's symptoms, limit kidney damage, and prevent complications. For many decades, the treatment of this condition has been at a relative standstill when compared to the advances in therapy in other kidney diseases. However, there are many exciting new developments and potential pharmacological interventions in ADPKD. [4] These may finally allow specific therapies aimed at slowing ADPKD progression, which has always been the unrestricted almost exponential growth of cysts within the kidney leading to ESRD.

The national institutes of health funded large clinical studies of ADPKD. Basic research facilitates testing of other potential drug therapies for ADPKD, and other clinical trials of ADPKD are implementing new imaging methods for assessing the progression of ADPKD. First of all, it must be stated clearly that at the present moment, our rationale with these new treatment modalities is not to cure, but to slow ADPKD progression. An increasing number of animal and human studies have enhanced our understanding of the molecular and cellular pathology of ADPKD. [5],[6],[7] Recent evidence indicates that the progressive increase in kidney volume in patients with ADPKD is primarily due to the accumulation of fluid within innumerable cysts and the proliferation of mural epithelial cells, [2],[8] involving a major role for cyclic adenosine monophosphate (cAMP)-stimulated signaling pathways in controlling both the rate of epithelial cell growth and fluid secretion in cysts. [9],[10]

In this review, we focus only on promising treatments including dual inhibition of the renin-angiotensin-aldosterone system (RAAS), vasopressin receptor antagonists, increased fluid intake, and oral antiglycemic agents that block certain receptors of cAMP, which in turn reduce the rate of growth of the cysts and ADPKD progression.

   Dual Inhibition of RAAS Top

Hypertension is one of the most frequent complications in ADPKD contributing to both an increased incidence of cardiovascular mortality and faster progression to ESRD. [1],[11],[12] Activation of the intra-renal development of hypertension and may be associated with ADPKD progression. [13]

Some progress has been made in the treatment and prognosis of ADPKD over the past decades [14],[15],[16] in spite of the failure of mammalian target of rapamycin (mTOR) inhibitor therapy. [17],[18] The main and most effective therapy remains control of hypertension by RAAS blockade. [14],[16] Effective inhibition of the RAAS and tight blood pressure control are being evaluated. [19]

Previously, our group demonstrated that better blood pressure control leads to improvement in ADPKD outcomes. [20] However, cardiovascular disease still remains the main cause of death in ADPKD. [11] We have also demonstrated a significant decrease of renal disease progression in ADPKD patients associated with attainment of better blood pressure control and increased use of angiotensin converting enzyme inhibitors (ACEIs). [14]

The question of whether treatment with either ACEIs and/or angiotensin receptor blockers (ARBs) has resulted in decreased rate of progression of renal disease in ADPKD will be answered by the HALT study. [19] This study is a prospective clinical interventional study for adult ADPKD patients. The investigation will test whether intensive blockade of the RAAS with combination of ACEI and ARB therapy will slow renal progression in ADPKD patients, compared with ACEI monotherapy alone. In addition, the study will test whether rigorous versus moderate blood pressure control will be more effective in slowing renal progression in early ADPKD.

Some investigators have thoughts to study the combination of aliskiren and ACEI or ARB in ADPKD patients. Unfortunately, a report from the Food and Drug Administration cautioned against combining the blood pressure medication aliskiren (Tekturna) with ACEIs and ARBs in patients with diabetes or renal impairment. This new warning, which will be accompanied by a label change, is based on results from the terminated ALTITUDE study, [21] which found an increased risk of adverse events in high-risk patients taking the direct renin inhibitor as an add-on to other anti-hypertensive medications.

   Vasopressin Antagonists Top

Vasopressin, also known as arginine vasopressin (AVP) or antidiuretic hormone (ADH), is a neurohypophysial hormone. It increases water permeability of the renal collecting duct. Vasopressin has also been mentioned to be involved in pathogenic processes in ADPKD. It promotes cAMP production by acting on V2 receptors in the distal nephron and collecting ducts. [22] The vasopressin V2 receptor is an attractive target, because cAMP plays such a principal role in the pathogenesis of growth of cysts in ADPKD. The ability to modulate cAMP in a cell-specific manner provides opportunities for targeting therapies. [23] Vasopressin V2 receptor (VPV2R) antagonists have shown success in lowering renal cAMP and slowing cystic growth by blocking V2 receptors. [24] Vasopressin acts on V2 receptors and regulates adenyl cyclase. [24] V2 receptors in the collecting duct and distal nephron, however, are overexpressed in ADPKD patients, who are not usually able to concentrate urine, and they pass more urine than most people. They tend to have increased levels of vasopressin in the blood and that causes an increase in growth of cysts. V2 receptor antagonists block cAMP, and it is hoped that it will slow down the growth of kidney cysts.

In several animal models, this approach has yielded good therapeutic results. [25] This treatment has slowed dramatically or even halted cystic disease. Human clinical trials in patients with ADPKD of a related vaopressin receptor antagonist, tolvaptan, which was developed for other clinical purposes, are under way. The TEMPO study [26] has demonstrated that the growth of ADPKD cysts progresses more slowly with tolvaptan than in historical controls, but adverse effects are common. Therefore, an eight-week study of tolvaptan dose forms in ADPKD (nocturne) was undertaken to compare the short-term effects of two tolvaptan formulations in patients with ADPKD.

   Increased Fluid Intake Top

In animal studies of ADPKD, giving the animal large quantity of water suppresses vasopressin levels in the blood and cAMP levels in the kidneys, slowing cyst enlargement. [27] It is postulated that large water intake in patients with ADPKD will decrease plasma AVP concentration and attenuates the action of cAMP on the renal tubule, resulting in the amelioration of ADPKD progression. These studies suggest that water ingestion is a potential therapeutic strategy in patients with ADPKD. Increased fluid intake may be effective at least in early stages of the disease. If increased fluid intake, either by itself or together with the administration of V2 receptor antagonists, is proved to slow the rate of growth of cysts in ADPKD, then its long-term safety will need to be considered. [28] A retrospective analysis of the MDRD study was performed to examine the relationship between fluid intake and renal disease progression. Higher urine volumes and lower urine osmolality are associated with faster decline of renal function regardless of whether the patient had ADPKD. [29]

A two-week pilot study was undertaken to evaluate the efficacy of water prescription in ADPKD. [30] This study demonstrated that the amount of additional water needed to achieve a urine osmolality target can be approximated from the urine osmolar excretion in ADPKD patients eating typical diets, providing a quantitative method to prescribe supplemental water for such individuals. However, the effects of long-standing water intake on plasma AVP level and cyst development in ADPKD patients are not known. Therefore, long-term (12 months) efficacy study of water diuresis induced by oral water intake on kidney volume and renal function in ADPKD patients is designed.

   Agonist Receptors of cAMP Top

Recent observations suggest that metformin may be effective on metabolism through the reduction of intracellular energy charge, [31],[32] which blocks adenosine triphosphate (ATP)-sensitive potassium channels and cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels and has been shown to block fluid secretion and growth into ADPKD cysts. [33],[34]

Metformin is a widely used drug for treatment of type-2 diabetes, with no defined cellular mechanism of action, and all our diabetic patients, except one, took this drug. [35]

There is evidence that overactivity of both mTOR and CFTR contributes importantly to the progressive expansion of renal cysts in ADPKD. [33] Recent research has established that AMP-activated kinase (AMPK) can suppress the activity of these proteins. Metformin is the best clinical activator of AMPK. [31] Recently, hyperglycemic suppression of AMPK activity, an effect associated with increased mTOR activity, has been shown to play a mediating role in the renal hypertrophy observed in diabetic rats. Conversely, metformin treatment suppresses renal hypertrophy in diabetic rats. These findings encourage the speculation that metformin can be used to suppress mTOR activation in the renal cyst epithelium of ADPKD patients. In addition, AMPK phosphorylates CFTR, blocking its activity. [33]

Currently, it is clear that AMPK is one of the many stress responses in cardiovascular tissues. Chronic activation of AMPK appears to confer adaptive resistance to stress in a number of conditions, including endothelial dysfunction, response to arterial injury, and myocardial injury. The precise mechanisms whereby AMPK confers a multitude of effects are not clear at the moment, but may be linked to the upregulation of mitochondrial biogenesis and antioxidant defenses. Recently, we have demonstrated that patients with ADPKD and type-2 diabetes have larger renal volumes, earlier age at diagnosis of hypertension, and may die at a younger age, compared to those with ADPKD alone. [36] This study emphasizes the importance of diabetes risk management in ADPKD, and the striking delay associated with type-2 diabetes in ADPKD-induced renal progression should be evaluated further.

   Conclusion Top

Currently, no treatment exists to prevent ADPKD progression and patients require kidney transplants or lifelong dialysis for survival. It is still unclear if and when many of these treatments will become available. Nowadays, the most commonly used and the optimal management of ADPKD patients is with the earlier introduction of RAAS blockers and better blood pressure control and to urge ADPKD patients to lead a healthy lifestyle. The development of new potential therapies for ADPKD raises the hope to slow the growth of cysts and delay the onset of ESRD. It is likely that patients with ADPKD will benefit from these scientific advances in the near future.

Conflict of interest: None

   References Top

1.Iglesias C, Torres V, Offord K, Holley K, Beard C, Kurland L. Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935-1980. Am J Kidney Dis 1983;2:630-9.   Back to cited text no. 1
2.Ecder T, Fick-Brosnahan GM, Schrier RW. Polycystic kidney disease. In: Schrier RW, ed. Diseases of the Kidney and Urinary Tract, 8 th ed. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 502-39.   Back to cited text no. 2
3.U.S. Renal Data System: USRDS 2011 Annual Data Report, 2011.   Back to cited text no. 3
4.Masoumi A, Reed-Gitomer B, Kelleher C, Schrier RW. Potential pharmacological interventions in polycystic kidney disease. Drugs 2007;67:2495-510.  Back to cited text no. 4
5.Wilson PD. Polycystic kidney disease: New understanding in the pathogenesis. Int J Biochem Cell Biol 2004;36:1868-73.  Back to cited text no. 5
6.Steinman TI. Polycystic kidney disease: A 2011 update. Curr Opin Nephrol Hypertens 2012;21: 189-94.  Back to cited text no. 6
7.Chapman AB. Approaches to Testing New Treatments in Autosomal. Clin J Am Soc Nephrol 2008;3:1197-204.  Back to cited text no. 7
8.Grantham JJ. The etiology, pathogenesis, and treatment of autosomal dominant polycystic kidney disease: Recent advances. Am J Kidney Dis 1996;28:788-803.  Back to cited text no. 8
9.Grantham JJ. Lillian Jean Kaplan International Prize for advancement in the understanding of polycystic kidney disease. Understanding polycystic kidney disease: A systems biology approach. Kidney Int 2003;64:1157-62.  Back to cited text no. 9
10.Belibi FA, Reif G, Wallace DP, et al. Cyclic AMP promotes growth and secretion in human polycystic kidney epithelial cells. Kidney Int 2004;66:964-73.  Back to cited text no. 10
11.Fick GM, Johnson AM, Hammond WS, Gabow PA. Causes of death in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1995;5:2048-56.  Back to cited text no. 11
12.Gabow PA, Johnson AM, Kaehny WD, et al. Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease. Kidney Int 1992;41:1311-9.  Back to cited text no. 12
13.Loghman-Adham M, Soto CE, Inagami T, Cassis L. The intrarenal renin-angiotensin system in autosomal dominant polycystic kidney disease. Am J Physiol Renal Physiol 2004;287:F775-88.  Back to cited text no. 13
14.Schrier RW, McFann KK, Johnson AM. Epidemiological study of kidney survival in autosomal dominant polycystic kidney disease. Kidney Int 2003;63:678-85.  Back to cited text no. 14
15.Orskov B, Rømming Sørensen V, Feldt-Rasmussen B, Strandgaard S. Improved prognosis in patients with autosomal dominant polycystic kidney disease in Denmark. Clin J Am Soc Nephrol 2010;5:2034-9.  Back to cited text no. 15
16.Patch C, Charlton J, Roderick PJ, Gulliford MC. Use of antihypertensive medications and mortality of patients with autosomal dominant polycystic kidney disease: A population-based study. Am J Kidney Dis 2001;57:856-62.  Back to cited text no. 16
17.Serra AL, Poster D, Kistler AD, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med 2010;363: 820-9.  Back to cited text no. 17
18.Walz G, Budde K, Mannaa M, et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2010;363: 830-40.  Back to cited text no. 18
19.Chapman AB, Torres VE, Perrone RD, et al. The HALT polycystic kidney disease trials: Design and implementation. Clin J Am Soc Nephrol 2010;5:102-9.  Back to cited text no. 19
20.Ecder T, Edelstein CL, Fick-Brosnahan GM, et al. Progress in blood pressure control in autosomal dominant polycystic kidney disease. Am J Kidney Dis 2000;36:266-71.  Back to cited text no. 20
21.Parving HH, Brenner BM, McMurray JJ, et al. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE): Rationale and study design. Nephrol Dial Transplant 2009;24: 1663-71.  Back to cited text no. 21
22.Elhassan EA, Schrier RW. The use of vasopressin receptor antagonists in hyponatremia. Expert Opin Investig Drugs 2011;20:373-80.  Back to cited text no. 22
23.Torres VE. Vasopressin antagonists in polycystic kidney disease. Semin Nephrol 2008;28:306-17.  Back to cited text no. 23
24.Torres VE. Role of vasopressin antagonists. Clin J Am Soc Nephrol 2008;3:1212-8.   Back to cited text no. 24
25.Meijer E, Gansevoort RT, de Jong PE, et al. Therapeutic potential of vasopressin V2 receptor antagonist in a mouse model for autosomal dominant polycystic kidney disease: Optimal timing and dosing of the drug. Nephrol Dial Transplant 2011;26:2445-53.  Back to cited text no. 25
26.Higashihara E, Torres VE, Chapman AB, et al. TEMPO Formula and 156-05-002 Study Investigators. Tolvaptan in autosomal dominant polycystic kidney disease: Three years' experience. Clin J Am Soc Nephrol 2011;6:2499-507.  Back to cited text no. 26
27.Gattone VH 2nd, Maser RL, Tian C, Rosenberg JM, Branden MG. Developmental expression of urine concentration-associated genes and their altered expression in murine infantile-type polycystic kidney disease. Dev Genet 1999;24: 309-18.  Back to cited text no. 27
28.Torres VE. Water for ADPKD? Probably, yes. J Am Soc Nephrol 2006;17:2089-91.   Back to cited text no. 28
29.Hebert LA, Greene T, Levey A, Falkenhain ME, Klahr S. High urine volume and low urine osmolality are risk factors for faster progression of renal disease. Am J Kidney Dis 2003;41:962-71.  Back to cited text no. 29
30.Wang CJ, Creed C, Winklhofer FT, Grantham JJ. Water prescription in autosomal dominant polycystic kidney disease: A pilot study. Clin J Am Soc Nephrol 2011;6:192-7.   Back to cited text no. 30
31.Hawley SA, Gadalla AE, Olsen GS, Hardie DG. The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes 2002;51:2420-5.  Back to cited text no. 31
32.Viollet B, Mounier R, Leclerc J, Yazigi A, Foretz M, Andreelli F. Targeting AMP-activated protein kinase as a novel therapeutic approach for the treatment of metabolic disorders. Diabetes Metab 2007;33:395-402.  Back to cited text no. 32
33.McCarty MF, Barroso-Aranda J, Contreras F. Activation of AMP-activated kinase as a strategy for managing autosomal dominant polycystic kidney disease. Med Hypotheses 2009; 73:1008-10.   Back to cited text no. 33
34.Backenroth R, Popovtzer MM. Does type 2 diabetes mellitus delay renal failure in autosomal dominant polycystic kidney disease?. Ren Fail 2002;24:803-13.  Back to cited text no. 34
35.Goldman-Levine JD. Beyond metformin initiating combination therapy in patients with type 2 diabetes mellitus. Pharmacotherapy 2011;31: 44S-53.  Back to cited text no. 35
36.Reed B, Helal I, McFann K, Wang W, Yan XD, Schrier RW. The impact of type II diabetes mellitus in patients with autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 2012;27:2862-5.  Back to cited text no. 36

Correspondence Address:
Imed Helal
University of Colorado Denver, Division of Renal Diseases and Hypertension, Box C-281. 1270 East 19th. RC2 7th floor Room 7001, Aurora, Colorado 80045, USA

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.109561

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