Adenosine A1 Receptor Antagonists in Clinical Research and Development Berthold Hocher1,2

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Adenosine A1 receptor antagonists in clinical research and development Berthold Hocher1,2

1Institute of Nutritional Science, University of Potsdam, Potsdam, Germany and 2Center for Cardiovascular Research/Department of Pharmacology and Toxicology, Charite´, Campus Mitte, Berlin, Germany

Selective adenosine A1 receptor antagonists targeting renal Various lines of evidence implicate impaired renal function as microcirculation are novel pharmacologic agents that are a risk factor in patients with congestive heart failure (CHF). currently under development for the treatment of acute Conventional diuretics may aggravate renal dysfunction and heart failure as well as for chronic heart failure. Despite can result in neurohumoral activation and activation of the several studies showing improvement of renal function TGF mechanism in the kidney.1 Impaired kidney function and/or increased diuresis with adenosine A1 antagonists, might not just be a risk factor, but is also currently observed particularly in chronic heart failure, these findings were as having a role—and thus potentially as target—in disease not confirmed in a large phase III trial in acute heart failure progression of heart failure patients.1 Evolving new ther- patients. However, lessons can be learned from these and apeutic strategies that enhance renal function include other studies, and there might still be a potential role for administration of B-type natriuretic peptide, adenosine the clinical use of adenosine A1 antagonists. and vasopressin antagonists, and ultrafiltration methods. We review the role of adenosine A1 receptors in the Prospective studies are needed to evaluate whether these new regulation of renal function, and emerging data regarding renal-enhancing strategies will improve patient outcome in the safety and efficacy of A1 adenosine receptor antagonists CHF. This review is focused on the up-to-now available based on all available completed and reported clinical trials clinical data with A1 adenosine receptor antagonists. using A1 adenosine receptor antagonists. The majority of trials were done in heart failure patients. However, there is clear clinical evidence for a role of this new class in BIOCHEMISTRY AND PHYSIOLOGY OF ADENOSINE hepatorenal syndrome, hypotension on dialysis, and Adenosine is produced from the hydrolysis of adenosine radiocontrast media-induced nephropathy. triphosphate. The actions of adenosine are mediated by Kidney International (2010) 78, 438–445; doi:10.1038/ki.2010.204; G-protein-coupled receptors that activate second messenger published online 30 June 2010 systems mediating effects in the vascular beds as well as other KEYWORDS: acute renal failure; diuretics; heart failure structures (for example, macula densa and renal tubular cells) of the kidney, brain, and heart. Four subtypes of adenosine receptors have been identified: A1, A2a, A2b, and A3. The receptors A1 and A3 are coupled to the pertussis toxin- sensitive Gi proteins and inhibit adenylyl cyclase, whereas the A2a and A2b receptors activate Gs proteins to stimulate adenylyl cyclase and cyclic adenosine monophosphate production.2–4 In the heart and many other vascular beds, adenosine functions primarily as a vasodilator through the activation of A2a receptors,2,3 but there is also evidence for functional cardiac A1 adenosine receptors.2–4 In the kidney, activation of adenosine A1 receptors in the afferent arteriole results in vasoconstriction that reduces the glomerular filtration rate (GFR) and renal blood flow and mediates TGF. This net vasoconstriction occurs despite the presence of A2a receptors Correspondence: Berthold Hocher, F. Hoffmann-La Roche, pRED-Pharma in the efferent arteriole. In the kidney, A1 adenosine receptors Research & Early Development Metabolic DTA, Basel, Switzerland. have been localized in the afferent arteriole, glomerulus, E-mail: [email protected] proximal tubule, and collecting ducts, whereas A2a adeno- Received 23 February 2010; revised 1 April 2010; accepted 14 April sine receptors are located primarily in efferent arterioles. 2010; published online 30 June 2010 Infusion of selective A1 adenosine antagonists into the renal

438 Kidney International (2010) 78, 438–445 B Hocher : The role of adenosine A1 receptors mini review

vasculature causes diuresis and natriuresis, indicating that The ability of specific adenosine A1 receptor antagonists these receptors also mediate sodium and water reabsorption.5 to induce diuresis and natriuresis while not compromising The ability of A1 adenosine receptor blockers to preserve GFR and also renal blood flow has thus become an attractive GFR by inhibiting TGF further promotes salt and water therapeutic option for the treatment of fluid retention excretion by the kidney.5 disorders, especially in (1) severe kidney disease, (2) liver cirrhosis with ascites, and (3) in acute heart failure (AHF) and chronic heart failure. We review below the available information on clinical trials of A1 adenosine antagonists Table 1 | Direct comparison of Ki values from different A1 in these indications. Key information on the characteristics of adenosine receptor blockers currently in clinical different compounds is summarized in Table 1, whereas the development (data obtained from Solvay Pharmaceuticals, Hannover, Germany) key trial information is summarized in Table 2.

BG9928 KW3902 ALTERING KIDNEY FUNCTION IN ADVANCED LIVER Ki (nM) SLV320 (Adentri) (Rolofylline) CIRRHOSIS A1-receptor, human 1 7.4 5 Liver cirrhosis is associated with a progressive deterioration A2A-receptor, human 398 6600 158 of kidney function, starting with diuretic-resistant ascites in A2B-receptor, human 3981 90 316 A3-receptor, human 200 22,000 2000 liver cirrhosis followed by hepatorenal syndrome type 1 and A2A/A1 398 892 31.6 2. Although urgently needed, there is, however, no estab- Synonyms are given in booklets; SLV320 has no synonym so far. lished pharmacological approach for the treatment of these

Table 2 | Summary of all phase II and III clinical studies performed so far using A1 adenosine receptor antagonists Study title/references Study design Study population Findings Compound Natriuretic effect of an Open-labeled pilot 12 patients with liver Urine sodium excretion and urine flow rate FK352 adenosine-1 receptor study cirrhosis and ascites increased after FK352. Plasma cAMP and antagonist in cirrhotic refractory to loop angiotensin II levels and plasma renin activity patients with ascites8 diuretics also increased. No change was detected in renal blood flow, glomerular filtration rate, and cardiac output Adenosine A1 receptor Double-blind, 30 patients on FK352 significantly improved intradialytic FK352 antagonist improves placebo-controlled hemodialysis hypotension. The frequency of discontinuation of intradialytic hypotension9 dialysis was significantly reduced by FK352. No apparent side effects were observed The effects of KW-3902, an Double-blind, 146 ADHF patients In ADHF protocol, 146 patients with volume KW-3902 adenosine A1-receptor placebo-controlled with renal overload and an eGFR of 20 to 80 ml/min were antagonist, on diuresis and impairment randomized to placebo or 1 of 4 doses of KW- renal function in patients with + 3902 (rolofylline) infused over 2 h daily for up to acute decompensated heart 35 diuretic-resistant 3 days. On day 1, KW-3902 monotherapy failure and renal impairment ADHF patients increased urine output during the first 6 h or diuretic resistance10 compared with placebo. On day 2, serum creatinine decreased in all KW-3902 groups and increased with placebo. By day 4, or day of discharge if earlier, intravenous furosemide administration tended to be lower in the KW-3902 groups compared with placebo. In diuretic- resistant protocol, 35 patients with an average eGFR of 34 ml/min were randomized to a single infusion of placebo or KW-3902. Compared with placebo, KW-3902 increased hourly urine volume and eGFR with peak effects occurring at 2 to 3 h and at 24 h, respectively. Adverse events were not different between placebo and KW-3902 Cardio-renal effects of the A1 Double-blind, 111 chronic Heart rate, blood pressure, PCWP, MPAP, RAP, SLV320 adenosine receptor antagonist placebo-controlled HF patients SVR, and CO were not altered by any dose of a SLV320 in patients with heart single i.v. SLV320 dose. Changes from baseline failure13 cystatin C plasma concentrations decreased after 10 mg SLV320, whereas furosemide treatment resulted in a significant increase in cystatin C versus baseline. SLV320 increased significantly sodium excretion and diuresis when compared with placebo during 0–6h collection period after dosing. SLV320 was well tolerated, and no serious adverse events were observed

Kidney International (2010) 78, 438–445 439 mini review B Hocher : The role of adenosine A1 receptors

Table 2 | Continued

Study title/references Study design Study population Findings Compound BG9719 (CVT-124), an A1 Double-blind, 63 chronic BG9719 alone caused an increase in urine output BG9719 adenosine receptor antagonist, ascending-dose, HF patients and sodium excretion. Although administration of (CVT-124) protects against the decline in crossover study furosemide alone caused a large diuresis, addition renal function observed with of BG9719 to furosemide increased diuresis. diuretic therapy12 BG9719 alone improved GFR at the two lower dosages. Furosemide alone caused a decline in GFR. However, when BG9719 was added to furosemide, creatinine clearance remained at baseline at the two lower doses. BG9719 was well tolerated Effects of BG9719 (CVT-124), Randomized, 12 chronic GFR was 84.6 ml/min per 1.73 m2 after receiving BG9719 an A1-adenosine receptor double-blind, HF patients placebo, 82.6 after BG9719 administration, and antagonist, and furosemide placebo-controlled, decreased to 63.6 after furosemide. Total renal on glomerular filtration rate parallel design plasma flow was similar in all groups. Sodium and natriuresis in patients with excretion increased after BG9719 and furosemide. congestive heart failure14 Diuresis was more pronounced in the furosemide group, but also increased after BG9719 The effect of KW-3902, an Double-blind, 32 chronic GFR increased by 32% and renal plasma flow KW-3902 adenosine A1 receptor placebo-controlled, HF patients increased by 48%. Furthermore, subjects who antagonist, on renal function two-way crossover initially received KW-3902 returned for the and renal plasma flow in study crossover phase (median 6 days) with a persistent ambulatory patients with heart 10 ml/min increase in GFR more than their failure and renal impairment15 previous baseline Effects of multiple oral doses Randomized, 50 chronic BG9928 increased sodium excretion compared BG9928 of an A1 adenosine antagonist, double-blind, HF patients with placebo, and natriuresis was maintained over BG9928, in patients with heart placebo-controlled 10 days with little kaliuresis. GFR was unchanged failure17 study over 10 days. Patients who received BG9928 had a reduction in body weight compared with placebo. At the end of study, BG9928 was well tolerated The PROTECT pilot study: a Randomized, 301 ADHF patients There was a trend of rolofylline toward greater KW-3902 randomized, placebo- double-blind, with renal proportions of patients with marked or controlled, dose-finding study placebo-controlled, impairment moderately improved dyspnea and fewer patients of the adenosine A1 receptor parallel design with worsening heart failure or renal function. antagonist rolofylline in patients The trend was driven by improvement in dyspnea. with acute heart failure and Serum creatinine increased in patients receiving renal impairment19 placebo and remained stable or tended to decrease in those receiving rolofylline. On day 14 the absolute differences between placebo and rolofylline for change in creatinine increased with increasing rolofylline dose. Treatment with 30 mg, the dose selected for the pivotal trials, was associated with a trend toward reduced 60-day mortality or readmission for cardiovascular or renal cause The PROTECT study20 Randomized, 2033 ADHF patients Dyspnea improved at both 24 and 48 h after KW-3902 double-blind, with renal dosing in 51.2% in the rolofylline group and 44.5% placebo-controlled, impairment in the placebo group. Death or cardiovascular parallel design or renal hospitalization occurred in 30.7% of rolofylline patients (25.7% were hospitalized and 8.9% died) and 31.9% of placebo patients (25.6% were hospitalized and 9.5% died). Serum creatinine increase of X0.3 mg/dl through day 7 confirmed at day 14 was observed in 12.3% in the rolofylline group and in 10.6% in the placebo group. Initiation of hemofiltration was needed in 0.4% of all patients in the rolofylline group and in 0.9% in the placebo group. More patients on rolofylline experienced nervous system disorders, with 11 patients (0.8%) experiencing seizure and 16 patients (1.2%) experiencing stroke on rolofylline, with no patients experiencing seizure and 3 patients (0.5%) experiencing stroke in placebo Abbreviations: ADHF, acute decompensated heart failure; cAMP, cyclic adenosine monophosphate; CO, cardiac output; eGFR, estimated glomerular filtration rate; HF, heart failure; MPAP, mean pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; SVR, systematic vascular resistance.

440 Kidney International (2010) 78, 438–445 B Hocher : The role of adenosine A1 receptors mini review

conditions.6 Animal studies suggest that a resetting of TGF TARGETING DIURETIC RESISTANCE may contribute to the pathophysiology of kidney impairment Resistance to loop diuretics may occur in patients with heart in liver cirrhosis.7 This hypothesis was even tested clinically failure and also in different forms of advanced renal disease some years ago in a small phase II study using FK352, a novel (secondary renal diseases such as later stages of diabetic pyrazolopyridine derivative that has been characterized nephropathy and also primary renal diseases such as focal in vitro as a highly selective A1 adenosine receptor segmental glomerulonephritis). When conservative app- antagonist.4 This study was a phase II open-labeled study, roaches including sequential nephron blockade do not work, designed primarily to assess the efficacy and safety of FK352. costly and invasive techniques such as hemofiltration may A dose escalation was built into the study to identify any dose became the only way to improve the fluid status of the response. p-Aminohippuric acid and inulin clearance, urine patient. It was suggested that an activated TGF might be a key flow rate, sodium and potassium excretion, and free water pathophysiological cause of resistance to diuretics. This clearance were measured for 2 h before and after FK352 hypothesis was tested in heart failure patients resistant to administration. Cardiac output, systemic vascular resistance, diuretics in a randomized, double-blind, placebo-controlled, plasma angiotensin II level, plasma renin activity, noradrena- dose-escalation study.6 Resistance to diuretics was defined line, adrenaline, and adenosine 30-50-cyclic monophosphate clinically by the blinded physician. The patients had to have levels were also measured before and after FK352.8 Urine reached the point in which a further increase in diuretic sodium excretion and urine flow rate increased after FK352 therapy was unlikely to be effective or would worsen renal substantially. Plasma cyclic adenosine monophosphate and function and in which the investigator was considering more angiotensin II levels and plasma renin activity also increased. aggressive management of fluid overload, including the use of No change was detected in any other parameters.8 These data further intravenous (i.v.) vasoactive medications, mechanical indicate that an A1 adenosine receptor antagonist may induce circulatory support, ultrafiltration, or dialysis. Examples of water and salt excretion in patients with liver cirrhosis without diuretic refractoriness included: the combination of i.v. compromising renal blood flow and GFR. This may offer a new furosemide plus oral metolazone given X1 times (nephron horizon in the so far disappointing attempts to treat kidney blockade) per day, or an infusion of furosemide at dysfunction in liver cirrhosis.6 Clearly, larger studies, including 420 mg/h that does not yield any significant increase in studies in patients with even more advanced disease stages, are urine output or reduction in edema, weight, or fluid volume needed before coming to final conclusions. status.10 A total of 35 patients with an average creatinine clearance of 34 ml/min were randomized to a single infusion INFLUENCING INTRADIALYTIC HYPOTENSION IN of placebo, 10, 30, or 60 mg of KW-3902. Compared with END-STAGE RENAL DISEASE PATIENTS placebo, KW-3902 increased hourly urine volume and Sudden hypotension during dialysis (intradialytic hypoten- estimated GFR with peak effects occurring at 2 to 3 h and sion) is a frequent complication of hemodialysis. This may at 24 h, respectively.10 This indicates that A1 adenosine contribute to cardiovascular events and high mortality and is receptor antagonists may overcome resistance to diuretics in limiting both qualities of life of the patients on hemodialysis heart failure. This needs to be confirmed in larger studies and the quality of dialysis itself. This condition is particularly including other conditions also of resistance to treatment frequent in patients with diabetic nephropathy and occurs with diuretics. usually 1 h after initiation of dialysis. There were indications that an increase in adenosine generation during hemodialysis TREATMENT OF CHRONIC HEART FAILURE may cause vasodilation and a decrease in cardiac output, Baseline kidney function, measured most often as estimated which results in systemic hypotension. The effects of an GFR, is associated with a poor outcome in heart failure A1 antagonist, FK352, injection in 30 chronic hemodialysis patients. Moreover, worsening of GFR (mainly characterized patients with frequent intradialytic hypotension were investi- as change of baseline estimated GFR versus day 2) is gated in a prospective, multicenter, double-blind placebo- frequently observed in patients with AHF syndromes and controlled study for 4 weeks.9 Intradialytic hypotension was adds additional mortality risk. On the other hand, improve- defined as systolic blood pressure of o110 mm Hg, ment in estimated GFR is associated with a somewhat better with its drop of 430 mm Hg from the predialysis level. outcome even in terms of mortality.1,11 Thus, it was proposed The efficacy of FK352 was primarily assessed by the reduction that therapeutic strategies to improve kidney function in rate of dialysis hypotension between the FK352 and placebo heart failure patients may translate in symptomatic and even groups. Incidence of emergency treatments caused by mortality benefits in patient with both chronic heart failure hypotension was evaluated. FK352 significantly improved and AHF. This hypothesis was first investigated in patients intradialytic hypotension. The frequency of discontinuation with chronic stable heart failure. The pioneering work was of dialysis was also significantly reduced by FK352. No carried out by Gottlieb et al.12 They performed a randomized, apparent side effects were observed from treatment with double-blind, ascending-dose, crossover study evaluating FK352.9 Taken together, patients with frequent hypotension three doses of BG9719 in 63 patients with CHF. Patients on dialysis may benefit from a prophylactic treatment with an received placebo or 1 of 3 doses of BG9719 on one day and A1 adenosine receptor antagonist. the same medication plus furosemide on a separate day.

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Renal function and electrolyte and water excretion were evidence was missing simply because of lack of adequate assessed. BG9719 alone caused an increase in urine output animal models for AHF. The PROTECT pilot study, and sodium excretion. Although administration of furose- however, showed very promising data, indicating that this mide alone caused a large diuresis, addition of BG9719 to class of drugs might improve mortality, symptoms of AHF, furosemide increased diuresis. BG9719 alone improved GFR and kidney function with an acceptable safety profile.19 The at the two lower doses. Furosemide alone caused a decline in main driver for success in this study was improvement in GFR. However, when BG9719 was added to furosemide, dyspnea.19 creatinine clearance remained at baseline at the two lower The PROTECT pilot study was primarily designed to doses and diuresis was even further improved. The direct develop the primary end point for the phase III registration opposite effects of furosemide and an A1 adenosine receptor trial: the PROTECT study. The PROTECT data were antagonist (SLV320) on kidney function in terms of GFR presented at the European Society of Cardiology meeting were later confirmed using cystatin C as biomarker for 2009 in Barcelona, Spain. The abstract and the presentation GFR.13 This study furthermore showed that an A1 adenosine were made available on the web site of the European Society receptor antagonist has no immediate cardiac effects of Cardiology, 2 September 2009.20 PROTECT was a multi- (no effects on any of the hemodynamic parameters: heart center, randomized, double-blind, placebo-controlled study rate, blood pressure, pulmonary wedge pressure, mean in patients hospitalized for AHF syndromes manifest by pulmonary arterial pressure, systemic vascular resistance, dyspnea at rest and signs of volume overload requiring i.v. right atrial pressure, and cardiac output). However, it is loop diuretic therapy. Patients were anticipated to require important to note that furosemide led in this study to a ongoing i.v. furosemide X40 mg/day for at least 24 h after significant increase in total peripheral resistance. This was enrollment and had to have impaired renal function not observed with any of the SLV320 dosages.13 (estimated creatinine clearance 20–80ml/min). In addition, The finding that an A1 adenosine receptor antagonist patients were required to have a brain natriuretic peptide improves GFR while simultaneously promoting natriuresis level of X500 pg/ml or N-terminal prohormone brain and diuresis with minor effects on potassium excretion was natriuretic peptide level of X2000 pg/ml. Key exclusions consistent in several studies in chronic heart failure were ongoing or planned i.v. vasoactive therapy (except for patients.12–16 It is noteworthy that in chronic heart failure nitrates), mechanical/circulatory support, ultrafiltration, patients,15 the effect of a single injection of the A1 adenosine dialysis, acute coronary syndromes, severe cardiac valve receptor antagonist seems to persist for several days15—much stenosis, or high risk for seizures. Randomization was to longer as the half-life time of the A1 adenosine receptor occur within 24 h and rolofylline 30 mg/day i.v., or matching antagonist in the plasma of these patients, suggesting long- placebo was infused shortly thereafter for 4 h/day for up to lasting, yet on a molecular basis not understood, effects of an 3 days. The primary end point was a three-category ordered A1 adenosine receptor antagonist on the TGF. outcome of treatment success, lack of change, or treatment Effects of an orally available A1 adenosine receptor failure, assessed through day 7 or discharge. Treatment antagonist were analyzed in a randomized, double-blind, success was defined as moderate-to-marked improvement in placebo-controlled study in patients with heart failure and dyspnea at both 24 and 48 h after randomization in the systolic dysfunction who were receiving standard therapy. absence of treatment failure. Treatment failure included any Patients were randomized to receive BG9928 (3, 15, 75, or of the following: death or readmission for heart failure 225 mg) or placebo orally for 10 days. This study showed that through day 7, worsening symptoms and/or signs of heart oral BG9928 over the dose range of 3 to 225 mg/day failure after day 2 through 7, or discharge with the need for produced significant increases in sodium excretion in rescue therapy and persistent renal impairment (serum patients with stable heart failure without causing kaliuresis creatinine increase of X0.3 mg/dl through day 7 confirmed or reducing renal function.17 All studies performed so far at day 14, or initiation of hemofiltration or dialysis through in stable heart failure patients9–14 consistently show that A1 day 7). Secondary end points included time to death or adenosine receptor antagonists increase sodium excretion rehospitalization for cardiovascular or renal causes through and dieresis without compromising renal blood flow and day 60 and the proportion of patients with persistent renal GFR. Loop diuretic-induced compromising of GFR seems to impairment (serum creatinine increase of X0.3 mg/dl from be abolished by A1 adenosine receptor antagonists. randomization to day 7, confirmed at day 14, initiation of hemofiltration or dialysis, or death up to day 7). TREATMENT OF AHF A total of 2033 patients were randomized to rolofylline It was assumed that the claimed mechanism of action of (n ¼ 1356) and placebo (n ¼ 677). For the primary end point, A1 adenosine receptor blockade in chronic heart failure rolofylline was associated with more successes than placebo, (A1 adenosine receptor blockade may abolish the loop but also more failure (odds ratio versus placebo 0.92, 95% diuretic-induced disturbance of renal microcirculation and confidence interval 0.78–1.09, P ¼ 0.348). It is noteworthy hence improve kidney function) also holds in acutely that moderate-to-marked improvement in dyspnea at both decompensated heart failure patients. Two clinical phase II 24 and 48 h was observed in 51.2% in the rolofylline group studies18,19 supported this hypothesis. However, preclinical and 44.5% in the placebo group. The secondary composite

442 Kidney International (2010) 78, 438–445 B Hocher : The role of adenosine A1 receptors mini review

end point of death or cardiovascular or renal hospitalization induced aggravation of tubular damage) might explain the occurred in 30.7% of rolofylline patients (25.7% were overall neutral PROTECT study results. This might also hospitalized and 8.9% died) and 31.9% of placebo patients explain the discrepancy between findings in CHF and AHF (25.6% were hospitalized and 9.5% died), yielding a time-to- patients. The effect of A1 adenosine receptor blockers on first-event hazard ratio of 0.98 (95% confidence interval hypotension-induced reperfusion injury of the kidneys might 0.83–1.17, P ¼ 0.86). be much less important in CHF patients, simply because they Serum creatinine increase X0.3 mg/dl through day 7 are stable with respect to blood pressure. confirmed at day 14 was observed in 12.3% in the rolofylline It must be kept in mind that kidney function was assessed group and in 10.6% in the placebo group. Initiation of in the PROTECT trial with an exploratory renal end point hemofiltration was needed in 0.4% of all patients in the invented in the PROTECT pilot study. This renal end point rolofylline group and in 0.9% in the placebo group. More was never used before in any clinical study.24–28 Therefore, patients on rolofylline experienced nervous system disorders, the renal end point of the PROTECT study was at high risk with 11 patients (0.8%) experiencing seizure and 16 patients for failure and its clinical implications (predictive value for a (1.2%) experiencing stroke on rolofylline, with no patients morbidity/mortality end point of a phase III trial) are experiencing seizure and 3 patients (0.5%) experiencing unknown and remain to be investigated. stroke in placebo.20 In conclusion, PROTECT showed A post hoc analysis was conducted to identify the dose and that rolofylline treatment was almost neutral with respect time points after drug administration with the highest trend to mortality/hospitalization. The treatment also showed an of benefit. Other time points after intervention or other improvement in dyspnea, but seemed to worsen kidney dosages did not show any clear signal. There was no clear function. It is noteworthy that the rolofylline effect on dose dependency and also no clear time dependency of the dyspnea was sustainable when compared with brain na- renal effects observed.19 Thus, the PROTECT investigators triuretic peptide/nesiritide effects. Nesiritide was approved by took a very high risk for failure of the end point for their the regulatory authorities for treatment of AHF and showed phase III study based on the way of how they used the only a relatively short-term improvement of clinical symp- PROTECT pilot trial to define this end point. In addition, the toms.21 Rolofylline treatment seems to have a much longer major disadvantage of such an invented renal end point is effect on dyspnea.20 Rolofylline treatment was associated with indeed that the clinical implications remain uncertain.24–28 an increased number of seizures (a seizure risk was The trend toward increase of strokes in the rolofylline group anticipated, as A1 adenosine receptors have a pivotal role of the PROTECT trial raises the question of an off-target in the brain)3 and a trend for an increased number of strokes. effect. Careful head-to-head comparison with respect to The finding of even a moderate worsening of kidney function risk factors for stroke of all A1 adenosine receptor is in contradiction to the underlying hypothesis of the antagonists3,13,19,20,22) currently under development is urgently development programs of A1 adenosine receptor blockers in needed. In any case, a genetic disruptor of the A1 adenosine AHF. Currently, three different compounds, SLV320,4,13 receptor gene in mice (A1 adenosine receptor knockout mice) Rolofylline,19,20 and Adentri,22 are in development for this is not known to increase the risk for strokes in these animals. indication. Adentri is currently in a phase IIb trial versus Treatment with theophylline, a non-selective adenosine placebo in addition to standard of care, called the TRIDENT- receptor antagonist, is also not associated with an increased 1 (TReatment with Intravenous BG992822 for patients with risk for strokes, supporting an off-target effect of rolofylline. In acutely Decompensated heart failure and reNal insufficiency contrast, non-selective adenosine receptor blockade was even Trial) study.18 considered for the treatment of stroke.29 Blockade of the TGF by A1 adenosine receptor antagonists Receptor selectivity toward the four different adenosine (in volume overloaded, AHF patients with concomitant renal receptors might also be an efficacy and safety factor for impairment) was expected to improve renal function.2,3 potential cardiorenal indications. Blocking the A1 adenosine However, a substantial proportion of these patients might receptor increases blood flow in the vas afferens of the also suffer from acute renal failure because of hypotension- glomerulum, whereas blockade of the A2a receptor in the vas induced acute tubular necrosis. Data in A1 adenosine efferens decreases blood flow in the glomerulus.2,3 Thus, the knockout mice suggest that blocking the A1 receptor in A1/A2a ratio and the A1 adenosine receptor affinity are most these patients might even further harm kidney function by likely efficacy parameters (see Table 1). However, this needs promoting reperfusion injury.23 Taken together, there might to be shown in adequate studies (for example, analyzing be two independent mechanisms with respect to the A1 the effects of A1 adenosine receptor antagonists in vas adenosine receptor acting in AHF on the kidney: the TGF afferents and efferens of isolated glomeruli). The cardio- mechanism and the A1 adenosine receptor-mediated effects vascular research unit of Solvay Pharmaceuticals (Hannover, on reperfusion injury after hypotension-induced acute Germany) performed a head–to-head comparison of A1 tubular necrosis. The first is protective for the kidney; the adenosine receptor antagonists in clinical development latter will rather be harmful for the kidney function. The net (Table 1) showing differences in the A2a/A1 ratio of the effect of both pathways (A1 adenosine receptor-mediated different compounds. Similar concepts were shown to be of blockade of the TGF and A1 adenosine receptor blockade- clinical impact for b-receptor blockers in heart failure.30,31

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OTHER INDICATIONS FOR A1 ADENOSINE RECEPTOR DISCLOSURE ANTAGONISTS? BH was a research employee of Solvay Pharmaceuticals. A genetic as well as pharmacological blockade of the A1 adenosine receptor has been shown to prevent radiocontrast REFERENCES 32 1. Boerrigter G, Burnett Jr JC. Cardiorenal syndrome in decompensated media-induced nephropathy in an animal model. There are heart failure: prognostic and therapeutic implications. Curr Heart Fail Rep even supportive clinical data available using the non-selective 2004; 1: 113–120. adenosine receptor antagonist theophylline.33–35 Radiocon- 2. Vallon V, Muhlbauer B, Osswald H. Adenosine and kidney function. Physiol Rev 2006; 86: 901–940. trast media-induced nephropathy in high-risk patients for 3. Modlinger PS, Welch WJ. Adenosine A1 receptor antagonists and the this disease (for example, diabetics with pre-existing renal kidney. Curr Opin Nephrol Hypertens 2003; 12: 497–502. 4. Kalk P, Eggert B, Relle K et al. 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Natriuretic effect of an adenosine-1 receptors may be effective in the prevention of alcohol- receptor antagonist in cirrhotic patients with ascites. Gastroenterology induced fatty liver.38 Considering the already shown potential 1998; 115: 406–411. 8 9. Imai E, Fujii M, Kohno Y et al. Adenosine A1 receptor antagonist improves clinical effects of A1 adenosine receptor antagonists on intradialytic hypotension. Kidney Int 2006; 69: 877–883. kidney function in advanced stages of alcoholic liver disease 10. Givertz MM, Massie BM, Fields TK et al. The effects of KW-3902, an might further support clinical work in this field. adenosine A1-receptor antagonist, on diuresis and renal function in patients with acute decompensated heart failure and renal impairment or Adenosine produces bronchoconstriction in allergic rab- diuretic resistance. J Am Coll Cardiol 2007; 50: 1551–1560. bits, primates, and humans by activating A1 adenosine 11. Dickstein K, Navis G, Voors AA et al. 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Effects of BG9719 (CVT-124), an CONCLUSIONS A1-adenosine receptor antagonist, and furosemide on glomerular A1 adenosine receptor antagonists are currently in clinical filtration rate and natriuresis in patients with congestive heart failure. development in AHF and chronic heart failure. Recent data J Am Coll Cardiol 2000; 351: 56–59. 15. Dittrich HC, Gupta DK, Hack TC et al. The effect of KW-3902, an adenosine from the PROTECT trial may suggest that the pathophysiol- A1 receptor antagonist, on renal function and renal plasma flow in ogy of the adenosine system is different in AHF and chronic ambulatory patients with heart failure and renal impairment. J Card Fail 2007; 138: 609–617. heart failure. In the cardiovascular clinical field, treatment 16. Gottlieb SS, Skettino SL, Wolff A et al. Effects of BG9719 (CVT-124), an targets of A1 adenosine receptor antagonists remain AHF and A1-adenosine receptor antagonist, and furosemide on glomerular chronic heart failure, particularly in situations in which filtration rate and natriuresis in patients with congestive heart failure. J Am Coll Cardiol 2000; 351: 56–59. renal impairment and/or resistance to diuretics is highly 17. Greenberg B, Thomas I, Banish D et al. Effects of multiple oral doses of an relevant. Other indications may be liver cirrhosis and A1 adenosine antagonist, BG9928, in patients with heart failure: results of sudden hypotension on dialysis. Preclinical data clearly a placebo-controlled, dose-escalation study. J Am Coll Cardiol 2007; 507: 600–606. support clinical work in patients with radiocontrast media- 18. The TRIDENT-1 study. http://clinicaltrials.gov/ct2/show/NCT00709865? induced nephropathy, cardiac fibrosis, fatty liver disease, term=adentri&rank=1. and asthma. 19. Cotter G, Dittrich HC, Weatherley BD, et al., Protect Steering Committee, Investigators, and Coordinators. The PROTECT pilot study: a randomized, Considering the disappointing results from the first phase placebo-controlled, dose-finding study of the adenosine A1 receptor III trial using A1 adenosine receptor antagonist (PROTECT antagonist rolofylline in patients with acute heart failure and renal trial), the common characteristics and even more impor- impairment. J Card Fail 2008; 48: 631–640. 20. Metra M, Jessup M. Effects of rolofylline in patients with acute heart tantly the differences in the available A1 adenosine receptor failure syndrome and renal impairment: findings from the PROTECT- antagonists when it comes to their effects and side effects study presented at the ESC 2009 in Barcelona, Spain. http://www. need detailed study. Differences in receptor selectivity, brain escardio.org/congresses/esc-2009/congress-reports/Pages/708003- 708004-metra-jessup.aspx. penetration, and pharmacokinetics of the A1 adenosine 21. Arora RR. Nesiritide: trials and tribulations. J Cardiovasc Pharmacol Ther receptor antagonists currently in development might be key 2006; 11:165. factors for efficacy and safety of this promising new class of 22. Dohadwala MM, Givertz MM. Role of adenosine antagonism in the cardiorenal syndrome. Cardiovasc Ther 2008; 26: 276–286. cardiovascular compounds. A detailed understanding of the 23. Lee HT, Xu H, Nasr SH et al. A1 adenosine receptor knockout mice exhibit underlying pathophysiology of the adenosine system is a increased renal injury following ischemia and reperfusion. Am J Physiol Renal Physiol 2004; 286: F298–F306. must in any clinical development plan and was probably 24. Ronco C, Haapio M, House AA et al. Cardiorenal syndrome. J Am Coll missing in AHF. Cardiol 2008; 52: 1527–1539.

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