Part One Repurposing Drugs For Highly Prevalent Diseases: Pentoxifylline, An Old Drug And A New Opportunity For Diabetic Kidney Disease

ABSTRACT

Diabetic kidney disease is one of the most frequent complications in patients with diabetes and constitutes a major cause of end-stage kidney disease. The prevalence of diabetic kidney disease continues to increase as a result of the growing epidemic of diabetes and obesity. Therefore, there is mounting urgency to design and optimize novel strategies and drugs that delay the progression of this pathology and contain this trend. The new approaches should go beyond the current therapy focussed on the control of traditional risk factors such as hyperglycemia and hypertension. In this scenario, drug repurposing constitutes an economic and feasible approach based on the discovery of useful activities for old drugs. Pentoxifylline is a nonselective phosphodiesterase inhibitor currently indicated for peripheral artery disease. Clinical trials and meta-analyses have shown renoprotection secondary to anti-inflammatory and antifibrotic effects in diabetic patients treated with this old known drug, which makes pentoxifylline a candidate for repurposing in diabetic kidney disease.

KEYWORDS

diabetes, diabetic kidney disease, pentoxifylline, and repurposing.

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DIABETIC KIDNEY DISEASE, IS AN INCREASING PROBLEM

Diabetes mellitus (DM) is a world epidemic that affects ˃425 million people according to the International Diabetes Federation [1]. Recent estimates from this organization predict a prevalence of ˃630 million people with DM by the year 2045 [1]. One of the most relevant complications of DM is diabetic kidney disease (DKD) which occurs in ˃40% of diabetic patients, with no difference between patients with type 1 or type 2 DM [2–4]. Metabolic and hemodynamic insults drive the pathophysiology of DKD causing the deterioration of kidney functions. Until recently, chronic kidney disease (CKD) derived from DM was diagnosed as diabetic nephropathy, which begins with microalbuminuria, followed by a gradual decline in kidney function and overt macroalbuminuria. However, the report of patients with DM and impaired renal function without albuminuria has led to the concept of DKD. DKD is defined as CKD with diabetes being partially involved in the pathogenesis of kidney disease, encompassing the concept of classical diabetic nephropathy [5–8]. Despite advances in therapeutics, healthcare structures, and overall population health, DKD is the single most common cause of end-stage kidney disease (ESKD) [9, 10]. Patients with DKD present 20–40 times higher cardiovascular morbidity and mortality rates than patients with DM without kidney impairment; in fact, most patients with DKD die from cardiovascular disease before they start renal replacement therapy.

As a consequence of the ever-growing epidemic of diabetes and obesity, the absolute number of people with ESKD continues to rise [11]. This situation has made the prevention and treatment of DKD a global challenge and a threat to human health and mortality, with a significant social and economic burden [12, 13]. At present, there are no specific therapeutic strategies for DKD, which makes finding new approaches a formidable challenge for the scientific community, since simple control of risk factors is insufficient to cope with disease progression. In search of new therapies, researchers have explored several drug-repurposing opportunities [14].

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The pathogenesis of DKD comprises metabolic (hyperglycemia, dyslipidemia) and hemodynamic (glomerular hypertension) perturbations which, together, cause mesangial expansion, impairment of endothelial cell function, and loss of podocytes in the glomerulus and interstitial fibrosis in the tubular compartment [15–17]. However, the full pathogenesis of the disease remains to be understood, and specific therapeutic targets have not been determined. Current practice guidelines are focused on halting or delaying the progression of DKD through nonspecific multidisciplinary therapeutic approaches based on adequate metabolic control and in the control of blood pressure with the renin-angiotensin system (RAS) blockade as a cornerstone therapy [18, 19]. Although this approach improves systemic blood pressure as well as intraglomerular pressure, a key driver of albuminuria and CKD progression, and also decreases kidney inflammation and fibrosis [20, 21], it does not generally halt the progression to ESKD. Moreover, the combination of RAS blockers such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) did not improve monotherapy results and is associated with adverse events including hyperkalemia, acute kidney injury, and hypotension [22–25]. Importantly, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been recently added to these multidisciplinary treatments, as drugs of choice for DKD treatment [26]. Although the evidence demonstrates renoprotection with the use of SGLT2i on top of RAS blockade, patients with DM continue to suffer from kidney disease, and a high percentage of them progress to ESKD. Therefore, there is a need to evaluate new strategies to improve kidney function, delay the progression of the disease and eventually improve kidney survival. These new therapeutic approaches become even more necessary if we consider that recent trials designed to find effective renoprotection in DM patients have failed or were prematurely stopped because of safety concerns; i.e. ruboxistaurin and sulodexide failed to show clear-cut renoprotection in patients with type 2 DM and clinical trials with avosentan and bardoxolone methyl was prematurely terminated because of serious safety concerns [25, 27–31]. The efforts are focused on targeting key mechanisms involved in the onset and progression of DKD including hyperglycemia, oxidative stress [32], inflammation [33], and fibrosis [34].

The drug pentoxifylline is a methyl-xanthine derivative and a nonselective phosphodiesterase inhibitor with antiinflammatory, antiproliferative, and antifibrotic actions currently indicated for peripheral artery disease. Clinical trials and meta-analyses have shown renoprotection secondary to antiinflammatory and antifibrotic effects in diabetic patients treated with pentoxifylline when added to RAS blockade, making pentoxifylline a potential candidate for repurposing in DKD [35].

EMERGING THERAPIES AND POTENTIAL REPURPOSED DRUGS IN DKD

In recent years, promising nephroprotective therapeutic strategies have arisen with the use of new antidiabetic drugs on top of RAS blockade. As discussed above, the current main pharmacological agents in DKD are RAS blockers and SGLT2i. SGLT2i are anti-hyperglycaemic agents that block glucose reabsorption by SGLT2 channels at proximal tubules, thereby stimulating glucosuria and decreasing blood glucose levels in an insulin-independent fashion [36]. But, beyond glycaemic control, secondary outcome analyses in cardiovascular safety randomized controlled trials (RCTs) in type 2 DM patients have shown improved kidney outcomes in patients with CKD [26, 37, 38]. As a result of this evidence, recent consensus documents have placed SGLT2i as the antidiabetic drug of choice on top of RAS blockade for type 2 DM patients with evidence of kidney disease [39, 40]. Despite this success, the renal decline continues in many individuals with diabetes, and incident or worsening nephropathy occurs in 12.7% of individuals treated with empagliflozin [37], and new treatments are needed.

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The unexpected nephroprotective success of SGLT2i in DKD has not been replicated and a large number of drugs, even with added RAS blockade, have failed [41]. New drug candidates include the groups of steroidal and nonsteroidal mineralocorticoid receptor antagonists (MRA). MRAs exert antihypertensive actions by suppressing the action of aldosterone, the end product of RAS, and has been reported to decrease proteinuria [42– 47]. Two groups of anti-diabetic drugs that could present nephroprotective effects, possibly independently of the glycaemic control, are the glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RA) and the dipeptidyl peptidase-4 (DPP-4) inhibitors [48, 49]. These incretin-based drugs decrease albuminuria in DKD patients, but controversy persists over their potential to slow the rate of estimated glomerular filtration rate (eGFR) decline [50–59].

The effectiveness of inhibiting advanced glycation end product (AGE) accumulation has been also conducted. AGE accumulation in kidney samples correlates with DKD progression and, at present, the administration of AGE inhibitors in DKD patients is the focus of clinical and basic research, with controversial results in a decrease of proteinuria and the progression of GFR decline [60–63].

Except for SGLT2i and finer enone, there have been no new therapies for the treatment of nephropathy in type 2 DM since the approval of irbesartan and losartan by the Food and Drug Administration (FDA) ˃ 15 years ago. There is a desperate need to identify treatments for DKD, and several large-scale trials in people with DKD have been conducted and failed [24, 25, 29, 30]. In this sense, together with new antidiabetic drugs, drug repurposing is an alternative to de novo drug discovery, to find promising candidates to treat DKD. Drug repurposing offers multiple advantages, such as an accelerated and inexpensive drug development process. This approach decreases development risks, since the safety of the compound, which is one of the main reasons for high attrition rates, is already well established [35, 64, 65].

The strategy of drug repurposing has been widely employed in recent times during the coronavirus disease 2019 (COVID-19) pandemic, witnessing the evaluation and use of several existing molecules for their therapeutic potential against coronaviruses including hydroxychloroquine, remdesivir, ivermectin, lopinavir/ritonavir, baricitinib, dexamethasone and others [66]. Well-known examples of drug repositioning include thalidomide, which was used to prevent morning sickness and posteriorly repositioned for the treatment of multiple myeloma [67]; minoxidil and finasteride, initially approved for the treatment of hypertension and benign prostate hyperplasia, respectively, were repurposed for the treatment of male pattern baldness.

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Methyl bardoxolone is a semi-synthetic triterpenoid with anti-inflammatory effects [68]. Methyl bardoxolone, initially studied for the prevention and treatment of cancer, was repurposed for other diseases with an inflammatory component including DKD following the observation of decreased serum creatinine in cancer patients [69, 70]. These promising results led to the Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus: The Occurrence of Renal Events (BEACON NCT01351675) phase III clinical trial [30], which included 2185 participants with type 2 DM. Although this trial was terminated due to serious adverse events originating from high rates of heart failure-related hospitalizations and deaths in patients treated with bardoxolone, post hoc analyses showed that the increase in heart failure events was most likely caused by fluid overload in the first 4 weeks after randomization [71]. Moreover, elevated baseline B-type natriuretic peptide (BNP) levels (>200 pg/mL) and a history of hospitalization were identified as the only risk factors for heart failure. Patients without these two risk factors showed the same incidence of heart failure in the bardoxolone methyl and the placebo groups (2%) [72]. The Phase 2 Study of Bardoxolone Methyl in Patients with Chronic Kidney Disease and Type 2 Diabetes (TSUBAKI, NCT02316821) [73] for the treatment of CKD in Japanese patients without these clinical characteristics, again indicated an increase in the measured GFR in patients treated with methyl bardoxolone without cases of death or heart failure in any participant.

Other anti-inflammatory agents repurposed for DKD include CCX-140 and bariticinib, both originally developed for rheumatoid arthritis. CCX140-B is an inhibitor of C-C chemokine receptor type 2 (CCR2) that decreases macrophage migration and activation that was repurposed for DKD after the results of a phase II RCT showing kidney-protective effects in patients with type 2 DM when administered on top of standard medication [74]. Administration of baricitinib, which selectively inhibits Janus kinase 1 and 2 (JAK1 and JAK2), has been recently tested in a phase II RCT including 129 DKD patients, finding a decrease in albuminuria [75].

Endothelin A is a vasoactive peptide that exerts vasoconstrictive actions of glomerular afferent and efferent arterioles, crucial determinants of glomerular hemodynamics, which leads to a decrease in GFR [76] and also generates kidney injury via inflammation, endothelial injury, podocyte disruption, and fibrosis. Endothelin A receptor antagonists were first evaluated in men with metastatic hormone-refractory prostate cancer [77] and are currently approved for the treatment of pulmonary arterial hypertension [78]. The endothelin A receptor antagonist atrasentan decreases proteinuria in experimental kidney disease [79], which has led to clinical testing in DKD [80–82]. In DKD, atrasentan decreased blood pressure and albuminuria when added to stable RAS blockade, but was associated with fluid overload and heart failure exacerbation [83].

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Finally, pentoxifylline has recently been added to this group of potentially repurposed kidney protective drugs based on its anti-inflammatory and antiproteinuric effects. Pentoxifylline is currently indicated for peripheral artery disease, but open-label trials have shown beneficial results in DKD and also in nonspecific CKD and chronic allograft nephropathy. Along with the decrease in albuminuria and inflammation, the deceleration in the GFR decline rate and the preservation of the anti-aging factor Klotho are the most important findings in DKD patients treated with pentoxifylline [84–86].

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Javier Donate-Correa1,2,3, María Dolores Sanchez-Niño4, Ainhoa González-Luis1,5, Carla Ferri1,5, Alberto Martín-Olivera1,5, Ernesto Martín-Núñez1,3, Beatriz Fernandez-Fernandez4,6, Víctor G. Tagua1, Carmen Mora-Fernández1,2,3,∗, Alberto Ortiz 4,6, and Juan F. Navarro-González 1,2,3,7,8

1 Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain,

2 GEENDIAB (Grupo Español para el estudio de la Nefropatía Diabética), Sociedad Española de Nefrología, Santander, Spain,

3 RICORS2040 (RD21/0005/0013), Instituto de Salud Carlos III, Madrid, Spain,

4 Departamento de Nefrología e Hipertensión, IIS-Fundación Jiménez Díaz y Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain,

5 Escuela de doctorado, Universidad de La Laguna, La Laguna, Spain,

6 RICORS2040 (RD21/0005/0001), Instituto de Salud Carlos III, Madrid, Spain,

7 Servicio de Nefrología, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain

8 Instituto de Tecnologías Biomédicas, Universidad de La Laguna, Santa Cruz de Tenerife, Spain