C H A P T E R
72 Emerging Therapies Bijin Thajudeena,b, Sangeetha Murugapandiana,b, Prabir Roy-Chaudhuryc a
Division of Nephrology, University of Arizona College of Medicine, Tucson, AZ, United States; bBanner University Medical Center Tucson and South, Tucson, AZ, United States; cThe University of North Carolina Kidney Center, Chapel Hill, NC, United States developing and indeed developed economies may simply not have the healthcare resources. While recognizing the significant depth and breadth of emerging therapies for CKD, this chapter will focus on the following therapy domains (recognizing that these address most but not all aspects of innovation and entrepreneurship in CKD):
Abstract Chronic kidney disease (CKD) is likely to be the public health epidemic of the 21st century. Despite the magnitude of the clinical problem, there are currently no truly effective therapies for this condition. Novel therapies could influence the way we manage CKD patients in the future. Combining biology, technology, and processes of care to develop therapies that are not only clinically effective but which are also patient friendly and cost-effective and which lend themselves to being used within existing or improved process of care paradigms may affect outcomes.
• • • • • •
SCOPE OF THE PROBLEM Chronic kidney disease (CKD) is currently a global health epidemic. In the US, it is estimated there are approximately 30 million people with CKD. Recent USRDS data describe the Medicare CKD population as comprising 11.1% of the total Medicare population, but consuming 21.2% of overall Medicare costs, likely due to the high incidence of cardiovascular complications.1 The greatest impact of CKD, both with regard to morbidity/mortality and cost, however, is likely to be in the developing world (particularly in the large emerging economies of Brazil, China, and India), due to expected huge increases in the incidence of both diabetes and hypertension over the next 20 or more years in these locations.2,3 It is projected that there will be 366 million people with diabetes worldwide by 2030, of which 298 million (81%) will be in the developing world with limited resource utilization.3 Thus, it is critical for the renal community and for overall healthcare delivery systems that we develop innovative and cost-effective therapies for both the prevention and treatment of CKD, to prevent a future increase in end-stage renal disease (ESRD), for which most
Chronic Renal Disease, Second Edition https://doi.org/10.1016/B978-0-12-815876-0.00072-3
Prevention of CKD progression Novel therapies for CKD-associated anemia Therapies for vascular calcification Renal denervation therapies Novel therapies for vascular access dysfunction Innovative renal replacement therapy (RRT)
Our hope for the future is that the availability of a wide spectrum of safe, effective, and financially viable therapies for the prevention and treatment of both CKD and its complications will allow individualization of care for every CKD patient worldwide (regardless of whether they live in the developed world or in emerging economies).
PREVENTION OF CKD PROGRESSION There exist data on agents that may have a future role in the prevention of the final common pathway of interstitial fibrosis and tubular atrophy, albeit through the modulation of a variety of different pathways. Renal inflammation plays a key role in the progression of kidney disease. There are a number of drugs in clinical trials that decrease albuminuria, but whether this effect always translates to decreasing progression of kidney disease is yet to be studied. Only agents that have been used in clinical studies in humans are described.4
© 2020 Elsevier Inc. All rights reserved.
72. EMERGING THERAPIES
Pentoxifylline Pentoxifylline is a nonselective phosphodiesterase inhibitor with antiinflammatory and immunomodulatory activities. Clinical studies in patients with primary glomerular diseases, diabetic nephropathy, and CKD suggest the drug decreases proteinuria, possibly through the MCP-1 pathway, albeit without changing the rate of decline of glomerular filtration rate (GFR).5e7 The benefits of proteinuria reduction were more evident in patients with type 1 diabetes mellitus, earlier stages of CKD, and higher baseline proteinuria.8 In a post hoc analysis of the PREDIAN trial (Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease), pentoxifylline decreased serum and urinary TNF-a levels, but increased urinary and serum klotho levels in CKD stage 3e4 diabetic kidney disease, likely due to its antiinflammatory and antiproteinuric effects.9 More studies with longer follow-up and meaningful renal endpoints are needed to support use of this agent to prevent progression of CKD.
Statins In addition to their cholesterol-lowering effects, the statins as a group have important antiproliferative, antimacrophage, and endothelium stabilization effects, all of which could be beneficial in preventing the progression of CKD.10,11 In an observational prospective study of HIV-infected patients with CKD and hyperlipidemia, the rosuvastatin and atorvastatin groups had a lower decline in estimated GFR (eGFR) compared with the omega-3 fatty acid group.12 However, in the effects of atorvastatin on renal function in patients with dyslipidemia and chronic kidney disease: Assessment of clinical usefulness in CKD patients with atorvastatin (ASUCA) trial no renal protection was observed in the atorvastatin group.13 In patients with hypertensive nephropathy, statins were found to be renoprotective by downregulating the angiotensin II-AT1 pathway in hypertensive nephropathy.14 Although there may be a reduction in proteinuria, this has not translated into reduction in decline of eGFR.15
Mammalian Target of Rapamycin Inhibitors Based on in vitro and experimental data which suggested a central role for mammalian target of rapamycin (mTOR) in the pathogenesis of autosomaldominant polycystic kidney disease (ADPKD), two clinical trials have examined the role of these agents in early and late ADPKD patients.16 Unfortunately,
the results from these studies did not document a role for mTOR inhibitors in ADPKD. Serra et al.17 demonstrated no decrement in kidney size in ADPKD patients treated with sirolimus. In contrast, Walz et al.18 demonstrated a decrease in kidney size in patients with more advanced ADPKD treated with everolimus, but no benefit in GFR. There was no difference in the decline in GFR in patients in the everolimus group compared with the controls. Whether there is a role for mTOR inhibitors, perhaps in a subset of patients with ADPKD, is presently unclear.
V2 Receptor Antagonists V2 receptor antagonists, such as tolvaptan, decrease renal cAMP levels, thereby inhibiting cytogenesis and preventing renal enlargement in patients with polycystic kidney disease.19 In the tolvaptan in ADPKD (TEMPO 3:4 Trial), tolvaptan slowed the increase in total kidney volume and decline in kidney function over a period of 3 years. However, there was a higher discontinuation rate owing to aquaresis and hepatic events in the tolvaptan group.20 In the REPRISE trial (Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease), patients with later-stage ADPKD treated with tolvaptan had a slower decline in kidney function, if they could tolerate the drug.21 Tolvaptan is therefore now FDA approved to slow progression of kidney disease in patients with ADPKD. An important reason for this somewhat rare “success” in the CKD arena likely includes the availability of a surrogate endpoint (total kidney volume), which facilitated the product development pathway for ADPKD therapies.
Anti-Uric Acid Agents In addition to precipitating acute attacks of gouty arthritis, high levels of uric acid have significant proinflammatory and profibrotic effects, which could contribute to the progression of CKD. Current data suggest an association between high uric acid levels and CKD progression. However, there have only been a handful of interventional studies that have attempted to address the question of whether lowering uric acid levels results in slowing CKD progression. While studies suggest that there may be a role for uric acidlowering therapy in patients with CKD, more data are needed before this approach can be routinely recommended.22,23 A large randomized trial (PERL) is underway to study the efficacy of allopurinol vs. placebo on change in measured GFR in patients with type 1 diabetes.24
IX. SPECIAL CONSIDERATIONS
PREVENTION OF CKD PROGRESSION
SGLT-2 Inhibitors and Other Newer GlucoseLowering Drugs Sodium-glucose cotransporter type 2 (SGLT-2) inhibitors are a new class of antidiabetic drugs which have demonstrated promising results on cardiovascular and renal endpoints, that are distinct from their glucose lowering effects. Animal studies have shown that they inhibit glomerulosclerosis, with alteration of tubular cell metabolism to a more ketone-prone pathway.25 In the EMPA-REG OUTCOME trial, empagliflozin, a member of the SGLT-2 inhibitor family, reduced progression to ESRD in patients with type 2 diabetes mellitus and established cardiovascular disease.26 Similarly in the CREDENCE study, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group in patients with type 2 diabetes mellitus and kidney disease27 (Figure 72.1). The exact mechanisms that result in empagliflozin’s and canagliflozin’s renal protective effects are not fully understood, but it seems likely that the increase in sodium delivery to the macula densa results in a tubuloglomerular feedback loop that decreases afferent arterial blood flow.28,29 This results in an initial well-documented decrease in GFR, following which the decrease in intraglomerular pressures could potentially result in longerterm improvements in microalbuminuria and GFR slope (Figure 72.2). The SGLT-2 inhibitor agents are not the only glucoselowering drugs that appear to have beneficial cardiovascular and renal endpoints. In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, the glucagon-like peptide-1 analogue (GLP-1 analogue) liraglutide was shown
to decrease proteinuria with an albumin: creatinine ratio approximately 20% lower in the treatment compared with the control arm, regardless of the baseline level of eGFR.30 There is excitement at present regarding the potential impact of the SGLT-2 inhibitors on the progression of CKD. Their effects on the reduction of cardiovascular endpoints can only augur well for patients with diabetes, who in addition to the risks of diabetic kidney disease also have very high cardiovascular morbidity and mortality. Thus, the SGLT-2 inhibitors and drugs such as finerenone (see below) could potentially have opened a whole new therapeutic area of cardiorenal intervention which focuses on the cotargeting of cardiovascular and renal pathogenesis, pathology, morbidity, and mortality. The beneficial cardiovascular and renal effects of drugs such as the SGLT-2 inhibitors and GLP-1 analogues were initially discovered as a result of an FDA requirement for the conduct of cardiovascular outcome studies (CVOT) for glucose-lowering agents to identify adverse cardiovascular outcomes. These same agents are now being described by cardiologists and nephrologists as primarily cardiorenal agents that also have a glucose-lowering effect! There are three key issues that need to be addressed for these agents to have their true kidney and cardiovascular impact. First and foremost, we need more data from clinical studies with renal endpoints such as CREDENCE in both diabetic and nondiabetic patients. Secondly, we need to analyze these data to develop and inform clinical algorithms for the use of these agents in different clinical settings. Finally, we need to develop a comprehensive safety profile for these agents and identify whether different agents in the same class have differing adverse event rates and profiles.
FIGURE 72.1 30% relative risk reduction in the primary composite endpoint of ESRD, doubling of serum creatinine and renal or cardiovascular death, with line segments diverging as early as 12 months after randomization. Adapted from reference 27.
Finerenone is a nonsteroidal chemical entity that functions as a mineralocorticoid receptor antagonist in a fashion similar to spironolactone, but without steroid-induced side effects such as gynecomastia. Initial Phase II studies demonstrated a decrease in proteinuria compared with controls. There are currently two large ongoing Phase III clinical trials to elucidate both the cardiac and renal benefits of this agent, in the setting of diabetic kidney disease. The FIDELIO study has a primary cardiac endpoint with a secondary kidney endpoint, whereas the FIGARO study has a primary renal endpoint with a secondary cardiac endpoint. Similarly to the SGLT-2 inhibitors and GLP-1 analogue agents, the data from these two large studies should help to inform an algorithm for the most appropriate
IX. SPECIAL CONSIDERATIONS
72. EMERGING THERAPIES
FIGURE 72.2 Mechanism of action of the sodium-glucose cotransporter type 2 (SGLT-2) inhibitors. The key mechanism appears to be a tubuloglomerular feedback loop due to increased sodium delivery to the macula densa, resulting in afferent arteriolar constriction (arrows) and a decrease in intraglomerular pressures, which could then result in decreased albuminuria. Adapted from reference 28.
clinical use of both finerenone and the SGLT-2 inhibitors and GLP-1 analogue agents in patients with chronic kidney disease (diabetic or non-diabetic).31
Endothelin Receptor Antagonists Endothelin (ET) has vasoconstrictive and profibrotic properties which could contribute to the progression of renal disease. The specific ETa receptor antagonists atrasentan and sitaxsentan have been shown to result in significant reductions in albuminuria.32,33 The major side effect of this class of drugs is fluid overload. More trials with harder clinical outcomes are needed to clearly study the effect of this class of drugs on renal disease progression. The results from the SONAR (NCT01858532) study which compared the incidence of a composite renal endpoint in patients treated with atrasentan as compared to placebo were recently published and showed a significant reduction in renal events even though the the study was terminated early as a result of a business decision.34
Cellular Therapies Taking their lead from other branches of medicine, investigators are looking at the role of stem cells and bioengineering, in exploring the potential of human renal tissue to form patient-matched identical kidney tissues. With the help of cellular reprogramming
technology, one can develop nephron progenitor cells which can be converted into structurally complex and functionally rudimentary kidney tissues. This technology has the potential to replace renal transplantation and thus avoid expensive immunosuppressive medications. Based on in vitro35,36 studies, a prospective study is currently underway looking at the role of injecting neo-kidney augment, which is made from expanded autologous renal cells obtained from each individual participant’s kidney biopsy, back into the kidney.37
Other Potential Agents There is increasing interest in fibrotic pathway modulators such as bone morphogenetic protein (BMP)-7 and connective tissue growth factor which have a protective role against TNF-b1 in kidney fibrosis.38 However, further clinical trials aimed at specific renal endpoints are needed to recommend changes in clinical practice. Activation of the sirtuin-1 enzyme, a nicotinamide adenine dinucleotide-dependent deacetylase, which plays a role in preventing the diseases of aging, might be an important evolving therapy pertinent to the deterrence of age-related chronic diseases such as CKD. Resveratrol found in red wine and similar activators of sirtuin-1 are also in the development phase.39 Knowledge regarding the role of oxidative stress in the progression of vascular disease as well as CKD has led to the development of nuclear factor E2-
IX. SPECIAL CONSIDERATIONS
NOVEL THERAPIES FOR CKD-ASSOCIATED ANEMIA
related factor 2 activators, such as bardoxolone methyl.40 Bardoxolone, which attenuates inflammation, was studied in patients with type 2 diabetes with nephropathy. Unfortunately, the study had to be terminated due to an excess of serious adverse events and mortality in the bardoxolone methyl-treated group, likely related to fluid retention.41 Such agents may still have role in the treatment of CKD, if selection of patients is done more carefully. B7-1 receptors are present in podocytes and are involved in the pathogenesis of proteinuria through beta 1 integrin activation and cell motility. Abatacept, which is an antibody against B7-1 used in the treatment of rheumatoid arthritis, might help in reducing proteinuria and the ensuing reduction in GFR. This agent has also been used in the treatment of focal segmental glomerulosclerosis resistant to current therapies in patients who had high expression of B7-1.42
NOVEL THERAPIES FOR CKDASSOCIATED ANEMIA The introduction of erythropoietin (EPO) into clinical practice in the late 1980s completely changed the care of CKD and ESRD patients.43 More recently, conventional wisdom about the benefits of normalizing hemoglobin levels with EPO has not turned out to be accurate. Several nephrology and oncology studies have documented a higher incidence of cardiovascular events in patients treated to target higher hemoglobin levels.44e47 While the exact reasons for this remain unclear, much
attention has focused on the potential proliferative effects of exogenous EPO as a possible mechanism. Prolyl hydroxylase domain (PHD) inhibitors have therefore been developed as oral erythropoiesis-stimulating agents. Studies suggest an intriguing linkage between this class of drugs and oxygen biology, hypoxia, inflammation, and renal fibrosis.48e50
Mechanism of Action of PHD Inhibitors EPO gene transcription is under the control of the transcription factor hypoxia-inducible factor 2 alpha (HIF-2a). The stability and transcriptional activity of HIFa molecules is regulated by molecular oxygene dependent hydroxylation of two prolyl residues. These hydroxylation reactions are mediated through a family of PHD enzymes (Figure 72.3). Inhibition of these enzymes, which require oxoglutarate as substrates, theoretically should increase HIF and subsequently EPO levels.51e55 Oxoglutarate mimics could therefore serve as competitive inhibitors, which could potentially result in the development of a new class of PHD inhibitors, without the cardiovascular side effects of conventional ESAs.
Clinical Experience with PHD Inhibitors for the Treatment of Anemia There are currently a number of oral PHD inhibitors at different stages of clinical development. Initial published data on FG-2216 (FibroGen) demonstrated that the drug increases EPO levels not only in HD patients
FIGURE 72.3 Erythropoietin (EPO) regulation through hypoxia-inducible factor (HIF). Under normoxic conditions, the transcription factor HIF alpha is hydroxylated by prolyl hydroxylase domain (PHD) enzymes, which results in its ultimate degradation and an inability to increase EPO (an HIF target gene) levels. The obverse occurs under hypoxic conditions because of a decrease in PHD activity resulting in an increase in EPO levels. The presence of PHD inhibitors stabilizes HIF and results in an appropriate (hopefully not excessive) increase in EPO levels. Adapted from reference 64. IX. SPECIAL CONSIDERATIONS
72. EMERGING THERAPIES
who still had native kidneys but also in anephric HD patients.48 The increase in EPO in HD patients who still had native kidneys was more than in the anephric patients, who had increases in EPO levels similar to that of normal healthy volunteers. These results shed light on some important potential mechanisms linked to EPO gene regulation, and the source of EPO in patients with renal failure. The greater increase in EPO levels in patients who still had native kidneys, compared not only with anephric patients but also healthy volunteers, suggests that there could be an element of dysregulated EPO gene expression in uremia, because the nonfunctional kidneys still retained the ability to significantly increase EPO levels. Important proof to support this hypothesis comes from experimental data which suggest that indoxyl sulfate, which is increased in the circulation of uremic patients, could have independent effects on HIF transcription.56 In addition, the increase in EPO levels in response to PHD inhibitors in anephric patients suggests the presence of EPO-producing cells in organs other than the kidney, even in adults.57 Modulating physiological mechanisms related to EPO gene transcription and activation of downstream pathways may therefore be critical in ameliorating factors associated with the pathogenesis of cardiovascular disease linked with exogenous EPO administration that results in high hemoglobin levels.
Links Between Oxygen Biology, Inflammation, and Fibrosis Oxygen biology pathways affected by therapeutic strategies for renal anemia could have unexpected ancillary benefits on mechanisms associated with renal fibrosis. Tissue hypoxia occurs in the setting of experimental models of CKD.58,59 Hypoxia can activate downstream inflammatory, oxidative stress and fibrotic pathways.60 The resolution of tissue hypoxia could be potentiated through the use of PDH inhibitors. Unfortunately, all the currently available inhibitors are nonspecific. Thus, in addition to potentially beneficial effects on tissue hypoxia, they would also likely increase erythrocytosis and angiogenesis. Alteration of angiogenic pathways might then promote fibrosis50 or predispose to tumorigenesis. However, more specific PHD-1 inhibitors that could protect hypoxic tissues through a reduction in oxidative stress without affecting angiogenesis and erythropoiesis might have beneficial effects on mechanisms associated with fibrosis.61 Phase II clinical trials demonstrating safety and efficacy signals have been conducted using at least 5 PHD-1 inhibitors. Three large pivotal trials with roxadustat, vadadustat, and daprodustat are currently in progress, and the results are eagerly awaited. If successful, these data could allow targeting
of normal hemoglobin values in CKD and ESRD patients, without the fear of cardiovascular events and the potential for other beneficial effects on fibrogenesis.62e64
THERAPIES FOR VASCULAR CALCIFICATION Premature cardiovascular disease (including sudden cardiac death, coronary heart disease, acute myocardial infarction, and congestive heart failure) in CKD patients is perhaps the single most important problem currently faced by the renal community. To place the magnitude of this risk in perspective, the chances of a cardiovascular event in a 20- to 40-year-old treated with HD is equivalent to that of an 80-year-old without renal disease.65e68 Traditional cardiovascular interventions such as lifestyle changes and treatment of blood pressure and dyslipidemia do not appear to have the same beneficial impact on cardiovascular mortality as in patients without renal disease. This paradox has resulted in increased attention paid to interventions that target novel pathways such as bone mineral disorder, inflammation,69 oxidative stress,70 endothelial dysfunction,71,72 retention of uremic toxins,73 and vascular calcification.74,75 Perhaps the most exciting area in the context of emerging therapies for vascular disease in CKD patients is vascular calcification.74e76 Vascular calcification in the general population occurs mainly within the neointima and in atherosclerotic plaques, resulting in vascular stenosis and dysfunction, especially in the setting of a thrombotic event. In CKD and ESRD patients, however, vascular calcification could be due to either neointimal calcification in the context of accelerated atherosclerosis or medial vascular calcification, which results in increased arterial stiffness, left ventricular hypertrophy, heart failure, and sudden cardiac death.74,77
Mechanisms of Vascular Calcification The major mechanisms and mediators of vascular calcification have been well described.74 They include failed anti-calcific processes involving a decrease in Fetuin A and an increased serum osteoprotegerin (OPG)/RANKL ratio, promotion of vascular smooth muscle cells by Prelamin A, the induction of osteochondrogenesis involving diabetic/inflammatory pathways and specific microRNAs such as miR-125b, cell death, and apoptosis, dysregulated calcium-phospate homeostasis which is particularly relevant to CKD, calciprotein particles, and various effects on matrix degradation/ modification. Additional proteins that have associations with vascular calcification include matrix Gla protein and osteopontin, which inhibits calcium crystal growth,
IX. SPECIAL CONSIDERATIONS
RENAL DENERVATION THERAPIES FOR HYPERTENSION AND CKD
ectonucleotide pyrophosphatase phosphodiesterase which regulates extracellular phosphate, and inhibition of VSMC apoptosis. Novel therapies may inhibit vascular calcification through modulation of some of these pathways.
RANK/RANKL/OPG Pathways RANK is a type I membrane protein expressed on osteoclasts. When RANK binds to its ligand RANKL,78 osteoclasts are activated. The resulting release of calcium from bone can then cause increased vascular calcification. In contrast, OPG is produced by osteoblasts and is a potent inhibitor of osteoclast differentiation and survival by functioning as a decoy receptor for RANKL.78 OPG appears to protect against vascular calcification because OPG/ mice develop spontaneous arterial calcifications.79 RANKL on the other hand increases vascular smooth muscle cell calcification by increasing BMP-4 production.80 Interest in the RANK/RANKL/ OPG pathway as a mechanism to inhibit vascular calcification is particularly topical because of the availability of a monoclonal antibody (denosumab; indicated for patients with osteoporosis), which binds to RANKL, thus preventing RANKeRANKL interactions and subsequent osteoclast activation. Studies with denosumab have demonstrated reduced vascular calcification in a mouse model of glucocorticoid-induced calcification.81 An important caveat, however, is that treatment with denosumab has been associated with significant and prolonged hypocalcemia in some patients with CKD.82,83
Vitamin D Receptor Agonists Vitamin D receptor antagonists are thought to work by increasing levels of osteopontin and klotho. Vitamin D receptor antagonism reduces aortic calcification in uremic mice fed high phosphate diets.84 There are no available human data on the ability of this therapy to reduce vascular calcification in CKD patients, although lower levels of vitamin D may be associated with increased mortality in incident hemodialysis patients.85
Vitamin K CKD patients are often deficient in vitamin K, an important cofactor for a number of metabolic pathways, especially one involving matrix GLA protein.74 A specific mechanism by which vitamin K repletion may reduce vascular calcification is by more efficient utilization of menaquinone-4, which could then inhibit arterial calcification.86
Calcimimetics Cinacalcet is a calcimimetic agent which acts via allosteric activation of the calcium-sensing receptor on parathyroid tissue.87 A large multicenter study (EVOLVE) evaluated the impact of cinacalcet on a composite endpoint of time to death or first nonfatal cardiovascular event and demonstrated a nonsignificant, 7% reduction in treated HD patients vs. placebo. A parallel analysis with lag censoring of data at 6 months after study drug discontinuation, however, demonstrated a nominally significant 15% relative reduction in the primary endpoint and a 17% relative reduction in mortality (absolute reduction of 2e3%).87 In another large randomized clinical trial, the ADVANCE trial, cinacalcet plus vitamin D vs. vitamin D alone did not show a significant difference in the percentage change of coronary artery calcification scores.88
Role of Glucocorticoid-Inducible Kinase 1 Receptors Both glucocorticoids and aldosterone act on the kidney though serum and glucocorticoid-inducible kinase 1 receptors. These receptors are responsible for the deleterious effects of these hormones on the cardiovascular system such as cardiac hypertrophy, cardiac fibrosis, and promotion of arrythmias. An inhibitor to this receptor has been developed called EMD638683.89 In summary, emerging therapies for vascular calcification must still be developed. Although the field is rapidly moving forward with regard to understanding the mechanisms involved in vascular calcification, there are still no truly effective clinical therapies shown to reduce vascular calcification in CKD.
RENAL DENERVATION THERAPIES FOR HYPERTENSION AND CKD Despite the fact that a large array of effective therapeutic agents for the treatment of hypertension are available, treatment on a population and perhaps on an individual basis is still suboptimal. Indeed, if the target is set at 140/90 mm Hg, the success rate in the US is only 29%.90 An important reason for this remains the side effect profile of antihypertensive agents in the context of an asymptomatic disease. Another important issue is poor compliance with both follow-up and medication adherence.91 An alternate approach to the therapy of hypertension is the use of renal denervation. Renal denervation could potentially address the previously described problems with conventional treatment approaches to hypertension.92,93
IX. SPECIAL CONSIDERATIONS
72. EMERGING THERAPIES
Biologic Rationale for Renal Denervation Therapy The sympathetic nerve supply to the kidney is responsible for multiple renal effects, including increased production of renin, increased tubular reabsorption of salt and water, and renal vasoconstriction.94 The potential benefit of completely blocking the sympathetic nerve supply of the kidney could therefore be particularly effective in patients with renal disease because of increased sympathetic activity.95
Interventional Technique An important technological step forward that has allowed this concept to become a therapeutic reality was the development of an interventional technique that allowed selective renal sympathetic denervation. This was possible primarily because the sympathetic nerve supply to the kidney runs along the renal artery. As a result, the placement of a special catheter within the renal artery could allow low intensity radiofrequency ablation of the entire renal sympathetic nerve supply. There are currently a number of such catheters available for clinical use. The radiofrequency ablation (RFA) catheter is positioned in the distal portion of the renal artery and then gradually withdrawn in a spiral fashion while administering RFA charges.
Early Human Studies of Current Renal Denervation Approaches A landmark study documented significant reduction in renal sympathetic spillover, 30 days after bilateral renal denervation.96 This was followed by a nonrandomized 50-patient study of bilateral renal denervation, which documented blood pressure decreases of 14/ 10 mm Hg (systolic/diastolic) at 1 month and 27/17 mm Hg at 1 year.91
Randomized Clinical Trials These initial nonrandomized studies were followed by the Symplicity HTN-2 clinical trial, a randomized study of over 100 subjects with refractory hypertension (blood pressure greater than 160/90 mm Hg in a patient taking three antihypertensive medications).97,98 The results documented significant decreases in systolic blood pressure, from a 20-point reduction at 1 month to a 32point reduction at 6 months. There was no change in blood pressure in patients in the control arm. There were, however, a number of drawbacks to this study, including the lack of a sham procedure and also the
use of office blood pressures only, which could be more dependent on sympathetic nerve activity compared with 24-hour ambulatory blood pressures. These weaknesses were addressed in the Symplicity HTN-3 study, a prospective, single-blind, randomized, sham-controlled trial of renal denervation in participants with resistant hypertension. The primary safety endpoint was a composite of death, ESRD, embolic events resulting in end organ damage, renovascular complications, and new renal artery stenosis. The primary efficacy endpoint was a change in office systolic blood pressure of greater than 5 mm Hg compared with the control group, with a secondary efficacy endpoint of a 2-mm reduction in ambulatory systolic blood pressure. In marked contrast to the results from the Symplicity HTN-1 and Symplicity HTN-2 studies, Symplicity HTN-3 study did not demonstrate a statistically significant improvement in either the primary or secondary endpoints. There were no differences between the control and treatment groups with regard to the safety endpoint. Why were the results from Symplicity HTN-3 so different from the earlier Symplicity studies, and what do the results of this study mean for the future of renal denervation therapy? Above all, the Symplicity HTN-3 study once again emphasizes the importance of having a true control group. The control group in Symplicity HTN-3 (as opposed to Symplicity HTN-2) underwent a sham procedure and therefore believed that they had received therapy. This together with participation in the trial (Hawthorne effect) could have had a beneficial impact on blood pressure. A post hoc analysis of the data appears to demonstrate a statistically significant benefit in non-African Americans in the study.99 In addition, some concerns have been raised about the lack of experience of the Symplicity HTN-3 investigators100 as opposed to the greater experience currently available in Europe (over 15,000 cases have gone into the European Registry). In summary, while the results of the Symplicity HTN-3 study do not support use of renal denervation therapy, there is ongoing speculation about whether there are in fact certain subgroups such as nonAfrican Americans who might still benefit from this therapy. It is also unclear regarding whether there could be some benefit from its use in CKD patients. While an eGFR of less than 45 mL/min/1.73 m2 was an exclusion for the Symplicity HTN-3 study, there are some data which suggest that renal denervation therapy does not have a negative impact on GFR101 and may in fact have a beneficial effect on microalbuminuria.102 A recent study in a mouse model of renal fibrosis due to unilateral ureteral obstruction documented a significant reduction in renal fibrosis in animals subjected to sympathectomy.103 Future research is likely to be directed
IX. SPECIAL CONSIDERATIONS
NOVEL THERAPIES FOR VASCULAR ACCESS DYSFUNCTION
toward the identification of such niche populations. More than anything else, however, the Symplicity HTN-3 study emphasizes once again the absolute necessity of using an appropriate control group. One of the technical factors that might have been responsible for the failure of the Symplicity trial is incomplete denervation of the renal nerves due to inadequate cauterization. The Paradise Ultrasound Renal Denervation System (PRDS)-001 which uses ultrasound might be a solution to this issue. This system allows sufficient periarterial nerve damage using ultrasound. At the same time, it uses a cooling balloon which reduces the risk of overheating the arterial wall and prevents tissue damage.104 The safety and effectiveness of this technique has been demonstrated in porcine models and in humans. A clinical trial (REQUIRE), in which an ultrasound renal denervation system is being used to treat resistant hypertension, is ongoing in Japan and Korea.105 There are also two other ongoing clinical trials, the REDUCE HTN REINFORCE study which uses the Vessix system (Vessix ReduceÔ Catheter and VessixÔ Generator) and the SPYRAL HTN OFF-MED trial using the Symplicity Spyral catheter. Both will use advanced catheters which can more precisely induce nerve damage without injuring surrounding arterial tissue.106
A Holistic View of Renal Denervation The currently available data on renal denervation therapy is exciting, while also deserving of a note of caution. There is no question that the ability to have a significant impact on blood pressure levels using a one time interventional procedure that targets renal sympathetic nerves, does not require long-term therapy with medications, and which may have a role in the prevention of renal fibrosis is a step forward. On the other hand, we should be cognizant of the fact that (a) longterm efficacy data using a sham intervention and 24hour ambulatory blood pressure monitoring are still pending and (b) we are perhaps evaluating a potentially expensive and invasive therapy because lack of adequate processes of care addressing issues such as compliance and physician/patient fatigue pose challenges to current therapeutic approaches. It is possible that the advantages of a one-stop shop approach may be particularly valuable in the context of CKD patients in many parts of the world (both developed and developing), where poor compliance and a lack of adequate early referral and follow-up continue to be important deficiencies within CKD programs. The downstream result of poorly controlled blood pressure in CKD patients is of course ESRD, with its associated morbidity, mortality, and economic costs.
NOVEL THERAPIES FOR VASCULAR ACCESS DYSFUNCTION Dialysis vascular access is currently considered to be both the “lifeline” and the “Achilles heel” for patients on hemodialysis.107e111 Perhaps the most disturbing statistic regarding vascular access is that approximately 80% of incident patients start HD with a tunneled dialysis catheter (TDC),112 with as much as a fivefold increase in mortality in the first 90 days of treatment, compared with patients who start with an arteriovenous fistula (AVF) or arteriovenous graft (AVG).113 The battle for vascular access will therefore likely be won or lost during the CKD phase. The way to achieve vascular access success during the CKD phase is likely through a combinatorial approach that includes both process of care interventions and the development of novel and innovative therapies. Process of care interventions would include early referral to kidney disease specialists, prevention of delays in referrals by nephrologists to radiology and surgery for vessel mapping and surgery, availability of committed and dedicated vascular access surgeons, close patient and vascular access follow-up post surgery, and the use of master cannulators for the initial cannulations of an AVF (Figure 72.4). Investing in a dedicated vascular access coordinator would address many of the above issues.
Biology of AVF Maturation Failure Early AVF maturation failure is probably due to a combination of aggressive neointimal hyperplasia in combination with a lack of outward remodeling.108e111,114 At a more pathogenic level, it is likely that the interaction between hemodynamic shear stress and the vascular response of the uremic vein to these stressors determines ultimate AVF success or failure. Our group and others have documented a + GP/PCP Early referral to nephrologist
+ Vein preservaon (GFR = 30) Refer for mapping and surgery (GFR = 20)
+ AVF follow up at 4-6 weeks
+ Referral for angioplasty/surgery as needed
Surgeon decision on type of AVF
Placement of AVF in the OR
? Ready to use; Expert cannulator
+ Successful AVF
Process of care barriers for arteriovenous fistula (AVF) maturation. Note that each of these barriers (parallel lines) is also an opportunity (þ) for local and meaningful process of care innovation. GFR units mL/min/1.73 m2.
IX. SPECIAL CONSIDERATIONS
72. EMERGING THERAPIES
significant amount of neointimal hyperplasia within venous segment tissue collected from the site of AVF surgery, suggesting that uremia, oxidative stress, and endothelial dysfunction can result in preexisting neointimal hyperplasia even before AVF creation.115,116 This preexisting neointimal hyperplasia does not seem to be linked to future AVF stenosis and failure.117
Novel Therapies for AVF Maturation The goal of the therapies described in this section is primarily to enhance AVF maturation during the CKD phase, so that patients are able to start dialysis with a mature ready-to-use AVF. PRT 201 Elastase The rationale for this intervention is that the application of a recombinant elastase will destroy elastin fibers in both the artery and the vein and allow rapid AVF dilation and maturation. This concept is particularly important, because it goes to the heart not only of “fistula first” but also incorporates the “catheter last or catheter out” concept, because rapid AVF maturation would allow for the rapid removal of TDCs. Initial Phase II studies suggest that the mechanism may be somewhat more complex, in that the best results were seen in the low dose group,118 suggesting that fragmentation of elastin fibers into protein fragments with potential biological activity could be the mechanism of action. An initial large Phase III randomized clinical trial in the setting of radiocephalic fistulae using unassisted primary patency as the primary endpoint did not show a statistically significant difference between the control and treated arms. There was, however, a difference in the secondary endpoint of cumulative patency. The results from a larger Phase II study with cumulative patency as the primary endpoint have just been described and there was once again disappointingly, no difference between the treatment and control arms. Sirolimus COL-R Wraps Sirolimus is an antiproliferative agent that blocks neointimal hyperplasia in the setting of coronary restenosis. The COL-R wrap comprises a biodegradable sirolimuseluting wrap (antiproliferative agent) which is placed around the arteriovenous anastomosis of an AVF, or around the graft-vein anastomosis of a PTFE (polytetrafluoroethylene) graft (Figure 72.5). An initial Phase II study demonstrated primary unassisted AV graft patencies of 75% and 38% at 1 and 2 years, in patients treated with the COL-R wrap, albeit in the absence of a control arm.119 Similar pilot studies in AVFs have documented excellent AVF maturation rates. A Phase III randomized controlled trial to assess the safety, efficacy, and
FIGURE 72.5 Sirolimus COL-R wraps for arteriovenous fistula maturation. Elution of sirolimus from these biodegradable wraps is expected to enhance arteriovenous fistula maturation. Courtesy Dr. Iyer.
maturation outcomes of a perivascular sirolimus-eluting implant placed at the AVF anastomosis in hemodialysis patients is currently ongoing. Results are expected by 2022. Vascugel Endothelial CelleLoaded Wraps This comprises a gel-foam wrap, embedded with endothelial cells. The biological rationale behind “Vascugel” is that endothelial cells are bioreactors for “good” mediators. Thus, the delivery of “good” endothelial cells to the local vicinity of the AVF should allow a local milieu that inhibits neointimal hyperplasia and enhances outward remodeling. Initial experimental studies documented a beneficial effect of endothelial celleloaded gel-foam wraps in porcine models of AV fistula and graft stenosis.120,121 More recently, human studies have described the technical feasibility of improvement in primary patency when Vascugel wraps were used in diabetic patients with PTFE grafts.122,123 Patients on an active transplant list or who are likely to get a transplant in the future should not be treated with this therapy because of some risk of sensitization to HLA antigens. Shire Regenerative Medicine recently initiated two large studies using these wraps in the setting of AVFs and AVGs, respectively. Both studies were unfortunately stopped due to business considerations. It is therefore unclear as to whether this therapy will enter into clinical practice. Nitroglycerine Ointment Glyceryl trinitrate (GTN) is a nitrate-based vasodilator that can increase blood flow and prevent platelet aggregation. Use of GTN at the time of creation of an AVF may help in the maturation process. Although there were some positive results in early trials, a randomized controlled trial evaluating the role of locally administered nitroglycerin ointment to enhance local nitric oxide bioavailability in improving AVF maturation did not show significant effect on maturation.124
IX. SPECIAL CONSIDERATIONS
NOVEL THERAPIES FOR VASCULAR ACCESS DYSFUNCTION
Percutaneous AVF Creation An important cause of AVF maturation failure is thought to be the surgical handling and potential vascular torsion that occurs at the time of its surgical creation, which then predisposes to perianastomotic stenosis. Recently, there have been some exciting technological advances that have resulted in FDA approval of two techniques for the creation of percutaneous AVFs. One of the techniques uses ultrasound to place a percutaneous device across a vein and artery in the upper forearm that is close together and then delivers a burst of energy to create an AVF (Figure 72.6). The other technique uses catheters with magnets to bring the appropriate artery and vein close together and then creates a connection through a burst of energy (Figure 72.7). The important advantages of this technique include the avoidance of a surgical procedure, no need for preoperative evaluation, and the lack of a surgical scar. In addition, the initial nonrandomized data describe outstanding patency for these techniques.
It is important, however, for additional real-world data to be collected and evaluated. Perhaps the greatest impact of the percutaneous techniques could be on the process of care for AVF creation, because these technologies now allow the creation of AVFs by endovascular and ultrasound specialists (interventional radiologists and interventional nephrologists in particular). This more egalitarian approach to AVF creation may result in better access to care for AVF creation, and potentially for the ultrasound-based technology, in parts of the world where there is limited access to endovascular suites.125,126
Bioengineered Vessels The creation of a bioengineered vessel that could be used as a vascular conduit has for long been the holy grail for vascular surgery and applied vascular biology. In the context of dialysis vascular access, the availability of a vascular conduit that could be used in patients who are not suitable candidates for an AVF, without the
FIGURE 72.6 Percutaneous arteriovenous fistula (AVF) creation with the Ellipsys device. The proximal radial artery is initially punctured through the deep communicating vein and a guide wire is placed through the vein into the artery (a). The Ellipsys catheter is then advanced over the wire and traction (arrow) is applied to make sure that the device has captured the arterial wall (b). The device is then closed and activated with thermal energy, resulting in a communication between the DCM and the radial artery (c), to create an AVF (d). Adapted from reference 126.
Percutaneous arteriovenous fistula (AVF) creation with the WavelinQ device. Guidewires and special catheters are placed into an adjoining artery and vein (a). Catheter magnets are then activated resulting in the vessels coming close together, following which an electrode delivers a burst of radiofrequency energy to create an AVF (b). In a final step, a deep vein is coiled (horizontal arrow) in an attempt to preferentially drive blood through the superficial venous system (both basilic and cephalic; c).
IX. SPECIAL CONSIDERATIONS
72. EMERGING THERAPIES
stenosis and thrombosis that characterizes PTFE graft use, would be an important advance. Humacyte recently described a bioengineered vessel in which a biodegradable scaffold in the form of a dialysis access graft is seeded with mesenchymal cells which then produce matrix proteins, resulting in a collagenous tube. This device is then treated to remove all living cells to minimize allorecognition and potential sensitization to HLA antigens. The final device, which looks like a vessel, has been placed in a number of patients on hemodialysis in the form of an AVG. Initial results demonstrate a primary patency similar to PTFE grafts, but perhaps with less infection and with the need for fewer interventions to maintain patency. Humacyte is currently conducting two large randomized studies where these grafts are compared with standard ePTFE. The results will be available shortly.127
in that the basic construct of hemodialysis has not changed significantly over the last 40 years. The current survival on hemodialysis for all patients in the US is a dismal 41% at 5 years, which is lower than the fiveyear survival of most cancers (Figure 72.8). More importantly, patients treated with maintenance hemodialysis have poor quality of life, with an extremely limited ability to do the things that are important to them (such as being able to travel and not feeling washed out after dialysis). To address this issue, there has been a great deal of interest recently in home hemodialysis, portable and wearable hemodialysis, and in sensors that could create a real-time feedback loop (Figure 72.9).128e130 There has also been some exciting experimental work on an implantable kidney by a group led by Drs. Shuvo Roy and William Fissell (Figure 72.10).131 In addition, the Kidney Health Initiative, a publiceprivate partnership between the American Society of Nephrology and the FDA132,133 has recently described a road map for innovative RRT which we hope will serve as a catalyst to focus interest, investment, and innovation in this area.134 In parallel with the description of the innovative RRT road map, the Kidney Innovation Accelerator or KidneyX, a publiceprivate partnership between the Department of Health and Human Services and the American Society of Nephrology recently announced a prize competition which focuses on “Redesigning Dialysis.”135 We feel that these two policy and funding initiatives will nicely complement each other to truly jump start advances in this area. Thus, while the road map
INNOVATIVE RENAL REPLACEMENT THERAPIES Since the advent of chronic hemodialysis at Northwest Kidney Centers, in Seattle in the early 1960s, this technology has saved millions of lives. Dialysis still remains the only form of organ replacement therapy that is effective over prolonged periods of time. The huge success of this technology, however, has perhaps lulled the kidney community into a false sense of complacency,
100 Respiratory Cancer
Digestive System Cancer
Soft tissue Cancer Male Genital Cancer
Urinary System Cancer
Female Genital Cancer
Soft tissue Cancer
Digestive System Cancer
All Cancer Bones/Joint Cancer Female Genital Cancer Lymphoma Kaposi Sarcoma
FIGURE 72.8 Poor survival of hemodialysis patients. The 5-year survival of end-stage renal disease (ESRD) patients treated with hemodialysis is worse than many forms of cancer. Adapted from an original figure; courtesy Frank Hurst.
IX. SPECIAL CONSIDERATIONS
FIGURE 72.9 Prototype of a wearable artificial kidney. This would allow better quality of life using slow continuous dialysis. Adapted from reference 129.
In summary, we have presented data on a number of novel therapeutic concepts that could completely change the way we care for CKD patients in the coming years. The true way to move any field forward, however, is to synergize biological and technological advances with the clinical setting/process of care pathways and with regulatory/reimbursement pathways. The presence of publiceprivate partnerships such as the Kidney Health Initiative, which aims to create an innovation substrate for kidney diseases, is an important step forward to achieving this goal. Our hope for the future is that the availability of a number of novel therapies to individualize the management of CKD and its complications will allow us to get the right therapy to the right patient at the right time.
Disclosures Dr. Prabir Roy-Chaudhury is a consultant/advisory board member for Bard BD, WL Gore, Medtronic, Cormedix, Humacyte, Vifor, Akebia, Reata, and Bayer. He is also the Founder and Chief Scientific Officer of Inovasc LLC.
FIGURE 72.10 Implantable artificial kidney. Representation of an implantable artificial kidney with blood being initially filtered through a hemocartridge comprising silicon nanomembranes, followed by passage through a biocartridge comprising living tubular cells, thus mimicking the natural glomerulus-tubule construct. Adapted from reference 131.
could serve as the technical construct for the Redesign Dialysis initiative, the funds available for the Redesign Dialysis competition could function as the implementer arm for the milestones described in the innovative RRT road map.
1. United States Renal Data System. 2017 USRDS annual data report: epidemiology of kidney disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2017. 2. Jha V, Wang AY, Wang H. The impact of CKD identification in large countries: the burden of illness. Nephrol Dial Transplant 2012;27(Suppl. 3):32e8. 3. Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing world e a growing challenge. N Engl J Med 2007; 356:213e5. 4. Vilayur E, Harris DC. Emerging therapies for chronic kidney disease: what is their role? Nat Rev Nephrol 2009;5:375e83. 5. Navarro JF, Mora C, Muros M, Garcia J. Additive antiproteinuric effect of pentoxifylline in patients with type 2 diabetes under angiotensin II receptor blockade: a short-term, randomized, controlled trial. J Am Soc Nephrol 2005;16:2119e26. 6. Chen YM, Lin SL, Chiang WC, Wu KD, Tsai TJ. Pentoxifylline ameliorates proteinuria through suppression of renal monocyte chemoattractant protein-1 in patients with proteinuric primary glomerular diseases. Kidney Int 2006;69:1410e5. 7. Lin SL, Chen YM, Chiang WC, Wu KD, Tsai TJ. Effect of pentoxifylline in addition to losartan on proteinuria and GFR in CKD: a 12-month randomized trial. Am J Kidney Dis 2008;52:464e74. 8. Leporini C, Pisano A, Russo E, DA G, de Sarro G, Coppolino G, et al. Effect of pentoxifylline on renal outcomes in chronic kidney disease patients: a systematic review and meta-analysis. Pharmacol Res 2016;107:315e32. 9. Navarro-Gonzalez JF, Sanchez-Nino MD, Donate-Correa J, Martin-Nunez E, Ferri C, Perez-Delgado N, et al. Effects of pentoxifylline on soluble klotho concentrations and renal tubular cell expression in diabetic kidney disease. Diabetes Care 2018; 41(8):1817e20. 10. Athyros VG, Mikhailidis DP, Papageorgiou AA, Symeonidis AN, Pehlivanidis AN, Bouloukos VI, et al. The effect of statins versus
IX. SPECIAL CONSIDERATIONS
72. EMERGING THERAPIES
untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study. J Clin Pathol 2004;57:728e34. Campese VM, Nadim MK, Epstein M. Are 3-hydroxy-3methylglutaryl-CoA reductase inhibitors renoprotective? J Am Soc Nephrol 2005;16(Suppl. 1):S11e17. Calza L, Colangeli V, Borderi M, Manfredi R, Marconi L, Bon I, et al. Rosuvastatin and atorvastatin preserve renal function in HIV-1-infected patients with chronic kidney disease and hyperlipidaemia. HIV Clin Trials 2018;19(3):120e8. Kimura G, Kasahara M, Ueshima K, Tanaka S, Yasuno S, Fujimoto A, et al. Effects of atorvastatin on renal function in patients with dyslipidemia and chronic kidney disease: assessment of clinical usefulness in CKD patients with atorvastatin (ASUCA) trial. Clin Exp Nephrol 2017;21(3):417e24. Zhang Z, Li Z, Cao K, Fang D, Wang F, Bi G, et al. Adjunctive therapy with statins reduces residual albuminuria/proteinuria and provides further renoprotection by downregulating the angiotensin II-AT1 pathway in hypertensive nephropathy. J Hypertens 2017;35(7):1442e56. Zhang Z, Wu P, Zhang J, Wang S, Zhang G. The effect of statins on microalbuminuria, proteinuria, progression of kidney function, and all-cause mortality in patients with non-end stage chronic kidney disease: a meta-analysis. Pharmacol Res 2016;105:74e83. Watnick T, Germino GG. mTOR inhibitors in polycystic kidney disease. N Engl J Med 2010;363:879e81. Serra AL, Poster D, Kistler AD, et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med 2010;363:820e9. Walz G, Budde K, Mannaa M, Nurnberger J, Wanner C, Sommerer C, et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2010;363:830e40. Torres VE, Wang X, Qian Q, Somlo S, Harris PC, Gattone 2nd VH. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med 2004;10(4):363e4. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2012; 367(25):2407e18. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, et al. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N Engl J Med 2017;377(20):1930e42. Tsuji T, Ohishi K, Takeda A, Goto D, Sato T, Ohashi N, et al. The impact of serum uric acid reduction on renal function and blood pressure in chronic kidney disease patients with hyperuricemia. Clin Exp Nephrol 2018;22(6):1300e8. Srivastava A, Kaze AD, McMullan CJ, Isakova T, Waikar SS. Uric acid and the risks of kidney failure and death in individuals with CKD. Am J Kidney Dis 2018;71(3):362e70. Maahs DM, Caramori L, Cherney DZ, Galecki AT, Gao C, Jalal D, et al. Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study. Curr Diabetes Rep 2013;13(4):550e9. MacIsaac RJ, Jerums G, Ekinci EI. Cardio-renal protection with empagliflozin. Ann Transl Med 2016;4(20):409. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373(22):2117e28. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. CREDENCE Trial Investigators. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 2019;380(24):2295e306. Mima A. Renal protection by sodium-glucose cotransporter 2 inhibitors and its underlying mechanisms in diabetic kidney disease. J Diabet Complicat 2018;32(7):720e5.
29. Heerspink HJL, Kosiborod M, Inzucchi SE, Cherney DZI. Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int 2018;94(1):26e39. 30. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375:311e22. 31. Lytvyn Y, Godoy LC, Scholtes RA, van Raalte DH, Cherney DZ. Mineralocorticoid antagonism and diabetic kidney disease. Curr Diabetes Rep 2019;19(1):4. 32. Dhaun N, Melville V, Blackwell S, Talwar DK, Johnston NR, Goddard J, et al. Endothelin-A receptor antagonism modifies cardiovascular risk factors in CKD. J Am Soc Nephrol 2013;24(1):31e6. 33. Kohan DE, Pritchett Y, Molitch M, Wen S, Garimella T, Audhya P, et al. Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy. J Am Soc Nephrol 2011;22(4):763e72. 34. Heerspink HJL, Parving HH, Andress DL, et al. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebocontrolled trial. Lancet 2019;393(8):1937e47. 35. Bantounas I, Ranjzad P, Tengku F, et al. Generation of functioning nephrons by implanting human pluripotent stem cell-derived kidney progenitors. Stem Cell Reports 2018;10:766e79. 36. Weber EJ, Chapron A, Chapron BD, et al. Development of a microphysiological model of human kidney proximal tubule function. Kidney Int 2016;90:627e37. 37. Basu J, Genheimer CW, Rivera EA, Payne R, Mihalko K, Guthrie K, et al. Functional evaluation of primary renal cell/ biomaterial neo-kidney augment prototypes for renal tissue engineering. Cell Transplant 2011;20(11e12):1771e90. 38. Lee SY, Kim SI, Choi ME. Therapeutic targets for treating fibrotic kidney diseases. Transl Res 2015;165(4):512e30. 39. Hou X, Rooklin D, Fang H, Zhang Y. Resveratrol serves as a protein-substrate interaction stabilizer in human SIRT1 activation. Sci Rep 2016;6:38186. 40. Fernandez-Fernandez B, Ortiz A, Gomez-Guerrero C, Egido J. Therapeutic approaches to diabetic nephropathy–beyond the RAS. Nat Rev Nephrol 2014;10:325e46. 41. de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med 2013;369:2492e503. 42. Salant DJ. Podocyte expression of B7-1/CD80: is it a reliable biomarker for the treatment of proteinuric kidney diseases with abatacept? J Am Soc Nephrol 2016;27:963e5. 43. Eschbach JW, Kelly MR, Haley NR, Abels RI, Adamson JW. Treatment of the anemia of progressive renal failure with recombinant human erythropoietin. N Engl J Med 1989;321:158e63. 44. Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355:2071e84. 45. Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361:2019e32. 46. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:2085e98. 47. Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998;339:584e90. 48. Bernhardt WM, Wiesener MS, Scigalla P, Chou J, Schmieder RE, Gunzler V, et al. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J Am Soc Nephrol 2010;21:2151e6. 49. Beuck S, Schanzer W, Thevis M. Hypoxia-inducible factor stabilizers and other small-molecule erythropoiesis-stimulating agents in current and preventive doping analysis. Drug Test Anal 2012;4:830e45.
IX. SPECIAL CONSIDERATIONS
50. Miyata T, Suzuki N, van Ypersele de Strihou C. Diabetic nephropathy: are there new and potentially promising therapies targeting oxygen biology? Kidney Int 2013;84:693e702. 51. Franke K, Gassmann M, Wielockx B. Erythrocytosis: the HIF pathway in control. Blood 2013;122:1122e8. 52. Zhao S, Wu J. Hypoxia inducible factor stabilization as a novel strategy to treat anemia. Curr Med Chem 2013;20:2697e711. 53. Denny WA. Giving anemia a boost with inhibitors of prolyl hydroxylase. J Med Chem 2012;55:2943e4. 54. Muchnik E, Kaplan J. HIF prolyl hydroxylase inhibitors for anemia. Expert Opin Investig Drugs 2011;20:645e56. 55. Smith TG, Talbot NP. Prolyl hydroxylases and therapeutics. Antioxidants Redox Signal 2010;12:431e3. 56. Chiang CK, Tanaka T, Inagi R, Fujita T, Nangaku M. Indoxyl sulfate, a representative uremic toxin, suppresses erythropoietin production in a HIF-dependent manner. Lab Invest 2011;91:1564e71. 57. Minamishima YA, Kaelin Jr WG. Reactivation of hepatic EPO synthesis in mice after PHD loss. Science 2010;329:407. 58. Tanaka T, Miyata T, Inagi R, Fujita T, Nangaku M. Hypoxia in renal disease with proteinuria and/or glomerular hypertension. Am J Pathol 2004;165:1979e92. 59. Manotham K, Tanaka T, Matsumoto M, et al. Evidence of tubular hypoxia in the early phase in the remnant kidney model. J Am Soc Nephrol 2004;15:1277e88. 60. Prabhakar S, Starnes J, Shi S, Lonis B, Tran R. Diabetic nephropathy is associated with oxidative stress and decreased renal nitric oxide production. J Am Soc Nephrol 2007;18:2945e52. 61. Aragones J, Schneider M, Van Geyte K, Fraisl P, Dresselaers T, Mazzone M, et al. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nat Genet 2008;40:170e80. 62. Del Vecchio L, Locatelli F. Roxadustat in the treatment of anaemia in chronic kidney disease. Expert Opin Investig Drugs 2018;27(1): 125e33. 63. Joharapurkar AA, Pandya VB, Patel VJ, Desai RC, Jain MR. Prolyl hydroxylase inhibitors: a breakthrough in the therapy of anemia associated with chronic diseases. J Med Chem 2018;61(16):6964e82. 64. Hasegawa S, Tanaka T, Nangaku M. Hypoxia-inducible factor stabilizers for treating anemia of chronic kidney disease. Curr Opin Nephrol Hypertens 2018;27(5):331e8. 65. Stenvinkel P. Chronic kidney disease: a public health priority and harbinger of premature cardiovascular disease. J Intern Med 2010; 268:456e67. 66. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998;32: S112e9. 67. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004;351:1296e305. 68. Foley RN, Murray AM, Li S, et al. Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999. J Am Soc Nephrol 2005;16:489e95. 69. Mallamaci F, Tripepi G, Cutrupi S, Malatino LS, Zoccali C. Prognostic value of combined use of biomarkers of inflammation, endothelial dysfunction, and myocardiopathy in patients with ESRD. Kidney Int 2005;67:2330e7. 70. Himmelfarb J. Uremic toxicity, oxidative stress, and hemodialysis as renal replacement therapy. Semin Dial 2009;22:636e43. 71. Brunet P, Gondouin B, Duval-Sabatier A, Dou L, Cerini C, DignatGeorge F, et al. Does uremia cause vascular dysfunction? Kidney Blood Press Res 2011;34:284e90. 72. Jourde-Chiche N, Dou L, Cerini C, Dignat-George F, Brunet P. Vascular incompetence in dialysis patients e protein-bound uremic toxins and endothelial dysfunction. Semin Dial 2011;24:327e37.
73. Calaf R, Cerini C, Genovesio C, Verhaeghe P, Jourde-Chiche N, Berge´-Lefranc D, et al. Determination of uremic solutes in biological fluids of chronic kidney disease patients by HPLC assay. J Chromatogr B Analyt Technol Biomed Life Sci 2011;879:2281e6. 74. Wu M, Rementer C, Giachelli CM. Vascular calcification: an update on mechanisms and challenges in treatment. Calcif Tissue Int 2013;93:365e73. 75. Leonard O, Spaak J, Goldsmith D. Regression of vascular calcification in chronic kidney disease e feasible or fantasy? A review of the clinical evidence. Br J Clin Pharmacol 2013;76:560e72. 76. Rezg R, Barreto FC, Barreto DV, Liabeuf S, Drueke TB, Massy ZA. Inhibitors of vascular calcification as potential therapeutic targets. J Nephrol 2011;24:416e27. 77. Giachelli CM. Mechanisms of vascular calcification in uremia. Semin Nephrol 2004;24:401e2. 78. Liu C, Walter TS, Huang P, Zhang S, Zhu X, Wu Y, et al. Structural and functional insights of RANKL-RANK interaction and signaling. J Immunol 2010;184:6910e9. 79. Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, et al. osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 1998;12:1260e8. 80. Panizo S, Cardus A, Encinas M, Parisi E, Valcheva P, Lo´pezOngil S, et al. RANKL increases vascular smooth muscle cell calcification through a RANK-BMP4-dependent pathway. Circ Res 2009;104:1041e8. 81. Helas S, Goettsch C, Schoppet M, Zeitz U, Hempel U, Morawietz H, et al. Inhibition of receptor activator of NFkappaB ligand by denosumab attenuates vascular calcium deposition in mice. Am J Pathol 2009;175:473e8. 82. Ungprasert P, Cheungpasitporn W, Srivali N, Kittanamongkolchai W, Bischof EF. Life-threatening hypocalcemia associated with denosumab in a patient with moderate renal insufficiency. Am J Emerg Med 2013;31(756):e1e2. 83. McCormick BB, Davis J, Burns KD. Severe hypocalcemia following denosumab injection in a hemodialysis patient. Am J Kidney Dis 2012;60:626e8. 84. Lau WL, Leaf EM, Hu MC, Takeno MM, Kuro-o M, Moe OW, et al. Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet. Kidney Int 2012;82:1261e70. 85. Wolf M, Thadhani R. Vitamin D in patients with renal failure: a summary of observational mortality studies and steps moving forward. J Steroid Biochem Mol Biol 2007;103:487e90. 86. Spronk HM, Soute BA, Schurgers LJ, Thijssen HH, De Mey JG, Vermeer C. Tissue-specific utilization of menaquinone-4 results in the prevention of arterial calcification in warfarin-treated rats. J Vasc Res 2003;40:531e7. 87. EVOLVE Trial Investigators, Chertow GM, Block GA, CorreaRotter R, Dru¨eke TB, Floege J, et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 2012;367:2482e94. 88. Raggi P, Chertow GM, Torres PU, et al. The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus lowdose vitamin D on vascular calcification in patients on hemodialysis. Nephrol Dial Transplant 2011;26:1327e39. 89. Gan W, Ren J, Li T, et al. The SGK1 inhibitor EMD638683, prevents Angiotensin II-induced cardiac inflammation and fibrosis by blocking NLRP3 inflammasome activation. Biochim Biophys Acta 2018;1864:1e10. 90. Wolf-Maier K, Cooper RS, Kramer H, Banegas JR, Giampaoli S, Joffres MR, et al. Hypertension treatment and control in five European countries, Canada, and the United States. Hypertension 2004; 43:10e7. 91. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, et al. Catheter-based renal sympathetic denervation
IX. SPECIAL CONSIDERATIONS
109. 110. 111.
72. EMERGING THERAPIES
for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009;373:1275e81. Esler M. The 2009 Carl Ludwig Lecture: pathophysiology of the human sympathetic nervous system in cardiovascular diseases: the transition from mechanisms to medical management. J Appl Physiol 2010;108:227e37. Esler M. The sympathetic nervous system through the ages: from Thomas Willis to resistant hypertension. Exp Physiol 2011;96: 611e22. DiBona GF, Esler M. Translational medicine: the antihypertensive effect of renal denervation. Am J Physiol Regul Integr Comp Physiol 2010;298:R245e53. Converse Jr RL, Jacobsen TN, Toto RD, Jost CM, Cosentino F, Fouad-Tarazi F, et al. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med 1992;327:1912e8. Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. Renal sympathetic-nerve ablation for uncontrolled hypertension. N Engl J Med 2009;361:932e4. Symplicity HTN-2 Investigators Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, et al. Renal sympathetic denervation in patients with treatment-resistent hypertension (The Symplicity HTN-2 Trial): a randomized controlled trial. Lancet 2010; 376(9756):1903e9. Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370:1393e401. Schmieder RE. Hypertension: how should data from SYMPLICITY HTN-3 be interpreted? Nat Rev Cardiol 2014;11:375e6. Luscher TF, Mahfoud F. Renal nerve ablation after SYMPLICITY HTN-3: confused at the higher level? Eur Heart J 2014;35: 1706e11. Hering D, Mahfoud F, Walton AS, Krum H, Lambert GW, Lambert EA, et al. Renal denervation in moderate to severe CKD. J Am Soc Nephrol 2012;23:1250e7. Ott C, Mahfoud F, Schmid A, Ditting T, Veelken R, Ewen S, et al. Improvement of albuminuria after renal denervation. Int J Cardiol 2014;173:311e5. Kim J, Padanilam BJ. Renal nerves drive interstitial fibrogenesis in obstructive nephropathy. J Am Soc Nephrol 2013;24:229e42. Sakakura K, Roth A, Ladich E, et al. Controlled circumferential renal sympathetic denervation with preservation of the renal arterial wall using intraluminal ultrasound: a next-generation approach for treating sympathetic overactivity. EuroIntervention 2015;10:1230e8. Mauri L, Kario K, Basile J, et al. A multinational clinical approach to assessing the effectiveness of catheter-based ultrasound renal denervation: the RADIANCE-HTN and REQUIRE clinical study designs. Am Heart J 2018;195:115e29. Sanghvi K, McGrew A, Hegde K. Rationale and design for studies of renal denervation in the absence (SPYRAL HTN OFF-MED) and presence (SPYRAL HTN ON-MED) of antihypertensive medications. Am Heart J 2016;180:e1e2. Riella MC, Roy-Chaudhury P. Vascular access in haemodialysis: strengthening the Achilles’ heel. Nat Rev Nephrol 2013;9:348e57. Roy-Chaudhury P, Sukhatme VP, Cheung AK. Hemodialysis vascular access dysfunction: a cellular and molecular viewpoint. J Am Soc Nephrol 2006;17:1112e27. Roy-Chaudhury P, Lee TC. Vascular stenosis: biology and interventions. Curr Opin Nephrol Hypertens 2007;16:516e22. Roy-Chaudhury P, Spergel LM, Besarab A, Asif A, Ravani P. Biology of arteriovenous fistula failure. J Nephrol 2007;20:150e63. Lee T, Roy-Chaudhury P. Advances and new frontiers in the pathophysiology of venous neointimal hyperplasia and dialysis access stenosis. Adv Chron Kidney Dis 2009;16:329e38. USRDS. USRDS 2010 Annual data report: atlas of end-stage renal disease in the United States. Bethesda, MD: National Institutes of
128. 129. 130.
Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2011. Perl J, Wald R, McFarlane P, Bargman JM, Vonesh E, Na Y, et al. Hemodialysis vascular access modifies the association between dialysis modality and survival. J Am Soc Nephrol 2011;22:1113e21. Roy-Chaudhury P, Arend L, Zhang J, Krishnamoorthy M, Wang Y, Banerjee R, et al. Neointimal hyperplasia in early arteriovenous fistula failure. Am J Kidney Dis 2007;50:782e90. Lee T, Chauhan V, Krishnamoorthy M, Wang Y, Arend L, Mistry MJ, et al. Severe venous neointimal hyperplasia prior to dialysis access surgery. Nephrol Dial Transplant 2011;26: 2264e70. Wasse H, Huang R, Naqvi N, Smith E, Wang D, Husain A. Inflammation, oxidation and venous neointimal hyperplasia precede vascular injury from AVF creation in CKD patients. J Vasc Access 2012;13(2):168e74. Cheung AK, Imrey PB, Alpers CE, Robbin ML, Radeva M, Larive B, et al. Intimal hyperplasia, stenosis, and arteriovenous fistula maturation failure in the hemodialysis fistula maturation study. J Am Soc Nephrol 2017;28(10):3005e13. Peden EK, Leeser DB, Dixon BS, El-Khatib MT, Roy-Chaudhury P, Lawson JH, et al. A multi-center, dose-escalation study of human type I pancreatic elastase (PRT-201) administered after arteriovenous fistula creation. J Vasc Access 2013;14:143e51. Paulson WD, Kipshidze N, Kipiani K, Beridze N, DeVita MV, Shenoy S, et al. Safety and efficacy of locally eluted sirolimus for prolonging AV graft patency (PTFE Graft Plus Coll-R) first in man experience. Am Soc Nephrol Phila 2008;27(3):1219e24. Nugent HM, Groothuis A, Seifert P, Guerraro JL, Nedelman M, Mohanakumar T, et al. Perivascular endothelial implants inhibit intimal hyperplasia in a model of arteriovenous fistulae: a safety and efficacy study in the pig. J Vasc Res 2002;39:524e33. Nugent HM, Sjin RT, White D, Milton LG, Manson RJ, Lawson JH, et al. Adventitial endothelial implants reduce matrix metalloproteinase-2 expression and increase luminal diameter in porcine arteriovenous grafts. J Vasc Surg 2007;46:548e56. Conte MS, Nugent HM, Gaccione P, Guleria I, Roy-Chaudhury P, Lawson JH. Multicenter phase I/II trial of the safety of allogeneic endothelial cell implants after the creation of arteriovenous access for hemodialysis use: the V-HEALTH study. J Vasc Surg 2009;50: 1359e68. e1. Conte MS, Nugent HM, Gaccione P, Roy-Chaudhury P, Lawson JH. Influence of diabetes and perivascular allogeneic endothelial cell implants on arteriovenous fistula remodeling. J Vasc Surg 2011;54:1383e9. Field M, McGrogan D, Marie Y, et al. Randomized clinical trial of the use of glyceryl trinitrate patches to aid arteriovenous fistula maturation. Br J Surg 2016;103:1269e75. Rajan DK, Ebner A, Desai SB, Rios JM, Cohn WE. Percutaneous creation of an arteriovenous fistula for hemodialysis access. J Vasc Interv Radiol 2015;26:484e90. Mallios A, Jennings WC, Boura B, Costanzo A, Bourquelot P, Combes M. Early results of percutaneous arteriovenous fistula creation with the Ellipsys Vascular Access System. J Vasc Surg 2018;68(4):1150e6. Lawson JH, Glickman MH, Ilzecki M, et al. Bioengineered human acellular vessels for dialysis access in patients with end-stage renal disease: two phase 2 single-arm trials. Lancet 2016;387: 2026e34. Takahashi S. Future home hemodialysis - advantages of the NxStage system one. Contrib Nephrol 2012;177:117e26. Gura V, Rivara MB, Bieber S, et al. A wearable artificial kidney for patients with end-stage renal disease. JCI Insight 2016;1. Wieringa FP, Broers NJH, Kooman JP, Van Der Sande FM, Van Hoof C. Wearable sensors: can they benefit patients with chronic kidney disease? Expert Rev Med Devices 2017;14:505e19.
IX. SPECIAL CONSIDERATIONS
131. Salani M, Roy S, Fissell WH. Innovations in wearable and implantable Artificial kidneys. Am J Kidney Dis 2018;72(5):745e51. 132. Archdeacon P, Shaffer RN, Winkelmayer WC, Falk RJ, RoyChaudhury P. Fostering innovation, advancing patient safety: the kidney health initiative. Clin J Am Soc Nephrol 2013;8(9): 1609e17. 133. Linde PG, Archdeacon P, Breyer MD, Ibrahim T, Inrig JK, Kewalramani R, et al. Overcoming barriers in kidney health-
forging a platform for innovation. J Am Soc Nephrol 2016;27(7): 1902e10. 134. Kidney health initiative roadmap for innovative renal replacement therapy and press release at https://khi.asn-online.org/ pages/?ID¼8. 135. Kidney innovation accelerator (KidneyX) prize competition to redesign dialysis at http://www.kidneyx.org.
IX. SPECIAL CONSIDERATIONS