Emerging drugs for chronic kidney disease

Introduction: Chronic kidney disease (CKD) is a worldwide health problem. Despite remarkable headway in slowing the progression of kidney diseases, the incidence of end-stage renal disease (ESRD) is increasing in all countries with a severe impact on patients and society. The high incidence of diabetes and hypertension, along with the aging population, may partially explain this growth. Currently, the mainstay of pharmacological treatment for CKD, aiming to slow progression to ESRD are ACE inhibitors and angiotensin II receptor blockers for their hemodynamic/antihypertensive and anti-inflammatory/antifibrotic action. However, novel drugs would be highly desirable to effectively slow the progressive renal function loss.

Areas covered: Through the search engines, PubMed and ClinicalTrial.gov, the scientific literature was reviewed in search of emerging drugs in Phase II or III trials, which appear to be the most promising for CKD treatment.

Expert opinion: The great expectations for new drugs for the management of CKD over the last decade have unfortunately not been met. Encouraging results from preliminary studies with specific agents need to be tempered with caution, given the absence of consistent and adequate data. To date, several agents that showed great promise in animal studies have been less effective in humans.     

Erythropoietic stimulating agents

Importance of the field: The synthesis of recombinant forms of erythropoietin, epoetin α, β and darbepoetin α, has represented a major achievement in anemia therapy.

Areas covered in this review: This review analyzes the therapeutic options of existing erythropoietic stimulating agents (ESAs) in patients with cancer, renal and heart failure anemia and shows the main features of new ESAs under development. Peer-reviewed scientific literature and abstracts published during the last 10 years were reviewed.

What the reader will gain: Randomized clinical trials carried out in patients with anemia associated with chronic renal disease or malignancies have consistently demonstrated that ESAs increase hemoglobin levels, reduce blood transfusion requirements and improve quality of life. However, in spite of the positive effects, treatment with ESAs, particularly in oncologic patients, is associated with an increased mortality and cardiovascular complications. These observations imply the absolute need for using ESAs in the context of currently available guidelines.

Take home message: A razionalization in the clinical use of ESAs according to current guidelines is required to improve the benefits derived from therapy with these drugs. New ESAs are under development and their introduction in therapy could provide a significant improvement in anemia management.     

Recent advances in glucose-lowering treatment to reduce diabetic kidney disease

Introduction: The epidemic of diabetes has now taken on epic proportions and therefore reducing the impact of diabetic complications represents one of the major global challenges in improving health and well-being worldwide. Preventing the development of diabetic kidney disease (DKD) is particularly important, as diabetes is one of the main risk factors for the development of chronic kidney disease, which in turn is strongly linked to development of cardiovascular disease, end-stage renal failure, hospitalization and premature death. Intensive glucose-lowering treatment has been shown to prevent and slow progression of DKD, yet to date, only certain populations have benefited from this intervention.

Areas covered: We review the evidence for existing glucose-lowering treatments in the prevention of DKD, and research into techniques to better target individuals who will benefit from these therapies.

Expert opinion: Diabetic patients with established kidney disease may benefit from glucose-lowering treatment, particularly if a safer side-effect profile of these treatments is achieved. Better understanding of glucose homeostasis and evaluation of compounds inhibiting its downstream effects are required in order to improve the outlook for individuals with DKD. An additional approach to improve the success rate of glucose-lowering treatment is to improve the selection of individuals who may benefit from treatment. A potential means to identify such subjects could involve the use of biomarkers.     

Advances in pharmacotherapy for hyperphosphatemia in renal disease

Introduction: Hyperphosphatemia in chronic kidney disease (CKD) is considered as an independent risk factor for surrogate clinical end points like vascular calcification (VC) and bone disease, or hard clinical outcomes like cardiovascular events. Various treatment options are available for phosphate removal or reduction. Calcium-based phosphate binders (CBB) with their possible positive calcium balance became culprits for progressive VC and increased mortality risk. Non-calcium-based binders (NCBB) treatment allowed a comparable control of hyperphosphatemia with a lower risk of hypercalcemia and a slower progression of VC. Recent data have shown a 22% risk reduction in all-cause mortality with NCBB compared to CBB treatment. The appropriate timing of phosphate binder initiation in CKD patients is still unclear. Recent reports in patients with CKD stages 3b-4 showed increased VC progression when actively treated compared to placebo and a positive calcium, but no negative phosphate balance.

Areas covered: This review discusses the advantages and disadvantages of the pharmacological options to treat hyperphosphatemia.

Expert opinion: The use of phosphate binders is essential in preventing morbidity and mortality in dialysis patients. The choice of phosphate binder takes into account CKD stage, the presence of other components of CKD-mineral and bone disorders, concomitant therapies and drug side-effect profile.     

Cardiovascular disease in patients with renal disease: the role of statins

ABSTRACT

Objectives: Atherosclerosis is common in patients with chronic kidney disease (CKD), and cardiovascular disease (CVD) represents a major cause of death. The National Kidney Foundation guidelines favour the use of statin therapy for treatment of dyslipidaemia in patients with CKD. Much evidence supports statin therapy for reducing CVD and improving outcomes in the general population, but there is less evidence in patients with CKD. Consequently, prevention of CVD in CKD is based primarily on extrapolation from non-CKD trials. Significantly, in trials specifically designed to investigate patients with CKD, evidence is emerging for improved cardiovascular outcomes with statin therapy. This review describes available data relating to cardiovascular outcomes and the role of statins in patients with CKD, including pre-dialysis, dialysis, and renal transplant patients.

Research design and methods: The PubMed database was searched (1998–present) to ensure comprehensive identification of publications (including randomised clinical trials) relevant to CKD patients, patterns of cardiovascular outcome in such patients and their relationship to lipid profile, and the role of statins for the prevention and treatment of cardiovascular complications.

Results: There are conflicting data on the relationship between dyslipidaemia and cardiovascular outcomes, with one major study of statin therapy (4D – Deutsche Diabetes Dialyse Studie) providing equivocal results. Further studies, including AURORA (A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events; NCT00240331) in patients receiving haemodialysis, and SHARP (Study of Heart And Renal Protection; NCT00125593) in patients with CKD including those on dialysis, should help to clarify the role of statin therapy in these populations.

Conclusions: More studies are needed to elucidate the role of statins in improving cardiovascular outcomes for CKD patients. It is anticipated that ongoing clinical trials geared towards the optimal prevention and treatment of CVD in patients with CKD will help guide clinicians in the management of CKD.     

Targeting chemokines in proteinuria-induced renal disease

Introduction: Proteinuria is a common finding in glomerular diseases that contributes to the progression of chronic kidney injury. Tubular cells reabsorb the excess of albumin and other plasma proteins from the tubular lumen, triggering several pathophysiologic responses, such as overexpression of fibrogenic mediators and inflammatory chemokines. Chemokines are implicated both in the recruitment of inflammatory infiltrate and in a number of physiological and pathological processes related to protein overload.

Areas covered: In recent years, the specific chemokines and their receptors and the intracellular signaling pathways involved in proteinuria-induced renal damage have been identified. This review provides an overview of the role of chemokines and their receptors in proteinuria-related renal disease and summarizes novel therapeutic approaches to restrain the progression of renal damage.

Expert opinion: Inhibition of chemokine-induced biological activities is a promising therapeutic strategy in proteinuric disorders. Neutralizing antibodies and small organic molecules targeting chemokines and chemokine receptors have been proven to prevent inflammation and renal damage in experimental models of protein overload. Some of these compounds are currently being tested in human clinical trials.     

Statins in patients with chronic kidney disease: why,who and when?

Importance of the field: Patients with end-stage renal disease are at high risk of developing cardiovascular disease, which is characterized by early onset and rapid progression of atherosclerosis. Some analyses of large clinical trials have revealed that statins might reduce all-cause mortality and cardiovascular (CV) events in patients with chronic kidney disease (CKD). Preliminary studies have also suggested that they can reduce contrast-induced nephropathy (CIN) and the rate of loss of kidney function. However, the results concerning the efficacy and safety of statin therapy in patients with CKD, especially in those on renal replacement therapy, are still controversial.

Areas covered in this review: This review contains data on the atherosclerotic risk in patients with CKD; the role of statins in the reduction of CV risk in patients with CKD; the role of CIN; the effects of statins on retarding the progression of CKD; and the efficacy of statin therapy in CKD, dialysis and renal-transplant patients. We searched using the electronic databases [MEDLINE (1966 – June 2010), EMBASE and SCOPUS (1965 – June 2010), DARE (1966 – June 2010)]. Additionally, abstracts from national and international cardiovascular meetings were studied. Where necessary, the relevant authors of these studies were contacted to obtain further data. The main data search terms were: ‘statin/statins’, ‘dialysis’, ‘dyslipidemia’, ‘hemodialysis’, ‘kidney disease’, ‘microalbuminuria’, ‘clinical trials’, and ‘renal impairment’.

What the reader will gain: Readers will be acquainted with results of clinical trials, including the most recent ones (e.g., PLANETE I and II), and will be able to draw their own conclusions concerning the use of statins in CKD patients on the basis of the results of the studies presented and to compare them with the authors' suggestions presented in this review.

Take home message: Although the results of trials are conflicting, it is suggested that the benefits of statin use outweigh the drawbacks in patients with early-stage CKD, when the benefits can be effectively predicted. However, available large randomized clinical trials suggest a lack of efficacy in patients on renal replacement therapy.     

The farnesoid X receptor: a potential target for expanding the therapeutic arsenal against kidney disease

Introduction: Farnesoid X receptor (FXR) is a nuclear bile acid (BA) receptor widely distributed among tissues, a major sensor of BA levels, primary suppressor of hepatic BA synthesis and secondary regulator of lipid metabolism and inflammation. Chronic kidney disease is a common, multifactorial condition with metabolic and inflammatory causes and implications. An array of natural and synthetic FXR agonists has been developed, but not yet studied clinically in kidney disease.

Areas covered: Following a summary of FXR’s physiological functions in the kidney, we discuss its effects in renal disease with emphasis on chronic and acute kidney disease, chemotherapy-induced nephrotoxicity, and renal neoplasia. Most information is derived from animal models; no relevant clinical study has been conducted to date.

Expert opinion: Most available preclinical data indicates a promising outlook for clinical research in this direction. We believe FXR agonism to be an auspicious approach to treating renal disease, considering that multifactorial diseases call for ideally wide-reaching therapies.     

New approaches to the treatment of nephropathy in diabetes

Introduction: In individuals with diabetes, the presence and severity of kidney disease adversely affects their well-being, significantly contributes to burden of morbidity and increases their risk of a premature death. The efficiency of current management strategies for the treatment of diabetic nephropathy, even in optimal combination, is partial, at best. There remains an unmet need for additional renoprotective interventions in patients with diabetes.

Areas covered: This review presents a comprehensive summary of some of the ‘new contenders’ for the treatment of diabetic nephropathy that have been tested or are being tested in randomised clinical trials in patients with diabetes with a predefined renal endpoint, but are not currently indicated for renoprotective therapy. Many of these drugs have been in clinical use for other indications, or initially developed for other purposes.

Expert opinion: Although substantial progress has been made towards understanding the pathogenesis of diabetic nephropathy, at present there are no new drugs that provide the solutions we want for our patients. Even when used in combination with standard medical care, current data indicate that renal complications are at best only modestly reduced, at the expense of additional pill burden and exposure to off-target effects. Given the ever-growing burden of diabetic kidney disease, there is a substantial opportunity for better and more targeted (‘smarter’) therapeutic interventions in this context.     

Which antihypertensive drugs are the most nephroprotective and why?

Importance of the field: Hypertension is a major independent risk factor for kidney disease and for faster renal function loss. Choice of antihypertensive strategies with highest nephroprotective effect is crucial to prevent or reverse progression to end stage renal disease (ESRD).

Areas covered in this review: The present review focuses on the role of hypertension in the progression of chronic kidney disease (CKD), the renoprotective effects of different antihypertensive therapies, and the blood pressure levels that should be targeted in different patient populations. To this end, the PubMed (1975 – 2010) database was searched for English-language articles, using the following keywords: hypertension, kidney disease, ACE-inhibitor, angiotensin receptor blocker, aldosterone antagonist, renin inhibitor, proteinuria.

What the reader will gain: A comprehensive review of data on the association between hypertension and progression of chronic nephropathies and on the antihypertensive treatments with highest nephroprotective effects.

Take home message: Blood pressure should be targeted to 140/90 mmHg or less in patients with hypertension but no renal injury and 130/80 mmHg or less in those with CKD. Amongst different antihypertensive drugs, renin angiotensin aldosterone system (RAAS) inhibitors have an incremental nephroprotective effect in proteinuric patients. Maximal RAAS inhibition should be aimed to optimize renoprotection in hypertensive patients with CKD and proteinuria.     

Drug-induced renal injury in neonates: challenges in clinical practice and perspectives in drug development

Introduction: Acute kidney injury (AKI) is frequently diagnosed in the neonatal population, especially in those admitted to intensive care units, and poses several challenges for clinicians mainly because of difficulties in timely identification of renal impairment and the need to administer drugs with potential nephrotoxicity. In this context, research on biomarkers is growing for their implication in the early detection of renal damage and their higher sensitivity in monitoring renal activity, but also as an important tool for drug development.

Areas covered: We described the tools currently used to detect renal damage in neonatal settings, their limits and applicability, as well as the role of drugs on renal toxicity occurrence. Subsequently, we discuss current knowledge on new biomarkers for the detection of kidney injury and drug-induced kidney injury in neonates, and the qualification programs developed by regulatory agencies for biomarkers intended as tools in drug development.

Expert opinion: Some molecules are emerging as potential biomarkers for early detection of AKI: promising data has demonstrated higher sensitivity and accuracy compared with tools currently used in the clinical setting. In addition, novel techniques (e.g. high power magnetic resonance imaging) to assess long-term consequences of AKI in neonates are in early steps of development.     

Emerging antiangiogenics for renal cancer

Introduction: Antiangiogenic therapy is considered to be the backbone of treatment strategy in metastatic renal cell carcinoma (mRCC). New, more focused, targeted drugs are emerging, while other targeted drugs oriented toward resistance or alternative mechanisms are under development.

Areas covered: Antiangiogenic agents include two types of agents: the monoclonal antibody, targeting vascular endothelial growth factor (VEGF), bevacizumab and the tyrosine kinase inhibitors (TKIs). Data regarding efficacy and safety of these agents are reported. Differences between the first generation of TKIs, sunitinib, sorafenib, and the new generation, pazopanib, axitinib and tivozanib are also detailed. Most of these agents have been approved in the treatment of kidney cancer in specific settings of the disease.

Expert opinion: The class of antiangiogenic drugs for treatment of mRCC is already relatively full. After ‘me-too' drugs, more targeted drugs against VEGFR have been developed but have to demonstrate a benefit in first-line treatment. Another option for the development is to combine a known drug with an antiangiogenic inhibition profile and at least one additional target involved in resistance to an antiangiogenic or in an alternative pathway. The cost of approach with targeted drugs, including antiangiogenics, has led to a tremendous increase in the cost of care in mRCC.     

ARBs and ACEis together in the treatment of hypertension and its complications? current practical recommendations

Importance of the field: Arterial hypertension is highly prevalent in the general population. Its contribution to the development and evolution of cardiovascular and renal disease is well recognized. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) have demonstrated favorable effects on cardiovascular and renal prognosis; however, some limitations have been described, for example angiotensin and aldosterone breakthrough.

Areas covered in this review: This article describes several therapeutical strategies that can be administered with an ACEi or ARB, such as the direct renin inhibitors or the aldosterone receptor antagonists.

What the reader will gain: The addition of an ACEi to an ARB or vice versa was initially considered as a way of obtaining a stronger suppression of the renin–angiotensin–aldosterone system (RAAS), but recent evidence has shown that the combination of the two classes of drugs does not seem to afford the expected increase in benefit.

Take home message: RAAS suppression with monotherapy is associated with beneficial cardiovascular effects, but has several limitations. Direct renin inhibitors and aldosterone receptor antagonists will increase the benefits of dual blockade. We need randomized trial data supporting reduction of cardiovascular events with an adequate safety profile using combination therapies.     

Hypertensive nephropathy: prevention and treatment recommendations

Importance of the field: A worldwide epidemic of chronic kidney disease (CKD) exists; hypertensive nephropathy is second only to diabetes as a leading cause of progressive CKD. Due to the increasing morbidity and mortality and escalating costs associated with end-stage renal disease (ESRD), novel therapeutic strategies are needed urgently to maximally reduce albuminuria, control blood pressure, and delay progression of hypertensive nephropathy to ESRD. In particular, rational use of renin–angiotensin–aldosterone (RAAS) blockers and achieving blood pressure targets are crucial to reduce cardiovascular and renal outcomes.

Areas covered in this review: We discuss the pathophysiology of hypertensive nephropathy and review current research evidence in support of i) albuminuria reduction as a key factor to maximally slow CKD progression, ii) the blood pressure (BP) goal of < 130 mmHg, and iii) strategies for prevention and optimal treatment of hypertensive nephropathy.

What will the reader gain: Insight into the complexity of treating patients with hypertensive nephropathy and the effective strategies required for reducing albuminuria, achieving BP goals and delaying progression of hypertensive nephropathy.

Take home message: Patients with hypertensive proteinuric nephropathy need aggressive BP-lowering with multiple agents that should include RAAS blockers, calcium antagonists and diuretics to maximally slow progression to ESRD.     

New targeted therapies for renal cell carcinoma

Introduction: The aim of treatment in metastatic renal cell carcinoma is palliation. In the last 5 years, multiple targeted agents have been developed which have resulted in prolongation of patients' lives, but complete responses remain rare. New therapies and approaches are required to further improve the prognosis for patients with this disease.

Areas covered: This review discusses the molecular targets in renal cell carcinoma relevant to the development of new treatments and describes the progress of novel therapies. The evidence is compiled from the PubMed database and proceedings of scientific meetings, searched up to December 2010.

Expert opinion: A multitude of experimental agents are in clinical development and offer theoretical advantages over those currently in use. It is hoped that these treatments will result in better long-term control of metastatic renal cell carcinoma, with improved side effect profiles, but curative treatment in this disease remains elusive until the mechanisms underlying response and resistance to therapy are elucidated. Progress in the field has been limited by inadequate tissue collection within clinical trials; current and future clinical trial design will incorporate a larger translational component in an attempt to establish predictive biomarkers.     

Emerging drugs for managing kidney disease in patients with diabetes

Introduction: The need for new approaches to manage the increasing numbers of patients with diabetes and their burden of complications is urgent. Of these, chronic kidney disease imposes some of the highest costs, both in dollars and in terms of human suffering. In individuals with diabetes, the presence and severity of kidney disease adversely affects their well-being, contributes to disease morbidity and increases their risk of a premature death.

Areas covered: To collect information for the strategies previously or currently under investigation for managing kidney disease in patients with diabetes, a literature search was performed through the search engines PubMed and ClinicalTrials.gov.

Expert opinion: Despite advancing knowledge on the pathogenesis of diabetic kidney disease, and promising effects in experimental models, at present there are no new drugs that come close to providing the solutions we desire for our patients. Even when used in combination with standard care, renal complications are at best only modestly reduced, at the considerable expense of additional pill burden and exposure to serious off-target effects. Some of the most exciting advances over the last decade, including thiazolidinediones, direct renin inhibitors, endothelin antagonists and most recently bardoxolone methyl have all fallen at this last hurdle. Better targeted (‘smarter') drugs appear to be the best hope for renoprotective therapy.     

Emerging drugs for treatment of anemia of chronic kidney disease

Introduction: Erythropoiesis-stimulating agents (ESAs) prevent transfusions among anemic patients with chronic kidney disease (CKD). Clinical trials, meta-analyses, and guidelines identify arterial and venous thromboembolism as well as myocardial event risks with the traditional ESAs, erythropoietin (EPO), and darbepoietin. Side effects of anemia treatment, considering frequency and dosage of treatment as well as targeted hemoglobin levels when utilizing ESAs, greatly impact overall well-being and the quality of life. There is a need for less frequent but equally effective ESAs in this setting.

Areas covered: The three generations of ESAs used in CKD-associated anemia are described. Cost effectiveness of the utilization of these therapies, in addition to emerging therapies, is also presented. The few clinical and controlled trials only highlight the need for clarity in molecular biology surrounding the components that control EPO levels and utilization.

Expert opinion: Anemia associated with CKD is an important area for development of newer therapies which are potentially safer and more convenient to administer.     

Finerenone: third-generation mineralocorticoid receptor antagonist for the treatment of heart failure and diabetic kidney disease

Introduction: The mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone reduce the risk of hospitalizations and mortality in patients with heart failure (HF) with reduced ejection fraction (HFrEF), and attenuate progression of diabetic kidney disease. However, their use is limited by the fear of inducing hyperkalemia, especially in patients with renal dysfunction. Finerenone is a novel nonsteroidal MRA, with higher selectivity toward the mineralocorticoid receptor (MR) compared to spironolactone and stronger MR-binding affinity than eplerenone.

Areas covered: This paper discusses the chemistry, pharmacokinetics, clinical efficacy and safety of finerenone.

Expert opinion: The selectivity and greater binding affinity of finerenone to the MR may reduce the risk of hyperkalemia and renal dysfunction and thereby overcome the reluctance to start and uptitrate MRAs in patients with HF and diabetic kidney disease. Studies conducted in patients with HFrEF and moderate chronic kidney disease and diabetic kidney disease, showed promising results. Phase III trials will have to show whether finerenone might become the third-generation MRA for the treatment of HF and diabetic kidney disease.     

Impaired renal function and atherosclerosis in a Pakistani cohort

ABSTRACT

Objective: To investigate the relationship of creatinine and calculated glomerular filtration rate (GFR) with coronary arterial disease (CAD) in Pakistani patients.

Subjects: Four hundred individuals with chest pain; 200 with angiographic disease matched with 200 without occlusive disease.

Design: A prospective case-control study.

Setting: A tertiary referral cardiology unit in Pakistan.

Results: Impaired renal function as estimated by calculated GFR was common in this population. Creatinine and glomerular filtration rate, as calculated by the Cockcroft–Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulae, were associated with CAD and atherosclerotic burden in Pakistani patients. Calculation of creatinine clearance, correcting for age, sex and body mass index, showed that clearance was 81 (17–257)?mL/min/1.73?m² in patients with CAD compared with 88 (23–167)?mL/min/1.73?m² in controls with a significant number of patients (18.5 vs. 6.5%; RR = 2.85; p < 0.001) showing significant renal impairment (< 60?mL/min/1.73?m²) by CG and more by the MDRD equation (26 vs. 9%; RR = 2.88; p < 0.001). The unadjusted odds ratios for CAD for a GFR < 60?mL/min/1.73?m² were 3.66 (1.87–7.16) and 3.29 (1.81–6.01), respectively and, after adjustment for diabetes, smoking, insulin resistance, inflammation and apolipoprotein A1, 1.04 (1.02–1.09) and 1.04 (1.02–1.09), respectively.

Conclusions: Impaired renal function is common in Pakistani patients with coronary arterial disease and is strongly associated with a risk of atherosclerosis independent of insulin resistance.