Chronic kidney disease (CKD) represents a leading cause of death in the United States. There is no cure for this disease, with current treatment strategies relying on blood pressure control through blockade of the renin-angiotensin system. Such approaches only delay the development of end-stage kidney disease and can be associated with serious side effects. Recent identification of several novel mechanisms contributing to CKD development - including vascular changes, loss of podocytes and renal epithelial cells, matrix deposition, inflammation and metabolic dysregulation - has revealed new potential therapeutic approaches for CKD. This Review assesses emerging strategies and agents for CKD treatment, highlighting the associated challenges in their clinical development.

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The next generation of therapeutics for chronic kidney disease

The autonomic nervous system, the renin-angiotensin-aldosterone system, and the natriuretic peptide system represent critical regulatory pathways in heart failure and as such have been the major targets of pharmacological development. The introduction and approval of angiotensin receptor neprilysin inhibitors (ARNi) have broadened the available drug treatments of patients with chronic heart failure with reduced ejection fraction. Neprilysin catalyses the degradation of a number of vasodilator peptides, including the natriuretic peptides, bradykinin, substance P, and adrenomedullin, as well as vasoconstrictor peptides, including endothelin-1 and angiotensin I and II. We review the multiple, potentially competing, substrates for neprilysin inhibition, and the resultant composite clinical effects of ARNi therapy. A mechanistic understanding of this novel therapeutic class may provide important insights into the expected on-target and off-target effects when this agent is more widely prescribed.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ejhf.799

Neprilysin inhibition in heart failure: mechanisms and substrates beyond modulating natriuretic peptides

The term uraemic cardiomyopathy refers to the cardiac abnormalities that are seen in patients with chronic kidney disease (CKD). Historically, this term was used to describe a severe cardiomyopathy that was associated with end-stage renal disease and characterized by severe functional abnormalities that could be reversed following renal transplantation. In a modern context, uraemic cardiomyopathy describes the clinical phenotype of cardiac disease that accompanies CKD and is perhaps best characterized as diastolic dysfunction seen in conjunction with left ventricular hypertrophy and fibrosis. A multitude of factors may contribute to the pathogenesis of uraemic cardiomyopathy, and current treatments only modestly improve outcomes. In this Review, we focus on evolving concepts regarding the roles of fibroblast growth factor 23 (FGF23), inflammation and systemic oxidant stress and their interactions with more established mechanisms such as pressure and volume overload resulting from hypertension and anaemia, respectively, activation of the renin–angiotensin and sympathetic nervous systems, activation of the transforming growth factor-β (TGFβ) pathway, abnormal mineral metabolism and increased levels of endogenous cardiotonic steroids. Uraemic cardiomyopathy is the major phenotype of fatal cardiac disease in patients with end-stage renal disease. This Review focuses on the molecular mechanisms of uraemic cardiomyopathy, crosstalk between these mechanisms and implications for therapy

Evolving concepts in the pathogenesis of uraemic cardiomyopathy.

The development and progression of cardiovascular disease (CVD) and renal disorders are very closely related. In patients with chronic kidney disease (CKD), therapies proven to protect the cardiovascular and renal systems simultaneously are generally used only at low doses or not at all. In particular, patients with CKD who receive angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, or mineralocorticoid-receptor antagonists (MRAs) often do not experience complete blockade of the renin-angiotensin-aldosterone system, primarily owing to the risk of hyperkalaemia. In this Review, we provide an overview of the available treatments required for adequate cardiorenal protection in patients with CKD. Drugs such as β-blockers that interfere with renin secretion will be discussed, in addition to agents that can prevent hyperkalaemia, such as potassium binders and nonsteroidal MRAs. Furthermore, the current literature on the role of statins, in addition to new compounds and dosing recommendations for the treatment of patients with CKD will also be reviewed. Further studies with these new compounds and doses are needed to ascertain whether these approaches can improve the long-term cardiovascular and renal prognosis in patients with CKD.

Global cardiovascular protection in chronic kidney disease.

H2S dependent and independent anti-inflammatory activity of zofenoprilat in cells of the vascular wall.

Introduction: Cardiovascular disease (CVD) is the leading cause of death worldwide. Blockade of this system is commonly used in the treatment of cardiovascular (CV) and renal disease.Areas covered: Data from multiple clinical trials have provided good evidence about the benefit of blocking the system as a therapeutic target to reduce CV and renal events. We have reviewed all the tested combinations of different drugs counteracting the effects of the renin–angiotensin–aldosterone system.Expert opinion: Monotherapy with an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II receptor blocker (ARB) remains valid in all the guidelines, whereas their dual combination has been discarded due to the absence of proven benefits in high CV risk patients and in patients with chronic kidney disease (CKD). The combination of the standard therapy with an ACEi or an ARB with a mineralocorticoid receptor blocker is a valid option, but has the inconvenience of frequent hyperkalemia in patients with CKD. Simi...

An update of the blockade of the renin angiotensin aldosterone system in clinical practice

Since the association of microalbuminuria (MAU) with cardiovascular (CV) risk was described, a huge number of reports have emerged. MAU is a specific integrated marker of CV risk and targets organ damage in patients with hypertension, chronic kidney disease (CKD), and diabetes and its recognition is important for identifying patients at a high or very high global CV risk. The gold standard for diagnosis is albumin measured in 24-hour urine collection (normal values of less than 30 mg/day, MAU of 30 to 300 mg/day, macroalbuminuria of more than 300 mg/day) or, more practically, the determination of urinary albumin-to-creatinine ratio in a urine morning sample (30 to 300 mg/g). MAU screening is mandatory in individuals at risk of developing or presenting elevated global CV risk. Evidence has shown that intensive treatment could turn MAU into normoalbuminuria. Intensive treatment with the administration of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, in combination with other anti-hypertensive drugs and drugs covering other aspects of CV risk, such as mineralocorticoid receptor antagonists, new anti-diabetic drugs, and statins, can diminish the risk accompanying albuminuria in hypertensive patients with or without CKD and diabetes.

Microalbuminuria and cardiorenal risk: old and new evidence in different populations.

Arterial hypertension and chronic kidney disease (CKD) are intimately related. The control of blood pressure (BP) levels is strongly recommended in patients with CKD in order to protect the kidney against the accompanying elevation in global cardiovascular (CV) risk. Actually, the goal BP in patients with CKD involves attaining values <140/90 mmHg except if albuminuria is present. In this case, it is often recommended to attain values <130/80 mmHg, although some guidelines still recommend <140/90 mmHg. Strict BP control to values of systolic BP around 120 mmHg was recently shown to be safe in CKD according to data from the SPRINT trial, albeit more data confirming this benefit are required. Usually, combination therapy initiated with an angiotensin receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACEi) and commonly followed by the addition of a calcium channel blocker and a diuretic is needed. Further studies are required as well as new drugs in particular after the positive data obtained from new oral anti-diabetic drugs.

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Diego F Marquez

Papers

An update of the blockade of the renin angiotensin aldosterone system in clinical practice

Microalbuminuria and cardiorenal risk: old and new evidence in different populations.

The impact of antihypertensives on kidney disease.