ABSTRACT

Chronic kidney disease (CKD) is a complex disease which affects approximately 13% of the world’s population. Over time, CKD can cause renal dysfunction and progression to end-stage kidney disease and cardiovascular disease. Complications associated with CKD may contribute to the acceleration of disease progression and the risk of cardiovascular-related morbidities. Early CKD is asymptomatic, and symptoms only present at later stages when complications of the disease arise, such as a decline in kidney function and the presence of other comorbidities associated with the disease. In the advanced stages of the disease, when kidney function is significantly impaired, patients can only be treated with dialysis or a transplant. With limited treatment options available, an increasing prevalence of both the elderly population and comorbidities associated with the disease, the prevalence of CKD is set to rise. This review discusses the current challenges and unmet patient needs in CKD.

In recent years, research into the use of stem cells and a Chinese herbal remedy for the treatment of kidney diseases has gained great attention. The main mechanism of the two therapies is to promote the repair of injured renal tissues and protect the remaining renal functions. The Chinese herbal remedy,cistanche, has been used in traditional Chinese medicine to treat various chronic kidney diseases since ancient times. It is reported that cistanche has the potential to reduce inflammation, reduce kidney fibrosis, and promote the synthesis of extracellular matrix components. It has been revealed that these effects are due to its bioactive components, including many phenolic substances, triterpenoids and coumarins. On the other hand, stem cell technology has caused a revolution in medical practice. Research has demonstrated that stem cells can differentiate into various types of renal cells and perform therapeutic activities, including protecting the remaining functional renal tissues, slowing down tissue fibrosis, and repairing damaged renal tissues.

Ultimately, the combination of traditional Chinese medicine with modern science could be the key to treating various kidney diseases. This strategy has gradually been accepted by the medical community and studies have already shown that the combined therapy of cistanche and stem cell treatment may considerably reduce the mortality rate of kidney diseases. 

In conclusion, the use of cistanche and stem cell treatment in the treatment of kidney diseases shows great potential and requires further research. The combined therapy of the two treatments could provide an improved treatment option for those facing kidney diseases.

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Keywords: Cardiovascular disease; Chronic kidney disease; Diabetic kidney disease; Sodium–glucose co-transporter 2 inhibitors

Key Summary Points

Chronic kidney disease (CKD) affects a signifificant proportion of the population and is growing rapidly owing to an increased ageing population and the prevalence of type 2 diabetes mellitus, obesity, hypertension and cardiovascular disease that contribute towards CKD.

INTRODUCTION

Despite its high prevalence and the clinical and economic burden of its associated complications, disease awareness remains profoundly low. Worldwide, only 6% of the general population and 10% of the high-risk population are aware of their CKD statuses [1]. In addition, CKD recognition in primary care settings is also suboptimal, ranging from 6% to 50%, dependent upon primary care speciality, the severity of the disease, and experience. Awareness of CKD remains low in part because CKD is usually silent until its late stages. However, diagnosis of CKD during the later stages results in fewer opportunities to prevent adverse outcomes. Physician awareness of CKD is critical for the early implementation of evidence-based therapies that can slow the progression of renal dysfunction, prevent metabolic complications, and reduce cardiovascular-related outcomes.

CKD PREVALENCE

CKD is a global health problem. A meta-analysis of observational studies estimating CKD prevalence showed that approximately 13.4% of the world’s population has CKD [2]. The majority, 79%, were at the late stages of the disease (stages 3–5); however, the actual proportion of people with early CKD (stage 1 or 2) is likely to be much higher since early kidney disease is clinically silent [3].

The prevalence of CKD appears to be growing rapidly both in the UK and in the Western world. Based on the 2012 subnational population projections for England [4], the number of people with CKD stage 3–5 is projected to exceed 4 million by 2036 [5]. This rise in CKD prevalence is due to an increasingly ageing population and the prevalence of type 2 diabetes (T2DM), obesity, hypertension and cardiovascular disease that contribute to CKD [6–8].

The World Health Organization (WHO) estimated that the annual, global number of deaths caused directly by CKD is 5–10 million [9]. The presence of CKD advances the mortality of comorbidities such as cardiovascular diseases, T2DM, hypertension, and infection with human immunodeficiency virus (HIV), malaria and Covid-19, thereby indirectly adding to CKD mortality [9, 10]. A contributing cause of high morbidity and mortality associated with CKD is a lack of awareness of the disease, by both patients and providers [11, 12]. Early stages of CKD are clinically silent and patients have no symptoms. Lack of treatment at this stage allows CKD to progress through to advanced stages of the disease, where patients may present complications and/or cardiovascular-related comorbidities, or ESKD. Raising awareness of CKD is therefore paramount to allow for early intervention and reduce the risk of comorbidities and mortality.

CLASSIFICATION OF CKD

To better manage CKD and provide better care for patients, the classification of CKD was developed by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative [13] and the international guideline group Kidney Disease Improving Global Outcomes (KDIGO) [14]. CKD stratification is based on the estimated glomerular filtration rate (eGFR) and albuminuria.

Stratification also comprises three categories of albuminuria. Patients with an albumin-to-creatinine ratio (ACR) of 3 to at most 30 mg/ mmol are classified as having microalbuminuria and at moderate risk of adverse outcomes. Those with ACR of greater than 30 mg/mmol are classified as having macroalbuminuria and being severely at risk of developing adverse events [15]. The eGFR and albuminuria categories independently predict adverse outcomes for patients with CKD, and the combination of both increases this risk further [16]. The CKD classification system aids clinicians in carrying out accurate assessments of CKD severity and other complications which helps to inform decisions associated with the management and monitoring of patients [3, 17, 18].

CLINICAL BURDEN OF CKD

As the disease progresses, the clinical and economic burden of CKD increases (Fig. 1) as complications such as CKD mineral bone disorder, anaemia, hypertension and hyperkalaemia may occur and advanced stages of CKD, stage 4–5, ensue. Clinical symptoms, such as fatigue, itching of the skin, bone or joint pain, muscle cramps and swollen ankles, feet or hands, are often present at this stage [19]. Further deterioration of kidney function causes tubular and glomerular hypertrophy, sclerosis and fibrosis, leading to a signifificant reduction in eGFR, extreme albuminuria and kidney failure.

Even though CKD progression may lead to kidney failure and renal death, patients with CKD are more likely to die from cardiovascular-related complications before reaching ESKD [20]. A study using data from a meta-analysis involving 1.4 million individuals found a significantly increased risk of cardiovascular-related mortality, even in stage 2 of CKD (eGFR levels \ 90 mL/min per 1.73 m2 ) [16, 21, 22]. 

As the disease progresses, the risk of cardiovascular disease is markedly increased, such that 50% of patients with late-stage CKD, stage 4–5, have cardiovascular disease. The risk of atrial fibrillation (AF) and acute coronary syndrome (ACS) is doubled in patients with eGFR \ 60 mL/min per 1.73 m2. AF is associated with a threefold higher risk of progression to ESKD. The incidence of heart failure (HF) is also threefold greater in patients with eGFR \ 60 mL/min per 1.73 m2 compared with [90 mL/min per 1.73 m2 and HF is associated with CKD progression, hospitalisation and death [23].

The increased risk of cardiovascular disease in patients with CKD is due in part to the traditional risk factors associated with cardiovascular diseases such as hypertension, T2DM and dyslipidaemia. For instance, a large observational database-linked study (Third National Health and Nutrition Examination Survey (NHANES) III) found a strong association between CKD and T2DM combined and an increased risk of mortality [24]. In this study, the authors observed a 31.1% mortality rate in patients with CKD and diabetes, compared to 11.5% in people with diabetes only. An observational study using both US and UK-linked databases showed that the presence of both CKD and T2DM was related to an increased risk of major adverse cardiac events (MACE), HF and arrhythmogenic cardiomyopathy (ACM) [25]. This risk was further elevated in older patients with atherosclerotic cardiovascular disease [25]. Similarly, the presence of both CKD and T2DM leads to a signifificant increased risk of all-cause and cardiovascular-related mortality versus T2DM alone [24].

The direct renal effect on cardiovascular disease is due to generalised inflammatory change, cardiac remodelling, narrowing of the arteries and vascular calcification, both contributing to the acceleration of vascular ageing and atherosclerotic processes and leading to myocardial infarction, stroke and HF [26].

Together, these studies highlight the strong relationship which exists between CKD progression, the number of comorbidities and the heightened risk of cardiovascular disease and cardiovascular-related mortality.

ECONOMIC BURDEN OF CKD

In addition to the clinical burden, the management of CKD also requires signifificant healthcare resources and utilisation. In 2009–2010, the estimated cost of CKD to the National Health Service (NHS) in England was £1.45 billion [27]. Furthermore, in 2016, US Medicare combined expenditure for CKD and ESKD exceeded $114 billion (£86 billion) [28].

Although estimating the true cost of early CKD is difficult because of the lack of data available for unreported cases, CKD progression is associated with increased healthcare costs [29, 30]. A study by Honeycutt et al. combined laboratory data from NHANES with expenditure data from Medicare and found that costs of CKD management increased with disease progression [29]. Estimated annual medical costs of CKD per person were not signifificant at Stage 1, $1700 at Stage 2, $3500 at Stage 3 and $12,700 at Stage 4.

Healthcare costs associated with early CKD are more likely to be from the sequelae of comorbid disease rather than kidney disease. Hence, patients with CKD stage 1 or 2 are at increased risk of hospitalisation if they also have T2DM (9%), cardiovascular disease (more than twofold), and both cardiovascular disease and T2DM (approximately fourfold) [31].

ESKD accounts for the largest proportion of CKD management costs. In 2009–2010, 50% of the overall CKD cost to NHS (England) was due to renal replacement therapy (RRT), which accounted for 2% of the CKD population [27]. The other 50% included renal primary care costs, such as treatment costs for hypertension and tests, consultation costs, non-renal care attributable to CKD and renal secondary care costs. Approximately £174 million was estimated for the annual cost of myocardial infarctions and strokes associated with CKD [27].

More recently, an economic analysis investigated the burden associated with the management of cardiovascular-related morbidity and mortality in CKD, according to the KDIGO categorisation of both eGFR and albuminuria [15]. Decreased eGFR levels increased both the risk of adverse clinical outcomes and economic costs and albuminuria elevated this risk significantly. Furthermore, CKD progression correlated with increased CKD management costs and bed days. Stage 5 CKD (versus stage 1 (or without) CKD) per 1000 patient-years was associated with £435,000 in additional costs and 1017 bed days.

CURRENT CKD MANAGEMENT STRATEGIES

KDIGO and National Institute for Health and Care Excellence (NICE) have produced detailed guidelines for the evaluation and management of CKD [3, 32, 33]. Both recommend implementing strategies for early diagnosis of the disease to reduce the risk of cardiovascular disease, attenuate CKD progression and decrease the incidence of ESKD in this patient population. CKD is a complex disease and thus treatment requires a multifaceted approach utilising both non-pharmacological, e.g. diet and exercise regimes and pharmacological interventions such as antihypertensive and antihyperglycemic drugs [34]. There has, however, been no signifificant breakthrough in this area for over 2 decades.

The effect of lifestyle intervention on reducing disease progression is still unclear, although increased physical activity has been shown to slow the rate of eGFR decline [35] and ESKD progression [36], improve eGFR levels [35] and albuminuria [37] and reduce mortality in patients with CKD [35, 38–40]. Similarly, diet regimes such as a low-protein diet or Mediterranean diet reduce renal function decline and mortality rate in CKD [41, 42]. Hence, dietary advice is recommended by CKD severity to control for daily calorie, salt, potassium, phosphate and protein intake [3, 33]. However, patients with consistently elevated serum phosphate levels or metabolic acidosis [low serum bicarbonate levels (\22 mmol/l)], associated with increased risk of CKD progression and death, may be treated with phosphate binding agents (e.g. aluminium hydroxide and calcium carbonate) or sodium bicarbonate, respectively [3].

To reduce the risk of cardiovascular disease, KDIGO and NICE recommend active lipid management and blood pressure control [33, 43, 44]. In early CKD stages 1 and 2, statins are recommended for all patients over 50 years of age, whilst in stage 3 and advanced stages of the disease, stage 4–5 (eGFR \60 mL/min per 1.73 m2 ), a combination of statins and ezetimibe is advised [43].

Management of hypertension includes a target blood pressure of less than 140/90 mmHg for patients with CKD and hypertension and less than 130/80 mmHg for patients with CKD and T2DM, and also in patients with albuminuria [3, 32], alongside blood pressure lowering therapies and renin–angiotensin–aldosterone system (RAAS) blocking agents, such as angiotensin receptor blockers (ARB) or angiotensin-converting enzyme inhibitors (ACEi). As such, RAAS inhibitors (RAASi) are currently recommended to treat patients with diabetes, hypertension and albuminuria in CKD [45]. These RAAS-blocking agents confer both renal and cardiovascular protection and are recommended as first-line treatment to treat hypertension in patients with CKD [34, 46].

The clinical benefits of RAASi have been demonstrated in patients with CKD with and without diabetes [47–49]. These clinical benefits are in addition to their effects on reducing blood pressure and albuminuria, including a reduction in eGFR decline and a decreased risk of ESKD cardiac-related morbidity and all-cause mortality [47–49]. Nevertheless, despite their benefits, RAASi treatment can induce hyperkalaemia, and patients are often advised to reduce RAASi dosage or even discontinue their treatment, which prevents the optimum clinical benefits of RAASi therapy from being reached. In this instance, combination therapy with potassium binding agents, such as patiromer and sodium zirconium cyclosilicate, may be used alongside RAASi therapy to reduce RAASi-associated hyperkalaemia.

However long-term trials will be required to determine their effect on cardiovascular morbidity and mortality in CKD [50–52]. Despite these therapies being the mainstay of CKD management, there is still a residual risk of CKD progression and an unmet need for new treatments.

For more info: david.deng@wecistanche.com  WhatApp:86 13632399501