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Chronic Kidney Disease Learning Zone

CKD

Read time: 90 mins
Last updated:26th Apr 2022
Published:22nd Oct 2021

Chronic kidney disease (CKD) is a complex debilitating condition affecting millions of people worldwide. Discover:

  • The unmet needs of CKD in our expert interview with Professor Hiddo Heerspink
  • The immense burden patients experience and risk factors for CKD in our expert interviews with Professor Vlado Perkovic and Dr George Bakris
  • The complex pathophysiology of CKD in our infographics

Unmet needs in chronic kidney disease

Professor Hiddo Heerspink, from the University Medical Centre Groningen in the Netherlands, highlights the unmet needs in chronic kidney disease, including early diagnosis. 

Why is early chronic kidney disease screening and diagnosis important?

All-stage CKD has a global prevalence of approximately 9.1% or around 697.5 million people (95% uncertainty interval [UI] 649.2 to 752.0 million)6.

Despite this high prevalence, various unmet needs exist for patients with CKD; many of whom are affected by multiple comorbidities7–9.

Numerous countries lack adequate resources to respond to the needs of patients with CKD and up to 30% of patients who begin dialysis do not receive appropriate follow-up10–15

Early referral to a nephrology specialist is essential for improving outcomes for CKD patients; however, CKD is largely asymptomatic until the later stages of the disease and identifying disease progression remains a challenge16.

While the introduction of the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines led to improvements in the early detection of different stages of CKD, CKD patients often receive late referrals to specialists that can potentially result in suboptimal care16. This could be due to a lack of awareness among health-care professionals and at-risk people, leading to inadequate screening and diagnostic testing17.

Early screening and diagnosis are necessary for risk stratification as well as providing earlier medical and lifestyle interventions with the aim of slowing disease progression and ultimately reducing morbidity and mortality16.

In Alport syndrome, a rare genetic disorder characterised by progressive kidney disease, time to renal replacement therapy was longer for patients who started renin–angiotensin system (RAS) inhibition early (Figure 1)18.

T1 CKD_Fig1.png

Figure 1. The impact of earlier treatment on time to dialysis (Adapted18). CKD, chronic kidney disease.

An important element of early medical intervention is the treatment of modifiable risk factors, such as diabetes and hypertension, and the use of preventative medicine and lifestyle modification19. Moreover, risk prediction models may help identify those at high-risk of having a reduced estimated glomerular filtration rate (eGFR) prior to CKD onset and allow for the individualisation of care16.

As diagnostic strategies and treatments are widely available for CKD, there is a key unmet need for appropriate guidance on early diagnosis that allows for appropriate management to prevent the progression of the disease16,20

The appropriate implementation of these targeted screening programmes that aim to provide timely identification, triage, and management of CKD are needed to help reduce disease progression to kidney failure, improve patient quality of life, and reduce healthcare costs16.

In an increasingly burdened healthcare system, the accurate stratification of risk also provides benefits in ensuring the appropriate allocation of resources based on need16. High income countries spend as much as 2–3% of their annual healthcare budget just on the treatment of kidney failure despite these patients representing only 0.03% of the total population17,21.

Why is it important to manage comorbid conditions in chronic kidney disease?

The aim of CKD treatment is to slow the progression of the disease and to prevent further CKD complication. This is largely accomplished by managing modifiable risk factors, such as diabetes, hypertension, cardiovascular disease (CVD), and the initiation of reno-protective medication16.

The difficulties that healthcare professionals face when providing this care were noted in a systematic review (N = 20) of primary care providers concerns regarding the management of CKD22.

The systematic review identified various barriers healthcare professionals face when identifying and managing CKD, including22:

  • The challenging nature of CKD
  • Difficulties in managing patients with multiple comorbidities
  • Dissatisfaction with the current CKD guidelines
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Burden of chronic kidney disease

Professor Vlado Perkovic, from the University of New South Wales in Australia, describes the complications and burden of chronic kidney disease.

Chronic kidney disease (CKD) is an immensely debilitating condition that is often diagnosed late in the disease cycle and can require a lifetime of dialysis or a kidney transplant at the later stages29. Around 700 million people have all-stage CKD; more than the number of people with diabetes, osteoarthritis, chronic obstructive pulmonary disease (COPD), asthma, or depressive disorders6.

What is the global burden of chronic kidney disease?

In 2017, CKD resulted in 1.2 million deaths6. This number is projected to increase to around two to four million by 20406.

Globally, CKD resulted in more deaths in 2017 than tuberculosis or HIV, and nearly as many deaths due to road accidents6

While prevalence estimates vary from approximately 2% to 44%, CKD prevalence is considered to be increasing in various countries around the world29. A useful proxy for CKD prevalence is the number of patients undergoing renal replacement therapies30. Figure 3 highlights the prevalence of renal replacement therapy, including haemodialysis, peritoneal dialysis and kidney transplantation per one million people by country30.

T1 CKD_Fig3.png

Figure 3. Global prevalence of renal replacement therapy (Adapted30).

The broad range in prevalence highlights the wide variety of unmet clinical, humanistic, and economic needs around the world29.

An analysis by the Kidney Early Evaluation Program (KEEP) found that the prevalence of CKD was highest in people aged ≥80 years and was as high as 44% in those ≥65 years31. Similar estimates were seen in the elderly of 23.4% to 44% in31,32:

  • Australia
  • Canada
  • China
  • Iceland
  • Italy
  • Japan
  • Mexico
  • Netherlands
  • Norway
  • Singapore
  • Spain
  • Switzerland
  • Thailand
  • USA

Adding to the complexity of the disease burden, notable increases in the prevalence estimates for modifiable risk factors that affect the initiation and/or progression of CKD have also been observed29.

What is the clinical burden of chronic kidney disease?

The symptom burden experienced by patients with CKD is high regardless of the stage of the disease with prevalent symptoms including33:

  • Fatigue
  • Feeling drowsy
  • Pain
  • Pruritus
  • Dry skin

In particular, people with more advanced stages of CKD can experience a particularly high symptom burden that impacts on their daily life33.

The Global Burden of Disease study has reported an increasing burden of CKD over the past 20 years, to which diabetes is the most significant contributor34,35. Mortality rates associated with CKD have also increased over the past 25 years; ranked originally at 25th in 1990, CKD became the 17th highest cause of mortality in 201535–37. CKD now contributes to 1.35% of the global burden of disability life years lost35–37.

CKD mortality is associated with decreases in estimated glomerular filtration rate (eGFR) and increases in albuminuria38, which is notably highest in patients on kidney replacement therapy; a 40–50% rate of 5-year survival of those on dialysis30.

Improved prospects are seen with patients receiving a kidney transplant, with 5-year survival rates of 86% and 93% for patients receiving deceased or living donor kidneys, respectively30.

Moreover, life expectancy is only one third of the age and sex­matched general population for patients on dialysis compared to patients who receive a kidney transplant with a life expectancy of 45–85% of the general population30.

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Risk factors for chronic kidney disease

Dr George Bakris provides insight into the risk factors for CKD.

The interlaced nature of CKD risk factors and comorbid illnesses can complicate the characterisation of CKD. Patients can have either risk factors that predispose them to developing CKD, risk factors that contribute to disease progression, or both29.

The ideal approach to CKD prevention therefore requires the identification of the incidence, prevalence, and distribution of these risk factors and appropriate mitigation strategies62.  

Who is most at risk of developing chronic kidney disease?

Professor Vlado Perkovic outlines the concordant comorbidities and key risk factors for chronic kidney disease (CKD).

Multiple risk factors and comorbid illnesses can lead to the progression of CKD and an increased mortality63.

A variety of patient characteristics are known to be non-modifiable risk factors for the development of CKD (Table 1)29. Age and gender are notable examples of a non-modifiable risk factor for CKD64. All stages of CKD are most common in people >65 years; however, the probability of developing end-stage renal disease (ESRD) is greater among people ≤65 years64.

While the prevalence of CKD is higher in women than in men, men are more likely to go on to develop end-stage renal failure64

As seen in table 1, a wide variety of known risk factors, emerging risk factors, and biomarkers have been reported65.

Table 1. Common chronic kidney disease risk categories and risk factors (Adapted29). Modifiable risk factors in bold. CKD, chronic kidney disease.

Risk category Risk factors
Susceptibility Older age, reduction in kidney mass, low birth weight, family history of CKD,
US racial or minority status
Initiation Diabetes, hypertension, autoimmune disease, systemic infections; urinary tract infections, stones, or obstruction; drug toxicity
Progression Higher proteinuria, hypertension, poor glycaemic control in diabetes, smoking, obesity, dyslipidaemia, cardiovascular disease, high dietary-protein intake, decreased nephron number
End-stage decline Lower dialysis dose, temporary vascular access for haemodialysis, anaemia, lower serum albumin, late referral to nephrologist, mineral and bone disorders,
metabolic acidosis

A number of these risk factors, including diabetes and cardiovascular disease, are modifiable and may be delayed with early and appropriate identification and treatment.

The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 guidelines, focusing on topics related to the prevention or management of individuals with kidney diseases, prioritise blood pressure, diabetes, and cardiovascular disease (CVD) as prominent risk factors in CKD23,25The lack of data from large cardiovascular outcome trials in the high-risk group of patients with CKD is a call to investigate new therapeutic options in dedicated trials in the CKD population; especially in people with advanced CKD26.

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Chronic kidney disease pathogenesis

Chronic kidney disease (CKD) describes a range of heterogeneous diseases that can compromise the structure and function of the kidneys. While the expression of CKD can be highly variable due to differing pathologies, severity, and progression rate, most forms of this burdensome disease are progressive and irreversible82.

What is chronic kidney disease?

Chronic kidney disease (CKD) can be described as the ongoing loss of renal function and excessive accumulation of extracellular matrix in the glomeruli and tubular interstitium over time83. Kidney dysfunction can manifest as hypertension, oedema, changes in urine output or quality, and delayed growth in children30.

Chronic kidney disease can be idiopathic or caused by a wide array of conditions, including82:

  • systemic diseases, such as diabetes and hypertension
  • autoimmune reactions and renal transplant rejection
  • drugs, toxins and metals
  • infections
  • mechanical damage
  • ischaemia
  • urinary tract obstruction
  • genetic alterations

What is the consequence of nephron loss in chronic kidney disease?

During gestation, a person will generate an average of 950,000 nephrons per kidney (ranging from 200,000 to >2.5 million)84. Following this period, new nephrons cannot be generated. Nephrons will instead increase in size to meet renal demands85.

T1 CKD_Fig5.png

Figure 5. Contributing factors to nephron loss throughout life (Adapted30). T2DM, type 2 diabetes mellitus.

While nephrons can adapt to temporary increases in filtration load by increasing glomerular filtration rate (GFR) without structural changes, using their renal reserve, various circumstances can lead to persistently increased GFR; promoting nephron hypertrophy and the eventual loss of nephrons (Figure 5)86.

Why does nephron hypertrophy occur in chronic kidney disease?

In response to the loss of nephrons, glomerular hypertension can induce hypertrophy; an increase in size of the remaining nephrons. This hypertrophy is triggered through a persistently increased GFR and filtration pressure across the glomerular filtration barrier resulting in glomerular hyperfiltration30.

The increase in nephron hypertrophy occurs through the activation of the renin–angiotensin system (RAS) in addition to increased transforming growth factor­α (TGF-α) and epithelial growth factor receptor (EGFR) expression. These activities are increased to reduce intraglomerular pressure while maintaining the glomerular filtration rate87,88. However, while this increased activity reduces glomerular hypertension due to the increased filtration surface, it also further promotes nephron hypertrophy and further nephron loss89.

Increased GFR and nephron hypertrophy can enable the appearance of an apparent ‘normal’ renal function even following a nephron loss of 50%30

While hyperfiltration can maintain a ‘normal’ renal function despite a loss of nephrons, increases in glomerular size through hyperfiltration can be damaging30.

Specialised epithelial cells that cover the outer surfaces of glomerular capillaries, known as podocytes, undergo hypertrophy to maintain the glomerular filtration barrier of the nephron. However, the increasing hypertrophy eventually hits a threshold where too much shear stress is placed on the podocytes30.

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