Around 850 million people currently are affected by different types of kidney disorders.
1
Up to 1 in 10 adults worldwide has chronic kidney disease (CKD), which is invariably
irreversible and mostly progressive. The global burden of CKD is increasing, and CKD
is projected to become the fifth most common cause of years of life lost globally
by 2040.
2
If CKD remains uncontrolled and if the affected person survives the ravages of cardiovascular
and other complications of the disease, CKD progresses to end-stage kidney disease,
where life cannot be sustained without dialysis therapy or kidney transplantation.
Hence, CKD is a major cause of catastrophic health expenditure.
3
The costs of dialysis and transplantation consume 2%–3% of the annual health care
budget in high-income countries, spent on less than 0.03% of the total population
of these countries.
4
Importantly, however, kidney disease can be prevented and progression to end-stage
kidney disease can be delayed with appropriate access to basic diagnostics and early
treatment including lifestyle modifications and nutritional interventions.4, 5, 6,
7, 8 Despite this access to effective and sustainable health care provision programs,
kidney care remains highly inequitable across the world. Indeed, of parallel importance
is the ongoing health inequity in CKD care including inequity of health care access
particularly among some of the indigenous populations in certain regions of the world,
and this may have a bearing on the preexisting and emerging health gaps between low-middle-income,
middle-income, and high-income countries. Kidney disease is crucially missing from
the international agenda for global health. It is notably absent from the impact indicators
for the Sustainable Development Goal Goal 3, Target 3.4, “By 2030, reduce by one third
premature mortality from noncommunicable diseases (NCDs) through prevention and treatment
and promote mental health and well-being,” and the latest iteration of the United
Nations Political Declaration on NCDs.
9
CKD is a major risk factor for heart disease and cardiac death, as well as for infections
such as tuberculosis, and is a major complication of other preventable and treatable
conditions including diabetes, hypertension, HIV, and hepatitis.4, 5, 6, 7 Moreover,
consumer engagement and self-help management are crucial to improving kidney health.
To that end, the World Kidney Day steering committee suggests adopting strategies
that focus on preventative interventions.
Definition and Classification of CKD Prevention
According to the expert definitions including the Center for Disease Control and Prevention,
10
the term “prevention” refers to activities that are typically categorized by the following
3 definitions: (i) primary prevention implies intervening before health effects occur
in an effort to prevent the onset of illness or injury before the disease process
begins, (ii) secondary prevention suggests preventive measures that lead to early
diagnosis and prompt treatment of a disease to prevent more severe problems developing
and includes screening to identify diseases in the earliest stages, and (iii) tertiary
prevention indicates managing disease after it is well established in order to control
disease progression and the emergence of more severe complications, which is often
by means of targeted measures such as pharmacotherapy, rehabilitation, and screening
for and management of complications. These definitions have important bearing in the
prevention and management of CKD, and accurate identification of risk factors that
cause CKD or lead to faster progression to renal failure, as shown in Figure 1, is
relevant in health policy decisions and health education and awareness related to
CKD.
11
Figure 1
Overview of the preventive measures in chronic kidney disease (CKD) to highlight the
similarities and distinctions pertaining to primary, secondary, and tertiary preventive
measures and their intended goals. Abbreviations: AKI, acute kidney injury; BP, blood
pressure; GFR, glomerular filtration rate; RAASi, renin-angiotensin-aldosterone system
inhibitors; SGLT2i, sodium-glucose cotransporter-2 inhibitors.
Primary Prevention of CKD
Measures to achieve effective primary prevention should focus on the 2 leading risk
factors for CKD including diabetes mellitus and hypertension. Other CKD risk factors
include polycystic kidneys or other congenital or acquired structural anomalies of
the kidney and urinary tracts, primary glomerulonephritis, exposure to nephrotoxic
substances or medications (such as nonsteroidal anti-inflammatory drugs), having 1
single kidney, for example, solitary kidney after cancer nephrectomy, high dietary
salt intake, inadequate hydration with recurrent volume depletion, heat stress, exposure
to pesticides and heavy metals (as has been speculated as the main cause of Mesoamerican
nephropathy), and possibly high protein intake in those at higher risk of CKD.
8
Among nonmodifiable risk factors are advancing age and genetic factors such as apolipoprotein
1 (APOL1) gene that is mostly encountered in those with sub-Saharan African ethnicity,
especially among African Americans. Table 1 shows some of the risk factors of CKD.
Table 1
Risk factors for de novo CKD as well as preexisting CKD progression
Risk Factor
Contribution to de novo CKD
Contribution to CKD Progression
Nonmodifiable risk factors
Age
Seen with advancing age, especially in the setting of comorbid conditions
Some suggests that older patients with CKD may have slower progression
Race, genetics and other hereditary factors:
•
APOL1 gene
•
Hereditary nephritis (Alport’s)
Common among those with African American ancestors
Acute GN
•
Postinfectious GN
•
Rapidly progressive GN
<10%
Recurrent GN or exacerbation of proteinuria
Polycystic kidney disorders
<10%, family history of cystic kidney disorders
Autoimmune disorders
•
Lupus erythematosus
•
Other connective tissue disorders (Sjogren’s syndrome)
Congenital anomalies of the kidney and urinary tract
Mostly in children and young adults
Malignancy
•
Myeloma, light chain deposition disease, AL amyloidosis, and other plasma cell dyscrasias
•
Lymphoma
Modifiable risk factors
Glycemic control in diabetes mellitus
Approximately 50% of all CKD
Blood pressure control
Approximately 25% of all CKD
Obesity
10%–20%
Smoking
Via both nonhemodynamic and hemodynamic pathways
AKI
•
ATN
•
Acute interstitial nephritis
Repeated AKI bouts can cause CKD
Repeated AKI bouts can accelerate CKD progression
Pharmacologic
•
Medications causing interstitial nephritides (NSAIDs, chemotherapy, PPIs, etc.), ATN
(aminoglycosides), renal ischemia and fibrosis (calcineurin inhibitors), crystal nephropathy
(phosphate-based bowel preparations, trimethoprim-sulfamethoxazole)
•
Herbs and herbal medications
•
Contrast media
Variable, e.g., in Taiwan, Chinese herb nephropathy (due to aristolochic acid) may
be an important contributor
Environmental
•
Heavy metal exposure
Rare
Acquired or congenital solitary kidney
•
Cancer, donor or traumatic nephrectomy
•
Congenital solitary kidney, unilateral atrophic kidney
Acquired urinary tract disorders and obstructive nephropathy
Benign prostatic hypertrophy and prostate cancer in menGynecologic cancers in womenNephrolithiasis
Inadequate fluid intake
•
Mesoamerican nephropathy
•
Others
Unknown risk, but high prevalence is suspected in Central America
Whereas in earlier CKD stages adequate hydration is important to avoid prerenal AKI
bouts, higher fluid intake in more advanced CKD may increase the risk of hyponatremia
High protein intake
Unknown risk, recent data suggest higher CKD risk or faster CKD progression with high-protein
diet, in particular, from animal sources
Higher protein intake can accelerate the rate of CKD progression
Cardiovascular risk factors and diseases (cardiorenal)
•
Heart failure
•
Atherosclerosis
Ischemic nephropathy
Liver disease (hepatorenal)
NASH cirrhosis, viral hepatitis
Endocrine derangements
•
Testosterone and other androgen supplements
•
Hypothyroidism
Note: Many of these risk factors contribute to both de novo CKD and its faster progression
and hence are relevant to both primary and secondary prevention.
Abbreviations: AKI, acute kidney injury; AL, amyloid light-chain; ATN, acute tubular
necrosis; CKD, chronic kidney disease; GN, glomerulonephritis; NASH, nonalcoholic
steatohepatitis; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton pump inhibitor.
Among measures to prevent emergence of de novo CKD are screening efforts to identify
and manage persons at high risk of CKD, especially those with diabetes mellitus and
hypertension. Hence, targeting primordial risk factors of these 2 conditions including
metabolic syndrome and overnutrition is relevant to primary CKD prevention as is correcting
obesity.
12
Promoting healthier lifestyle includes physical activity and healthier diet. The latter
should be based on more plant-based foods with less meat, less sodium intake, more
complex carbohydrates with higher fiber intake, and less saturated fat. In those with
hypertension and diabetes, optimizing blood pressure and glycemic control has shown
to be effective in preventing diabetic and hypertensive nephropathies. Persons with
solitary kidney should avoid high protein intake above 1 gram per kilogram body weight
per day.
13
,
14
Obesity should be avoided, and weight reduction strategies should be considered.
12
An emerging challenge relevant to these primary preventive efforts is the rise of
a new form of CKD that is of “unknown etiology” and is, hence, referred to as “CKDu,”
which has resulted in substantial morbidity and mortality including in certain regions
of the world with heavy agricultural occupation such as Nicaragua and Sri Lanka.
15
There are currently concerted efforts by the international nephrology community to
identify the potential modifiable and nonmodifiable risk factors of CKDu, and to develop
potential interventions to mitigate the burden of this emerging disease state.
Secondary Prevention in CKD
Evidence suggests that among those with CKD, the vast majority have early stage of
the disease, that is, CKD stages 1 and 2 with microalbuminuria (30–300 mg/d) or CKD
stage 3B (estimated glomerular filtration rate between 45 and 60 ml/min per 1.73 m2).
14
For these earlier stages of CKD, the main goal of kidney health education and clinical
interventions for “secondary prevention” is how to slow disease progression. Uncontrolled
or poorly controlled hypertension is one of the most established risk factors for
faster CKD progression.
The cornerstone of the pharmacotherapy in secondary prevention is the renin-angiotensin-aldosterone
system inhibitors. Low protein diet appears to have a synergistic effect on renin-angiotensin-aldosterone
system inhibitor therapy.
16
Recent data suggest that a new class of antidiabetic medications known as sodium-glucose
cotransporter-2 inhibitors can slow CKD progression, but this effect may not be related
to glycemic modulation of the medication.
17
Whereas acute kidney injury may or may not cause de novo CKD, acute kidney injury
events that are superimposed on preexisting CKD may accelerate disease progression.
18
A relatively recent case of successful secondary prevention that highlights the significance
of implementing preventive strategies in CKD is the use of a vasopressin V(2)-receptor
antagonists in adult polycystic kidney disease.
19
Tertiary Prevention in CKD
In patients with advanced CKD, management of uremia and related comorbid conditions
such as anemia, mineral and bone disorders, and cardiovascular disease is of high
priority, so that these patients can continue to achieve highest longevity. Whereas
many of these patients will eventually receive renal replacement therapy in the form
of dialysis therapy or kidney transplantation, a new trend is emerging to maintain
them longer without dialysis by implementing conservative management of CKD.
Approaches to Identification of Chronic Kidney Diseases
The lack of awareness of CKD around the world is one of the reasons for late presentation
of CKD in both developed and developing economies.20, 21, 22 The overall CKD awareness
among general population and even high cardiovascular risk groups across 12 low-income
and middle-income countries was less than 10%.
22
Given its asymptomatic nature, screening of CKD plays an important role in early detection.
Consensus and Positional Statements have been published by International Society of
Nephrology,
23
National kidney Foundation,
24
Kidney Disease Improving Global Outcomes,
25
National Institute of Clinical Excellence (NICE) Guidelines,
26
and Asian Forum for CKD Initiatives.
27
Most guidelines do not recommend population-based screening because of the potential
risk of overdiagnoses and the potential harms such as psychological burden of being
labeled with CKD. There is also a lack of trial-based evidence to support routine
screening and monitoring of CKD.
28
Currently, most will promote a targeted screening approach to early detection of CKD.
Some of the major groups at risk for targeted screening includes patients with diabetes
and hypertension, those with family history of CKD, individuals receiving potentially
nephrotoxic drugs or herbal medicines, patients with past history of acute kidney
injury, and individuals older than 65 years.
27
,
29
Early detection of CKD could be facilitated among high-risk groups using a urine test
for the detection of proteinuria and a blood test to estimate the glomerular filtration
rate.
24
,
27
Given that low- to middle-income countries may be ill-equipped to deal with the devastating
consequences of CKD, particularly the late stages of the disease, effective preventative
measures to avoid CKD or to slow progression are of immense importance in these regions.
There are suggestions that screening should primarily include high-risk individuals,
but also extend to those with suboptimal levels of risk, for example, prediabetes
and prehypertension.
30
Cost-effectiveness of Early Detection Programs
Secondary prevention of CKD relays on timely identification of early signs of CKD
including hyperfiltration, microalbuminuria, microscopic hematuria, sporadic foamy
urine, and minor elevations in serum creatinine level or other kidney filtration markers.
Prior economic evaluations have indicated routine screening using estimated glomerular
filtration rate, and urine tests are not cost-effective without risk stratification
in the general population. The incremental cost-effectiveness ratios were consistently
above $50,000 per life years saved or per quality-adjusted life years unless screening
is targeted to higher risk populations, such as those with diabetes mellitus and hypertension
and those with rapid CKD progression where routine use angiotensin pathway modulators
could be used for renal and vascular risk reduction. To this end, it is important
to note some of the key factors that may drive the incremental cost-effectiveness
of CKD preventative measures in different regions and health care jurisdictions.
Integration of CKD Prevention into National NCD Programs
Given the close links between CKD and other NCDs, it is critical that CKD advocacy
efforts be aligned with existing initiatives concerning diabetes, hypertension, and
cardiovascular disease, particularly in the low- and middle-income countries. Some
countries and regions have successfully introduced CKD prevention strategies as part
of their NCD management programs. As an example, in 2003, a kidney health promotion
program was introduced in Taiwan, with its key components including a ban on herbs
containing aristolochic acid, public-awareness campaigns, patient education, funding
for CKD research, and the setting up of teams to provide integrated care.
31
In Cuba, the Ministry of Public Health has implemented a national program for the
prevention of CKD. It is hoped that the integration of CKD prevention into the NCD
program may result in the reduction of renal and cardiovascular risks in the general
population. Over time there have been increasingly higher incidences of risk factors
for CKD including higher rates of diabetes mellitus and hypertension, and parallel
to that more blood pressure medications including renoprotective agents have been
prescribed including angiotensin-pathway modulators.
32
,
33
Recently, the US Department of Health and Human Services has introduced an ambitious
program to reduce the number of Americans developing end-stage kidney disease by 25%
by 2030. The program, known as the Advancing American Kidney Health Initiative, has
set goals with metrics to measure its success; among them is to put more efforts to
prevent, detect, and slow the progression of kidney disease, in part by addressing
traditional risk factors such as diabetes and hypertension.
34
Ongoing programs, such as the Special Diabetes Program for Indians, represent an important
part of this approach by providing team-based care and care management. Since its
implementation, the incidence of diabetes-related kidney failure among American Native
populations decreased by over 40% between 2000 and 2015.
35
The Interdisciplinary Prevention Approach
Since 1994, a National Institutes of Health consensus advocated for early medical
intervention in predialysis patients. Owing to the complexity of care of CKD, it was
recommended that patients should be referred to a multidisciplinary team consisting
of nephrologist, dietitian, nurse, social worker, and health psychologist, with the
aim to reduce predialysis and dialysis morbidity and mortality.
36
In Mexico, a nurse-led, protocol-driven, multidisciplinary program reported better
preservation in estimated glomerular filtration rate and a trend in the improvement
of quality of care of patients with CKD similar to those reported by other multidisciplinary
clinic programs in the developed world.
37
Future models should address region-specific causes of CKD, increase the quality of
diagnostic capabilities, establish referral pathways, and provide better assessments
of clinical effectiveness and cost-effectiveness.
38
Online Educational Programs for CKD Prevention and Treatment
The e-learning has also become an increasingly popular approach to medical education.
Online learning programs for NCD prevention and treatment, including CKD, have been
successfully implemented in Mexico. By 2015, over 5000 health professionals (including
non-nephrologists) had been trained using an electronic health education platform.
39
It is equally important to promote “Prevention” with education programs for those
at risk of kidney disease and with the general population at large. Education is key
to engaging patients with kidney disease. It is the path to self-management and patient-centered
care. Narva et al.
40
found that patient education is associated with better patient outcomes. Obstacles
include the complex nature of kidney disease information, low baseline awareness,
limited health literacy, limited availability of CKD information, and lack of readiness
to learn. Schatell et al.
41
found that Web-based kidney education is helpful in supporting patient self-management.
Reputable health care organizations should facilitate users to have easier access
to health information on their websites (Item S1). Engagements of professional society,
patient groups, charitable, and philanthropic organizations promote community partnership
and patient empowerment on prevention.
Renewed Focus on Prevention and Awareness Raising and Education
Given the pressing urgency pertaining to the need for increasing education and awareness
of the importance of the preventive measures, we suggest the following goals to redirect
the focus on plans and actions:
(i)
Empowerment through health literacy in order to develop and support national campaigns
that bring public awareness to prevention of kidney disease.
(ii)
Population-based approaches to manage key known risks for kidney disease, such as
blood pressure control and effective management of obesity and diabetes.
(iii)
Implementation of the World Health Organization “Best Buys” approach including screening
of at-risk populations for CKD, universal access to essential diagnostics of early
CKD, availability of affordable basic technologies, and essential medicines and task
shifting from doctors to front-line health care workers to more effectively target
progression of CKD and other secondary preventative approaches.
“Kidney Health for Everyone, Everywhere” with emphasis on prevention and early detection
should be a policy imperative that can be successfully achieved if policy makers,
nephrologists, health care professionals and the general public place prevention and
primary care for kidney disease within the context of their Universal Health Coverage
programs.