Diagnosing CKD

Is chronic kidney disease underdiagnosed?

As CKD is a progressive disease that leads to a gradual loss of kidney function, people living with CKD can be unaware of the disease until it advances to later stages (Figure 1)². Indeed, up to 82% of people with CKD stage 3 (moderately decreased kidney function) have not received a diagnosis of CKD (Figure 1)³.

Figure 1. Proportion of patients with diagnosed and undiagnosed chronic kidney disease across disease stages in adult patients with type 2 diabetes (Adapted⁴). ^aPercentage of study population at each indicated CKD stage. CKD, chronic kidney disease.

Approximately half of people with CKD remain undiagnosed by stage 4–5 when CKD symptoms begin to develop³

Late diagnosis drives up annual healthcare costs from nearly double at stage 2–3, to around four-fold with progression to stage 4–5⁵. This is especially detrimental to people with a lower socioeconomic status who have limited access to appropriate treatment and consequently face poorer outcomes¹. The adverse consequences of later treatment, such as the loss of employment due to the need for dialysis, also discourages patients from seeking treatment. This inevitably leads to preventable morbidity and death⁶.

Why is chronic kidney disease underdiagnosed?

Despite clear rationales and guidelines for early detection, risk stratification, treatment of CKD, and timely management with evidence-based strategies have not been universally adopted¹.

Just over half of governments around the world recognise kidney failure (58%) and CKD (51%) as health priorities, and even fewer (43%) have national strategies for improving CKD care⁷

Even in countries where guidelines and interventions have been established, various obstructions can reduce the effective implementation of these strategies, including^8–10:

• Inadequate delivery of kidney care
• Poor understanding of CKD and its risk factors among primary care physicians
• Low patient awareness
• Absence of locally appropriate or adapted guidelines

Moreover, unlike other chronic diseases, there is no consensus on early identification and intervention for CKD despite the potential beneficial impact on treatment outcomes¹. This could be due to low policymaker awareness with few countries having policies or public programmes aimed at CKD prevention and control¹¹.

How does early diagnosis impact chronic kidney disease treatment?

The early identification and management of patients can reverse, delay, or prevent progression of CKD and is a central aspect of international initiatives in kidney disease. The goals of early diagnosis and management include¹²:

1. Provision of specific therapy based on diagnosis
2. Slowing/arresting CKD progression
3. Evaluation and management of comorbid conditions
4. Prevention and management of cardiovascular disease
5. Identification, prevention, and management of CKD-specific complications (such as malnutrition, anaemia, bone disease, acidosis)
6. Planning and preparation for renal replacement therapy (such as the choice of modality, access-placement and care, pre-emptive transplantation)
7. Psychosocial support and provision of conservative care and palliative care options where required

Early diagnosis is also needed for determining appropriate blood pressure targets and management. Notably, the presence of albuminuria can impact the choice of antihypertensive agent as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) are first-line agents for patients with albuminuria¹.

Accurate diagnosis and staging of CKD are essential for the early and effective use of treatments¹

An accurate estimated glomerular filtration rate (eGFR) is also crucial for determining safe and effective doses for patients with CKD¹. For instance, gabapentinoids, a prevalent drug class in the treatment of CKD¹³, increase the risks of side-effects due to drug accumulation¹.

Similarly, the risks of encephalopathy associated with the use of baclofen increase with higher stages of CKD¹⁴. Diagnosis and appropriate staging also impact the need for nephrotoxin avoidance, such as the minimisation of non-steroidal anti-inflammatory drugs (NSAIDs)¹.

Why is early chronic kidney disease screening important?

CKD currently meets the World Health Organisation (WHO) principles of screening for disease (Table 1) as early CKD is asymptomatic, accurate and low-cost diagnostic tests are available, and effective treatments can be initiated in the early stages of the disease¹.

Table 1. Chronic kidney disease screening meets the WHO’s principles of screening for disease (Adapted¹). CKD, chronic kidney disease.

The development of a CKD screening programme is also considered to be essential for social equality. Currently, socially disadvantaged and vulnerable populations experience a disproportionate CKD burden, are less likely to receive effective treatments, and may face a greater risk of complications¹.

However, while a population-wide CKD screening programme may be a more complete approach to reducing the global burden of CKD, its implementation may have potential challenges¹:

• Higher costs
• Greater barriers than targeted high-risk CKD screening
• Lower identification of CKD cases attributable to less common or unrecognised risk factors

Narrowing focus towards the common and important CKD risk factors will prioritise the identification of high risk cases for CKD progression and may also beneficially impact expenditures by lowering the cost per case identified¹. Various characteristics that elevate the possibility of having CKD have already been identified, including^2,15:

• Age
• Race/ethnicity
• Systemic diseases (for example, systemic lupus erythematosus, HIV infection)
• Family history of kidney disease
• Genetic risk factors
• Poor access to health care or low socioeconomic status
• High-risk occupations and environmental exposures
• Prior acute kidney injury
• Preeclampsia
• Exposure to nephrotoxins
• Obesity

CKD screening for people with these risk factors should be guided by individualised clinical assessments and joint decision making¹.

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Professor Vlado Perkovic and Dr George Bakris discuss the recommendations for managing comorbid conditions in patients with or at risk of chronic kidney disease (CKD).

As hypertension, diabetes, or cardiovascular disease are well defined risk factors for CKD, it is recommended that people with these conditions be screened for CKD. Moreover, implementation of early CKD detection should first be implemented in people with established CKD risk factors, given the higher level of prevalence associated with these individuals¹.

Why is it important to diagnose diabetes and hypertension early?

At the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) conference, the consensus was that CKD screening should be based on comorbidities and individualised risk assessment rather than specific age¹. However, as previously noted by healthcare professionals, CKD can be a difficult condition to treat due to the wide and complex range of comorbidities (Figure 2) that patients can have associated with their disease¹⁶.

Figure 2. Venn diagram of the complex range of key comorbidities associated with chronic kidney disease patients from NPS MedicineWise’s MedicineInsight dataset (Adapted¹⁷). CVD, cardiovascular disease.

Of the range of possible comorbidities, intensively lowering blood pressure is known to reduce cardiovascular events and all-cause mortality in non-diabetic CKD¹⁸. Recent evidence is also revealing that intensive glucose control may help reduce the risk of kidney events; however, this benefit should be weighed against the risk of using agents that may cause hypoglycaemia¹.

How do you monitor glycaemic control in patients with diabetes and CKD?

According to the 2020 KDIGO clinical practice guideline for diabetes management in CKD, haemoglobin A1c (HbA1c) monitoring of glycaemic control in patients with diabetic kidney disease (DKD) is recommended¹⁹.

For patients with diabetes, it is also recommended to monitor long-term glycaemic control by HbA1c twice per year, although HbA1c can be measured as often as four times per year if the glycaemic target is not met or following a change in anti-hyperglycaemic therapy¹⁹.

The accuracy and precision of HbA1c measurement declines in patients with advanced CKD (G4–G5), particularly among patients on dialysis where HbA1c measurements have low reliability¹⁹

In diabetic patients with CKD, who are not treated with dialysis, an individualised HbA1c target range of <6.5%– <8.0% is recommended depending on a variety of patient factors (Figure 3)¹⁹.

Figure 3. Factors guiding decisions on individual HbA1c targets (Adapted²⁰). CKD, chronic kidney disease; G1, estimated glomerular filtration rate (eGFR) ≥90 ml/min/1.73 m²; G5, eGFR <15 ml/min/1.73 m²; HbA1c, glycated haemoglobin.

Continuous glucose monitoring (CGM) or self-monitoring of blood glucose (SMBG) may be used to safely achieve lower HbA1c targets (for example, <6.5% or <7.0%). In some patients, CGM may also be used as an alternative to HbA1c for defining glycaemic targets¹⁹.

What blood pressure targets are recommended for chronic kidney disease?

According to the 2021 KDIGO clinical practice guideline for the management of blood pressure in CKD, blood pressure targets and agents should be individualised according to²¹:

• Age
• Co-existent cardiovascular disease and other comorbidities
• Risk of progression of CKD
• Presence or absence of retinopathy (in CKD patients with diabetes)
• Tolerance of treatment

A potential benefit of a lower blood pressure is a decreased risk of both cardiovascular disease (CVD) and progression of CKD. Assessment of this benefit should consider issues such as the previous rate of CKD progression, the expected course of the disease, the level of urinary albumin excretion, and the presence or absence of other CVD risks²¹.

For example, an increase in conduit-artery stiffness is common in CKD and diabetic patients, as well as the elderly. This can lead to a high pulse pressure, with high systolic and low diastolic pressures, and a greater morbidity or mortality²¹.

The reduction of blood pressure in CKD patients can be difficult to achieve, especially in the elderly, patients with comorbidities, and patients with diabetes mellitus²¹

Difficulties can arise with treatment to reduce systolic blood pressure as this can result in lowering diastolic BP to below diastolic targets in older patients and patients with coronary artery disease (CAD), leading to a greater morbidity or mortality²¹.

Moreover, a J-shaped relationship has been highlighted between achieved blood pressure and outcomes in the elderly and patients with vascular disease. This also suggests that blood pressure can be reduced too far in these patients²¹.

While individual decision making is needed for BP targets and treatment choices, there is little evidence from randomised control trials (RCTs) to guide these decisions; as such, this recommendation on individualising BP targets has not been graded in the 2021 KDIGO clinical practice guideline²¹.

How do you detect and diagnose chronic kidney disease?

CKD can be detected during health assessments, as part of an evaluation of individuals at risk of CKD, due to incidental findings in abnormal laboratory values, while investigating symptoms and/or signs relating to the kidneys, or through a screen programme²³.

Regardless of the method of detection, two essential biochemical parameters used in the KDIGO matrix define CKD (Figure 4)²:

• Glomerular filtration rate (GFR)
• Albuminuria

In addition to these parameters, the addition of an aetiological diagnosis is recommended by the 2012 KDIGO clinical practice guidelines as a part of the cause/GFR/albuminuria (CGA) classification system². This allows for the underlying conditions to be treated first to halt the progression of CKD².

A number of tests can be used to confirm a CKD diagnosis as well as identify its cause; however a diagnosis of CKD will require persistence or progression of the abnormality for ≥3 months².

Figure 4. Heat map diagram highlighting chronic kidney disease risk in increasing colour intensity (Adapted²). CKD, chronic kidney disease; GFR, glomerular filtration rate; KDIGO, Kidney Disease: Improving Global Outcomes.

Alone, a GFR value or albuminuria result will not be sufficient for a diagnosis of CKD and may even lead to a high rate of false-positives²⁴. Progression is defined by changes in the estimated GFR (eGFR)².

How do you estimate and measure GFR to assess chronic kidney disease?

The assessment of GFR requires measuring the concentration of serum creatinine, under steady-state conditions, and using one of a number of formulae for estimating GFR²³. A variety of factors may however influence the results of this assessment including^25,26:

• Changes in muscle (atrophy or hypertrophy)
• Dietary intake of cooked red meat
• Alterations in tubular secretion of creatinine caused by exposure to drugs, such as trimethoprim and sulfamethoxazole

An alternative approach that uses serum cystatin C concentrations has been proposed to minimise these influences. However, the cystatin C­based formulae for eGFR are instead influenced by²⁷:

• Inflammation
• Obesity
• Thyroid disease, diabetes
• Steroid administration

Demographic variables, such as age and sex, may be used to correct for differences in creatinine generation. However, these may obfuscate prognostic inferences that can be made from measuring an eGFR²³

More recent eGFR formulae utilise serum creatinine, cystatin C, or combine the assessment of both to increase the accuracy of the assessment^28,29.

Considered a gold standard, measured GFR (mGFR) assessments can also be made in certain circumstances; for example, using urinary clearance methodology or following the removal of a kidney. However, these methods can be cumbersome and expensive^30–32.

How do you measure proteinuria to assess chronic kidney disease?

In cases of CKD where GFR appears normal, it becomes necessary to test for the abnormal excretion of albumin or total protein³³. This is determined through a variety of methods, including^34,35:

• Simple dipstick qualitative methods
• Point of care urinary albumin concentration tests
• Assessment of the urine protein to creatinine ratio (UPCR) or urine albumin to creatinine ratio (UACR) through random urine samples
• Timed 24­hour urine collections to measure absolute protein or albumin excretion

While UACR and UPCR are widely used to measure proteinuria, multiple samples must be collected as the measurement of urinary protein or albumin excretion is more variable than serum levels and can be influenced by posture activity, fevers, and drug use^34,35.

Sustained albuminuria (or proteinuria) is a powerful prognostic marker: Even with a normal eGFR, CKD can be diagnosed with a persistent and moderately increased UACR of >30mg/g with each incremental increase associated with an increased risk of mortality and end-stage renal disease (ESRD)²

UPCR and UACR can also be influenced by the urinary creatinine excretion rate. Specifically, a low level of creatinine excretion can increase the UPCR or UACR, even when absolute protein or albumin excretion rates are normal. Adjusting for this excretion effect can improve UPCR and UACR measurement accuracy^34,35.

In the 2012 KDIGO guidelines, the values for UACR are separated into three categories²:

• Normal or moderately increased
• Moderately increased
• Severely increased

Given the utility of albuminuria or proteinuria in determining the risk of CKD progression, they are important in CKD screening strategies.

Can you use kidney biopsy, imaging, or a urine examination for a CKD diagnosis?

Percutaneous kidney biopsy is a tool that can be used for the assessment of the underlying cause of CKD²³. They are commonly recommended for adults with³⁶:

• Nephrotic syndrome
• Unexplained, rapidly progressive loss of kidney function
• Low-grade proteinuria (0.5–3.0 g per day)
• Isolated proteinuria (1.0–3.0 g per day)

The indication for renal biopsy is based on a balance of the risks of biopsy-related complications against the benefits in precise diagnosis, prognostication, and treatment decisions²³. In terms of risks, fatal complications are only experienced in 1 in 10,000–20,000 biopsies and major complications in 0.7–1.8% of biopsies^37–39.

A less invasive method to detect and determine the cause of CKD is renal imaging through ultrasonography, computerised tomography (CT), and magnetic resonance imaging (MRI)²³. Through these imaging techniques, urinary sediment can be examined and specialised biochemical and serological tests can be used to detect specific disorders associated with CKD (Table 2)²³.

Table 2. Example diagnostic tests for conditions associated with chronic kidney disease risk (Adapted²³). ANCA, anti-neutrophil cytoplasmic antibodies; CKD, chronic kidney disease; MRI, magnetic resonance imaging.

Imaging tests can also provide valuable information on the urinary drainage system anatomy in addition to characteristics of the kidney that can be used to determine disease aetiology or confirm a specific diagnosis (Table 3)²³.

Table 3. Kidney characteristics that can be assessed through imaging (Adapted²³).

The examination of urine sediment can be important for the detection and quantification of haematuria, leukocyturia, and casts²³.

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Why is screening for chronic kidney disease important?

The early screening and risk-stratification of CKD has numerous benefits for patients with the disease, including⁴⁰:

• Early detection of the largely asymptomatic disease
• Early medical and lifestyle intervention, which may slow progression of disease
• Early treatment to reduce morbidity and mortality

This includes treatment of common coexisting comorbidities, such as diabetes and hypertension, in addition to the initiation of preventive medication and lifestyle modifications⁴¹.

Most guidelines recommend targeting high-risk populations, as it is advantageous to decrease the number of people needed to detect a single case⁴²

The benefits of screening have been highlighted in several targeted screening programmes, such as the Kidney Early Evaluation Program (KEEP) in the United States (N = 72,963), and the See Kidney Disease (SeeKD) program in Canada (N = 5,194). In the KEEP and SeeKD, a high prevalence of undiagnosed or unrecognised CKD was reported at 28.7% and 18.8%, respectively⁴³.

Point-of-care testing by the First Nations Community Based Screening to Improve Kidney Health and Prevent Dialysis (FINISHED) project (N = 1,700) was also shown to be efficacious in Canadian rural indigenous communities. Notably, while 25.5% showed signs of CKD, it was reported that 28.3% of people who were found to have CKD would have been missed if screening had only been offered to individuals with diabetes or hypertension⁴⁴.

Integrating preventive, risk-based care approaches into routine clinical practice could therefore enhance CKD surveillance and potentially improve management of underlying health conditions as a result⁴⁰.

What types of CKD screening strategies are there?

The screening of CKD can be carried out in two forms: opportunistic screening, through which a healthcare professional can carry out screening during encounters for other medical reasons; or population screening, through which samples are taken from specific populations²³.

Population-based screening can be further sub-divided into general population screening or targeted screening of high-risk population groups²³. General population screening is not currently recommended as the benefits and harms are poorly understood^45–47.

Opportunistic testing and targeted screening are considered to be useful strategies when risk factors, such as diabetes, hypertension, or a family history of CKD, are used to demarcate the screened population²³.

Management of CKD should focus on identifying people who are at high risk of adverse outcomes for more intensive treatment and referral to a specialist⁴⁸

In older people with CKD stage G3, that have been detected by screening, the prognosis over five years has been shown to be improved⁴⁸.

In a prospective cohort study of outcomes, a population with CKD stage 3 in primary care that did not meet criteria for referral to a nephrologist (N = 1,741) were assessed and managed. A low rate of ESRD (0.2%) and stable CKD or CKD remission was seen in 53% of older people after 5 years of follow up⁴⁸.

In these populations, screening should be carried out through measurements of eGFR and albuminuria, UACR, or UPCR²³.

Is there consensus for a specific CKD screening strategy?

At the 2021 KDIGO conference, it was concluded that CKD screening, together with risk stratification and treatment, should be implemented for high-risk individuals in a primary care setting¹.

After a comprehensive review of topics, a consensus was reached to recommend a broad and proactive strategy for CKD screening, risk stratification, and treatment, with the aim of reducing the global burden of kidney disease (Figure 5)¹.

Figure 5. Conceptual framework of a CKD screening, risk stratification, and treatment programme (Adapted¹). CKD, chronic kidney disease.

Moreover, preferably in primary or community-care settings, it was suggested that CKD screening coupled with risk stratification and treatment should be immediately implemented for high-risk individuals¹.

What are the challenges with CKD screening?

General population screening and targeted screening for CKD have a number of challenges that need to be overcome. These strategies create logistic difficulties due to the need for re-evaluation at defined intervals to fulfil the KDIGO duration requirement for diagnosis and staging of CKD²³.

Individual one-off tests of eGFR or proteinuria produce high false-positive detection and diagnosis rates and introduce further inaccuracies due to the use of non-age sensitive eGFR thresholds²³.

This can lead to a variety of issues, such as²³:

• Excessive follow-up diagnostic procedures
• Unnecessary referral of erroneously diagnosed individuals
• Anxiety causes by the possibility of having CKD
• Potential impacts on insurability in some countries

While the American College of Physicians has suggested that the evidence in support of CKD screening programmes is currently insufficient⁴⁹, various other countries have long established programmes, or have introduced these strategies as a part of their universal health care systems^50–54.

How can the challenges of CKD screening be overcome?

The difficulties in general population screening may be minimised by taking into account the:

• Age-specific likelihood of finding CKD
• The effectiveness of treatment in limiting CKD progression to ESRD
• Overall cost-effectiveness per quality-adjusted life years (QALY) gained

In a cost-effectiveness analysis using a Markov decision analytic model, it was shown that annual screening for CKD by dipstick proteinuria was more cost effective in at-risk groups, such as patients >60 years of age as well as in patients with hypertension or diabetes⁵⁵.

New predictive models could also prove useful in determining risk in specific patient populations. In an individual-level data analysis of 34 multinational cohorts from the CKD Prognosis Consortium (N = 5,222 ,711), multiple equations for identifying people at an increased risk of a reduced eGFR were developed and evaluated¹⁵.

The study found that 5-year risk prediction equations for CKD demonstrated high discrimination for the risk of developing reduced eGFR in populations with (median C statistic 0.845 [interquartile range (IQR), 0.789–0.890]) and without diabetes (median C statistic 0.801 [IQR, 0.750–0.819])¹⁵. The models also had variable calibration with 69% of the study populations having a slope of observed to predicted risk between 0.80 and 1.25¹⁵.

Adopting predictive models for CKD 5-year risk into routine clinical practice may enhance CKD surveillance and improve the management of related underlying health conditions⁴⁰.

Treating CKD