A practical guide to diagnosis and assessment of chronic kidney disease for the non-nephrologist

Introduction

Chronic kidney disease (CKD) is common with approximately 6% of the UK adult population having an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m², and the majority of non-nephrologists will care for people with CKD.¹ In contrast, end-stage kidney disease (ESKD) requiring renal replacement therapy is extremely uncommon with an incidence of around 120 per million population in the UK.² This paper aims to provide a brief overview of diagnosis and investigation of people with CKD for the non-nephrologist. The first part of the review focuses on the diagnosis of CKD that may be undertaken by the non-nephrologist and the second part provides an overview into how the nephrology team may manage CKD.

Part 1: diagnosis of CKD

Classification of CKD

The international Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend classification of CKD based on the cause of CKD, eGFR and albuminuria [measured by albumin:creatinine ratio (ACR)], abbreviated to the ‘CGA’ classification system.³ Identifying those with CKD and optimising treatment is important as CKD has a direct association with adverse patient outcomes. Increasing proteinuria and decreasing glomerular filtration rate (GFR) are both associated independently with adverse outcomes, including increased all cause mortality, in particular cardiovascular death, acute kidney injury (AKI) and progression to ESKD.⁴ Having both decreased GFR and significant proteinuria multiply that risk, as seen in the heat map in Figure 1.³

Who should undergo screening for CKD?

There is no population-based CKD screening programme in the UK. However, it is recommended that people at high risk, including those with conditions associated with CKD, structural abnormalities in their renal tract and those on nephrotoxic medication, should be screened for CKD at least annually, as shown in Table 1.⁵

Diagnosis of CKD

For the majority of people, a diagnosis of CKD is based primarily on the results of blood tests and urine protein testing as outlined in Figure 1, though patients with normal excretory renal function may still have CKD if they have an alternative marker of kidney damage. These include:

• • proteinuria
• • haematuria of renal origin
• • structural renal abnormality
• • genetic diagnosis affecting the kidneys, e.g. polycystic kidney disease
• • electrolyte abnormalities due to tubular damage
• • abnormalities on renal biopsy.

Figure 1 Classification of CKD using GFR and ACR categories. Adapted with permission from Kidney Disease: Improving Global Outcomes (KDIGO).^3
1Consider using eGFR-based cystatin C for patients with CKD G3aA1 (see recommendations 1.1.14 and 1.1.15 from KDIGO Group³).
ACR: albumin:creatinine ratio; CKD chronic kidney disease; eGFR: estimated glomerular filtration rate; GFR glomerular filtration rate

1. Blood tests: U+Es/eGFR

As an initial screening test, serum creatinine and eGFR are appropriate. With the finding of a first abnormal blood test (eGFR <60 ml/min/1.73 m²), it is important to exclude AKI in the first instance by repeat testing within 14 days.⁵ A diagnosis of CKD based on reduced eGFR requires two measurements of eGFR <60 ml/min/1.73 m² over 90 days apart. Although helpful for screening those at risk of CKD and initial testing, the use of eGFR does have some caveats and does not always reflect the severity of CKD on an individual basis and can be extremely variable within the same patient. It is less accurate in patients with extremes of muscle mass, such as body builders, and those with above-average muscle mass can be overdiagnosed with CKD. Similarly, those with low muscle mass, for example owing to muscle wasting, malnutrition, amputation or liver disease, may have relatively advanced renal disease with less abnormal biochemistry on initial testing.⁶ Cystatin C-based eGFR can be useful in these situations and may be more accurate at assessing their eGFR.⁷ This may be recommended by a nephrologist or clinical biochemist but should not be routinely used. The guidance from the National Institute for Health and Care Excellence (NICE) recommend checking cystatin C-based eGFR for those who have an unexpected/isolated finding of eGFR 45–60 ml/min/1.73 m² using serum creatinine-based eGFR without other evidence of renal disease to confirm the diagnosis.⁵

2. Urine dip (routine urine examination)

a. Proteinuria

Proteinuria is the strongest predictor of renal risk and is associated with adverse patient outcomes.⁸ Quantifying proteinuria is essential as mortality, cardiovascular events and progression of renal disease all increase with increasing levels of proteinuria.

Proteinuria causes both glomerular and tubular damage that through a variety of pathways leads to increased proteinuria and progression of CKD. As mentioned above, it is also independently linked to cardiovascular morbidity and mortality.

Proteinuria should be formally quantified with ACR or protein creatinine ratio (PCR) in people with suspected CKD (or nephrotic syndrome). These ratios are calculated by dividing the urine protein or albumin (measured in milligrams per litre) by the urine creatinine concentration (millimoles per litre) to correct for urine flow rate. There is no benefit of the routine use of 24-hour urine collections that are cumbersome for patients and usually poorly performed.⁹ Low-level proteinuria should be repeated to confirm, but levels above ACR 70 mg/mmol do not require this, though levels should be monitored regularly. ACR is generally used for assessment in diabetic kidney disease, however, ACR and PCR have both been found to be equally effective in predicting outcomes even at low levels.⁸

b. Haematuria

Patients with unexplained visible haematuria aged >45 years should initially have urological assessment including imaging to exclude renal tract malignancy unless there is significant AKI or other evidence of intrinsic renal disease.¹⁰

Assessment of nonvisible haematuria (NVH) should be undertaken using reagent strips rather than microscopy. Persistent NVH is defined as two or more positive tests from three consecutive samples of dipstick 1+ or more. Unlike proteinuria, NVH is often not due to an intrinsic renal pathology, but may be caused by urological disease. Referral to urology for exclusion of renal tract malignancy should also be considered for those aged >60 years with persistent NVH plus dysuria or raised white cell count in the absence of urinary tract infection.¹⁰ If urological disease is excluded, people with persistent NVH may have IgA nephropathy and, therefore, should have annual urinalysis (for protein and blood) plus quantification of proteinuria if indicated, and eGFR and blood pressure (BP) checks for as long as the NVH persists.¹¹

Table 1 Who should be tested for evidence of CKD

5-ASA: 5 aminosalicylic acid; ACE: angiotensin converting enzyme; ARB: angiotensin II receptor blockers; CKD: chronic kidney disease; NSAID: nonsteroidal anti-inflammatory drug

3. Cause

Once the diagnosis of CKD is confirmed and the CKD stage is established, it is important to also consider the underlying cause and progression of CKD.³ The leading causes of ESKD are shown in Figure 2. Family, medication and social histories are key as part of this assessment. Myeloma should be excluded in older adults or anyone with other suggestive features (e.g. anaemia, hypercalcaemia, infections, bone pain) as urgent referral to haematology may allow disease-specific therapy.

If the cause of CKD is uncertain, that may be reason to refer to nephrology, and a renal biopsy may be considered if there is haematuria and/or proteinuria suggesting a glomerular disorder.¹² Some renal disorders require specific intervention, such as immunomodulatory therapy, whilst others benefit from more generic therapies (discussed below). Identifying the aetiology of CKD is also helpful for education/discussion with the patient and can help predict progression (though this is variable). Despite investigation, the cause of a patient’s CKD remains unknown in around 15% of people reaching ESKD.¹³ In this situation the focus continues on prevention of progression, identification of metabolic complications of renal disease and preparation for renal replacement therapy where appropriate.

4. Imaging

Ultrasound is the imaging modality of choice for the kidneys and can be extremely informative. Ultrasound can confirm the following:

1. 1. Presence of two kidneys: a kidney may be congenitally absent, atrophied or been surgically removed.
2. 2. Renal size: small kidneys on ultrasound suggest chronicity of renal disease while nephromegaly is associated with diabetes, polycystic kidney disease and infiltrative disorders.
3. 3. Cortical thickness: cortical thinning is a sign of chronicity.
4. 4. Obstruction of the renal tract: hydronephrosis ± hydroureter is suggestive of an underlying urological disorder and the level of the obstruction may be apparent on the scan.
5. 5. Cysts: most commonly simple cysts are noted that are of no consequence, however, a complex cyst may be malignant and require urological assessment. Multiple, usually bilateral cysts in enlarged kidneys are suggestive of polycystic kidney disease.

AKI in context of CKD

Patients with CKD are at higher risk of developing AKI – both in frequency and severity. They are also more likely to require renal replacement therapy for AKI and less likely to recover to their previous baseline level of renal function.¹⁴ Therefore, it is essential to quickly identify any reversible causes of deterioration.

The causes of an acute deterioration in a patient with CKD remain the same as the causes of AKI in the general population and the following should be considered:

• • Pre-renal: hypovolaemia (reduced oral intake, increased losses, e.g. fever, gastrointestinal fluid loss), reduced renal perfusion (reduced cardiac output, e.g. heart failure, myocardial infarction, arrhythmia, sepsis, renovascular disease, e.g. renal artery stenosis, thrombosis).
• • Post-renal: commonly bladder outflow obstruction in older men (especially benign prostatic hypertrophy and prostatic carcinoma) though other obstructive causes should be considered, including stones, anticholinergic medication, neurological causes of incomplete bladder emptying.
• • Renal: toxins [e.g. nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers, aminoglycosides, contrast, rhabdomyolysis, haemolysis, hypercalcaemia], interstitial nephritis, glomerulonephritis, uncontrolled hypertension, urosepsis.

If medications are discontinued owing to AKI it is essential that a medication review takes place in a timely fashion after discharge to plan the controlled reintroduction of medication, such as diuretics and renin-angiotensin system (RAS) blockade, to avoid the risk of readmission to hospital with decompensated cardiac failure.¹⁵

Figure 2 Leading causes of end-stage kidney disease in the UK with figures from the UK Renal Registry Report 2018²