Background Information
Definition
CKD is defined as abnormalities in kidney function and/or structure, that present for at least 3 months
Aetiology
Top 4 causes of CKD: [Ref]
- Diabetes mellitus – most common (30-50%)
- Hypertension
- Glomerular diseases (nephrotic and nephritic syndromes)
- CKD of unknown aetiology
Diabetes, hypertension, and glomerular diseases all cause intrinsic kidney damage
Other causes of CKD (non-exhaustive list):
| Current or previous AKI | |
| Causes of obstructive uropathy |
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| Multisystem disease with renal involvement |
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| Hereditary kidney causes |
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| Cardiovascular disease |
|
| Drugs | See section on nephrotoxic drugs below |
Nephrotoxic Drugs
“Nephrotoxic drug” is a broad and often misused term. In practice, such drugs can be classified into two main groups: those associated with CKD, and those associated with AKI.
1) CKD-associated drugs are those that can cause intrinsic renal damage with prolonged use / repeated exposure:
- NSAIDs
- Analgesic nephropathy
Analgesic nephropathy is characterised by renal papillary necrosis and chronic interstitial nephritis resulting from prolonged, excessive consumption of analgesic mixtures, typically containing at least two antipyretic analgesics (e.g. phenacetin, aspirin, paracetamol), often combined with caffeine or codeine
NSAIDs can also contribute to the development of analgesic nephropathy, but it is less significant than the above-mentioned antipyretics.
*Phenacetin is largely withdrawn from the market.
- Lithium
- Calcineurin inhibitors (ciclosporin, tacrolimus)
- Cisplatin
- Tenofovir disoproxil
Note that although ACE inhibitors / ARBs need to be temporarily stopped in AKI, they are renoprotective in the context of CKD (in fact, used as 1st line management for proteinuria in CKD).
2) AKI-associated drugs. This is often a source of confusion. In practice, AKI-associated drugs can be grouped into 3 distinct categories based on their mechanism.
| Drugs that cause pre-renal AKI |
|
| Drugs that cause intrinsic AKI | Drugs that cause acute tubular necrosis (direct tubular toxicity):
Drugs that cause acute interstitial nephritis:
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| Drugs that should be withheld in AKI due to accumulation or toxicity risk, rather than direct nephrotoxicity |
|
The most exam-relevant “nephrotoxic drugs” to temporarily withhold in the acute setting of AKI:
- NSAIDs, ACE inhibitors, ARBs, diuretics (the ones that reduce renal perfusion)
- Aminoglycosides, vancomycin (the ones that cause direct tubular toxicity)
- LMWH (use UFH instead), metformin, lithium
Drugs associated with acute tubular necrosis can directly cause intrinsic AKI.
In contrast, drugs that cause pre-renal AKI typically impair renal haemodynamics and precipitate AKI in the presence of an additional insult, such as dehydration, sepsis, or hypotension.
Clinical Features
CKD is often asymptomatic in early stages.
Non-Specific Features
The clinical features of CKD itself, independent of the underlying cause, are often non-specific: [Ref]
- Generalised fatigue and lethargy
- Anorexia and disturbances in taste
- Frothy urine (non-specific sign that may indicate proteinuria)
- Altered urine output (polyuria / nocturia / oliguria)
- Generalised pruritus (common in advanced CKD, cause is not fully understood, may involve immune system deregulation or uraemia)
Complications
Key complications include: [Ref]
| Impaired kidney excretory function | Impaired fluid excretion → fluid overload
|
Electrolyte and metabolic disturbances due to impaired excretion:
|
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| In advanced CKD, impaired urea excretion → uraemia
Clinical syndrome of uraemia (non-exhaustive):
|
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| Impaired kidney synthetic function | Impaired EPOErythropoietin production → anaemia of CKD
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CKD-MBDChronic kidney disease-mineral bone disease:
Clinically manifest as renal osteodystrophy:
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| Systemic consequences |
|
Diagnosis
Indications for CKD Testing
CKD testing is recommended in adults with any of the following:
- Diabetes mellitus
- Hypertension
- Cardiovascular disease (ischaemic heart disease, chronic heart failure, peripheral vascular disease, cerebral vascular disease)
- Previous AKIAcute kidney injury
- Structural renal tract disease / recurrent renal calculi / prostatic hypertrophy
- Multi-system disease with potential kidney involvement (e.g. SLESystemic lupus erythematosus)
- Hereditary kidney disease / family history of end-stage renal disease
- Incidental detection of proteinuria or haematuria
- Gout
Test of Choice
If CKD testing is indicated (see above) or suspected, perform ALL the following investigations
| Test | Purpose |
|---|---|
| Serum creatinine and eGFR | eGFR reflects glomerular filtration (i.e. kidney function, indicating how effectively the kidneys filter creatinine) |
| Urine ACRAlbumin:creatinine ratio | ACRAlbumin:creatinine ratio quantifies proteinuria (which serves as a marker of structural kidney damage) |
| Urine dipstick | To check for haematuria
*Do NOT use a urine dipstick to test for proteinuria |
Be aware that testing with eGFR and ACRAlbumin:creatinine ratio only provides information about whether a patient has CKD or not, without giving information about the underlying cause.
eGFR Measurement
eGFR provides an estimate of the true GFR. NICE recommends using the CKD-EPI equation to calculate eGFR in adults, which incorporates the following variables:
- Serum creatinine
- Sex
- Age
The older MDRD equation, which also included a race adjustment, is no longer used. As race is a social construct, not a biological variable, it often overestimates kidney function in black patients. It also introduces health inequity.
Factors affecting eGFR interpretation:
| Factors that ↑ creatinine → falsely low eGFR (underestimated) | Factors that ↓ creatinine → falsely high eGFR (overestimated) |
|---|---|
|
|
Testing for Proteinuria
1st line test: urine ACRAlbumin:creatinine ratio
- Sample: early morning urine sample
- ≥3 mg/mmol is defined as clinically important proteinuria
- If the initial result is 3-70 mg/mmol → repeat the test
- If the initial result is >70 mg/mmol, no repeat is needed
Note that transient elevations of albuminuria can occur with:
- Menstrual blood contamination
- UTIUrinary tract infection
- Strenuous exercise
- Upright posture (orthostatic proteinuria)
- Other conditions that increase vascular permeability (e.g. sepsis)
Therefore, it is important to repeat the urine ACRAlbumin:creatinine ratio, if results are <70 mg/mmol to confirm if the albuminuria is transient (likely the listed causes here) or persistent (likely due to CKD).
Do NOT rely on urine reagent strips (dipsticks) to diagnose proteinuria, as they are insensitive and unreliable, particularly for low-level proteinuria. If urinalysis is +ve for protein (often an incidental finding), confirm with a urine ACRAlbumin:creatinine ratiotest.
Urine ACRAlbumin:creatinine ratio is preferred over PCRProtein:creatinine ratio to test for proteinuria, as it is more sensitive for low levels of proteinuria. PCRProtein:creatinine ratio should only be used as an alternative to ACRAlbumin:creatinine ratio if ACRAlbumin:creatinine ratio is ≥70 mg/mmol (where it is able to provide adequate quantification).
Haematuria Testing
If a urine dipstick shows 1+ or more blood on the dipstick:
- Arrange an MSUMid-stream urine for MC&SMicroscopy, culture and sensitivity to exclude a UTIUrinary tract infection
- If there is persistent haematuria
Defined as 2 out of 3 urine dipstick tests that show 1+ or more of blood.
After the exclusion of UTI.
→ consider the possibility of urological malignancy (see Bladder Cancer and Renal Cancer articles for more information)
Diagnostic Criteria
CKD can only be diagnosed if ANY of the following (right column) are present for at least 3 months
| eGFR |
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| Markers of kidney damage |
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Investigating the Cause of CKD
The selection of additional tests to investigate the underlying cause should be individualised based on the clinical context and working diagnosis.
Laboratory Testing
A standard panel would include:
- Serum electrolytes
- HbA1c
- Lipid panel
- Serological testing guided by clinical suspicion (e.g. ANA, complement levels, Hep B and C serology, ANCA, anti-GBM etc.)
Imaging
1st line: renal ultrasound (to evaluate for structural abnormalities / obstruction / polycystic kidney disease)
Indicated if any of the following are present:
- Accelerated progression of CKD
NICE defines it as:
- Sustained GFR decrease of ≥25% + change in GFR category within 12 months, or
- Sustained GFR decrease of 15 per year
- Visible / persistent invisible haematuria
- Symptoms of urinary tract obstructions
- >20 y/o with family history of polycystic kidney disease
- eGFR <30 (G4 or G5)
- Renal biopsy needed
Classic ultrasound findings in CKD:
- Bilaterally small kidneys + increased echogenicity suggest long-standing CKD
- Asymmetrically small kidneys suggest renal artery stenosis
However, some causes of CKD are associated with preserved or enlarged kidney size despite long-standing disease: [Ref1][Ref2]
- Diabetic nephropathy (due to mesangial expansion)
- Polycystic kidney disease and other cystic kidney diseases (e.g. medullary cystic disease)
- Amyloidosis, multiple myeloma and other infiltrative diseases (due to deposition of abnormal proteins or cells)
- HIV-associated nephropathy (due to interstitial inflammation)
- Chronic obstructive uropathy
However, note that advanced scarring from chronic injury can still cause kidney atrophy.
CKD Classification
CKD Staging
CKD staging based on eGFR:
| CKD stage | Criteria |
|---|---|
| 1 | eGFR >90 + marker of kidney damage Indicated by any of the following:
|
| 2 | eGFR 60-89 + marker of kidney damage Indicated by any of the following:
|
| 3a | eGFR 45-59 |
| 3b | eGFR 30-44 |
| 4 | eGFR 15-29 |
| 5 (end-stage renal disease) | eGFR <15 |
Although the reference range of CKD is often listed as >90, an eGFR of 60-89 alone does NOT constitute CKD
- While eGFR <60 alone (on 2 separate occasions and for at least 3 months) is enough to constitute CKD
- For someone to have CKD that has an eGFR of >60, they must have an additional marker of kidney damage
Indicated by any of the following:
- Urinary ACR >3 mg/mmol
- Urine sediment abnormalities
- Abnormalities on histology
- Structural abnormalities on imaging
- History of kidney transplantation
- Electrolyte or other abnormalities (e.g. acidosis) due to tubular disorders
CKD Risk Stratification
NICE recommends stratifying the risk of progression and complications of CKD based on BOTH eGFR and ACRAlbumin: creatinine ratio
| A1 (ACR <3) | A2 (ACR 3-30) | A3 (ACR >30) | |
|---|---|---|---|
| G1 (eGFR ≥90) | Low risk
*There is no CKD if there are no other markers of kidney damage Indicated by any of the following: |
Moderate risk | High risk |
| G2 (eGFR 60-89) | |||
| G3a (eGFR 45-59) | Moderate risk | High risk | Very high risk |
| G3b (eGFR 30-44) | High risk | Very high risk | |
| G4 (eGFR 15-29) | Very high risk | ||
| G5 (eGFR <15) |
Modern CKD classification incorporates both eGFR and ACR because they provide complementary prognostic information. Albuminuria is independently associated with faster CKD progression and increased cardiovascular risk, even when eGFR is preserved.
Classifying CKD using both parameters, therefore provides superior prognostic accuracy than eGFR alone.
Management
It is essential to identify and treat (or optimise the treatment of) the underlying cause of CKD. The management principles outlined below apply to the non-specific management of CKD, regardless of aetiology.
Risk Assessment and Referral Criteria
Assess 5-year risk of needing RRT with the 4-variable Kidney Failure Risk Equation
Refer adults with CKD for specialist assessment if any of the following:
- 5-year risk of needing RRT >5%
- ACR ≥70 mg/mmol (unless caused by diabetes and already appropriately treated)
- ACR ≥30 mg/mmol + haematuria
- Accelerated progression of CKDNICE defines it as: - Sustained GFR decrease of ≥25% + change in GFR category within 12 months, or - Sustained GFR decrease of 15 per year
- Suspected renal artery stenosis
- Known / suspected rare or genetic cause of CKD
Monitoring Disease Progression
Monitor CKD progression with eGFR and urine ACRAlbumin:creatinine ratio
Tests to monitor potential CKD complications:
- FBC to exclude anaemia of CKD in CKD stage 3-5, or if clinically indicated
- Calcium, phosphate and PTH levels should be routinely measured in CKD stage 4 and 5 (but not routinely in stage 1-3) to check for CKD-MBDChronic kidney disease-mineral bone disease
Conservative / General Management
Lifestyle advice is very personalised in CKD, depending on various factors (e.g. polyuric or oligouric, electrolyte levels, fluid status).
Some key lifestyle advice:
- Regulate protein intake (usually ~0.8g per kg per day)
- Usually advised by dietitian
- Do NOT routinely recommend a low-protein diet
- Limit sodium intake
- Some situational advice (usually only advised if there is a problem)
- Fluid restriction
- Low phosphate diet
- Low potassium diet
Pharmacological Management
There are 3 main aspects of CKD management (irrespective of underlying cause):
- Hypertension
- Proteinuria
- CVD secondary prevention
Hypertension Management
Manage hypertension as per those outlined in the Hypertension (Primary) article.
BP targets in CKD depend on ACRAlbumin:creatinine ratio level:
- ACRAlbumin:creatinine ratio <70 mg/mmol target: <140/90 mmHg
- ACRAlbumin:creatinine ratio ≥70 mg/mmol target: <130/80 mmHg
Proteinuria Management
1st line: ACE inhibitor / ARB
- Offer if CKD with ACRAlbumin:creatinine ratio >30 mg/mmol (even if there is no hypertension), or
- if CKD + diabetes (type 1 / 2) with ACRAlbumin:creatinine ratio >3 mg/mmol
2nd line: SGLT-2 inhibitor (dapagliflozin / empagliflozin)
- Add SGLT-2 inhibitor in addition to ACE inhibitor / ARB if
- eGFR 20-45, or
- eGFR 45-90 + T2DM / urine ACRAlbumin:creatinine ratio ≥22.6
The exact indications outlined by NICE are often not strictly adhered to in practice. All patients with CKD are typically started on an ACE inhibitor / ARB (unless contraindicated). It is more important to be aware that both ACE inhibitors (or ARB) and SGLT-2 inhibitors are used to treat proteinuria in CKD, than learning the exact indications outlined by NICE.
CVD Secondary Prevention
CKD alone is an indication for statin therapy (primary prevention):
- 1st line: atorvastatin 20mg
NICE recommends atorvastatin 20mg for both primary and secondary prevention in CKD.
Management of CKD Complications
The following outlines the key complications of CKD that are amenable to treatment or require specific management strategies.
Otherwise, the risk of other complications is best reduced by optimising the management of CKD itself and any underlying causes.
Anaemia of CKD
Investigation and Diagnosis
Test of choice: FBC to exclude iron deficiency
- There is no specific test that definitively confirms anaemia of CKD, it is diagnosed by excluding other causes of anaemia in conjunction with the clinical context
- Be aware that anaemia of CKD is unlikely if eGFR >60, but very likely if eGFR <30
Management
First, correct any iron deficiency (if present)
- High-dose IV iron is necessary for those with stage 5 CKD on haemodialysis
If there is persistent anaemia, despite correction of reversible causes / iron deficiency:
- Consider erythropoietic stimulating agent therapy (e.g. epoetin alfa, epoetin beta, darbepoetin alfa)
- Alternative: hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (e.g., roxadustat, vadadustat)
Hyperphosphataemia
Hyperphosphataemia is often only seen in CKD stage 4 / 5.
Step 1: dietary management
- Low phosphate diet
- Do NOT routinely recommend a low-protein diet
Step 2: phosphate binders
- 1st line: calcium acetate (avoid in hypercalcaemia)
- 2nd line: sevelamer carbonate
- Other: calcium carbonate, sucroferric oxyhydroxide, lanthanum carbonate
Although inexpensive and effective, calcium-based phosphate binders (e.g. calcium acetate, calcium carbonate) carry a significant risk of hypercalcaemia and accelerated vascular calcification.
Non-calcium binders (e.g. sevelamer carbonate, sucroferric oxyhydroxide, lanthanum carbonate) are associated with a lower risk of these complications, therefore preferred in patients with hypercalcaemia, vascular calcification, or related comorbidities.
Vitamin D Deficiency
Testing
Vitamin D should only be measured if deficiency is suspected
- Routine serum vitamin D testing is NOT indicated in CKD
Management
1st line (any CKD stage): standard oral vitamin D supplementation (cholecaliferol Vitamin D3. Vitamin D2.
Active vitamin D Calcitriol (1,25-dihydroxyvitamin D₃) and alfacalcidol (1-α-hydroxycholecalciferol) are “active” vitamin D forms because they bypass the kidney’s 1-α-hydroxylase step, which is impaired in CKD. Calcitriol is the fully active hormone, while alfacalcidol requires only liver conversion to become calcitriol. They effectively increase calcium and phosphate levels, therefore should be used with caution in advanced CKD due to risk of hypercalcaemia and hyperphosphataemia.
- Vitamin D deficiency has been corrected, and
- CKD-MBDChronic Kidney Disease–Mineral and Bone Disorder symptoms persist AND
- Patient is stage 4 or 5 CKD (eGFR <30)
References
NICE guideline Chronic kidney disease: assessment and management