Introduction

Epidemiology

• Strongly correlated with other chronic diseases – such as diabetes and cardiovascular disease
• Stage 3 to 5 CKD has a prevalence of about 8%
  • 10% in women
  • 6% in men
• Chronic kidney disease is of particular importance in terms of cost to the NHS; about 630 patients per 1 million are kept alive by renal replacement therapy, and the incidence of new patients having such treatment is about 110 per 1 million.
• In the USA, incidence is about 3 times higher than in the UK; over half of CKD patients in the US are diabetics
• There is a much higher incidence of ESRF in black populations than in white populations.  In this ethnic group CKD tends to be caused by hypertensive nephropathy.
• CKD due to atherosclerotic vascular disease in the renal artery is more common in elderly patients than in young patients.
• There is wide geographic variation in the incidence of conditions that cause CKD.
  • Malaria is the main cause of CKD throughout Africa.
  • Schistosomiasis – this is a parasitic disease caused by several species of fluke. The disease is most commonly found in parts of the Far East, Middle East and Africa where the water supply contains numerous freshwater snails carrying the parasite. After penetrating the skin, snail larvae affected by the parasite move into systemic circulation and then into portal circulation, maturing in the liver. Moving into veins surrounding the bladder, they then lay eggs which cross the urethral or bladder wall causing long-standing urinary obstruction which results in CKD.
• The incidence of diabetes, and thus diabetic nephropathy tends to be higher in Asian populations than in white populations.

Risk factors

• Cardiovascular disease
• Diabetes
• Smoking
  • Between 40% and 105% increased risk depending on pack years
• Hypertension
• Acute Kidney Injury (AKI)
• Obesity
  • Risk is doubled
  • Central obesity is a greater predictor compared to total weight
• Chronic use of NSAIDs

Causes

Signs and symptoms

Investigations

In addition to blood pressure, U+Es and urine ACR, many further investigations may be performed to identify the underlying cause.

The following is a list of tests that may be considered to look for an underling cause of CKD.

Blood

• FBC
  • Normochromic, normocytic anaemia – “anaemia of chronic disease” – may occasionally be microcytic, and can be confused with iron deficiency anaemia
• ESR – if this is raised it suggests myeloma or vasculitis
• U+E – raised urea and raised creatinine
  • Urea in particular is a poor marker of CKD. Levels vary according to hydration and diet
  • Creatinine levels can remain normal up to the point of loss of 50% of renal function
• eGFR – is usually calculated by most laboratories based on age, urea and creatinine
• Glucose – check for diabetes
• Sodium – often low
• Potassium – may be raised – and if it is raised – is often a sign of severe disease and requires urgent management
  • Hyperkalaemia in the main indication for dialysis
  • Urea and creatinine are only secondary considerations, and patients are not routinely dialysed without abnormalities of potassium
• Calcium – can be low, normal or high!
• Increased phosphate
• Raised parathyroid
• Albumin – often low – due to loss via the kidney
• Serology
  • Consider hepatitis B and C as well as HIV serology
  • Consider antibody screen
    • c-ANCA
    • p-ANCA
    • Anti-GMB – seen in Goodpasture’s Disease
    • Complement

Urine

• Haematuria – can differentiate glomerulonephritis from chronic renal failure; also rules out other conditions.
  • Patients with haematuria should have urine MC+S performed, to rule out UTI
  • If no UTI, but persistent haematuria and NO evidence of renal failure, then refer to urology for investigation for cause of haematuria (e.g. RCC or TCC)
• Proteinuria – if this is heavy it is strongly suggestive of glomerular disease.
• Glycosuria – this is common even with normal blood glucose in CKD.
• Casts – suggestive of renal disease; highly suggestive of glomerulonephritis.
• White cells – suggestive of infection / nephritis
• Red cells – can come from anywhere along the urinary tract, so their presence is not particularly useful in diagnosing CKD.
• 24-hour creatinine clearance – useful in determining the level of renal failure. Urine ACR is the recommended investigation (as opposed to “protein” which is less sensitive)
  • Single urine sample for ACR is preferred (first void of the day) for convenience and compliance, and can be used to estimate the 24-hour value
  • The degree of proteinuria strongly correlates to the level of kidney disease
  • Reference ranges:
    • Normal – 30 mg albumin / 1g creatinine
    • Microalbuminaemia – 30 – 300mg albumin / 1g creatinine
    • Macroalbuminaemia – >300 mg albumin / 1g creatinine
  • Confirms the diagnosis of CKD (Even if eGFR is normal) with 2 positive samples within 3 months
• Urinary electrolytes – an unhelpful investigation.
• Urine osmolality – this is low in cases of high fluid intake, but it is also low when fluid intake is inadequate in renal disease; demonstrates that the kidney is unable to concentrate urine.

Other

• ECG – to look for signs of underlying cardiac dysfunction – e.g. left ventricular hypertrophy
• Renal USS
  • Kidney often large in early stage of CKD and become small as disease progresses
  • Often multiple cysts are visible
  • May spot signs of renal tract disease (e.g. hydroneophrosis)
  • Indications
    • Have accelerated progression of disease
    • eGFR <30
    • Persistent haematuria
    • Any symptoms of urinary tract obstruction
    • Strong FHx of polycystic kidney disease
  • In Australia, recommended to perform USS on all CKD patients once diagnosis is confirmed
• Renal nucleotide scan
  • Can assess the presence of renal artery stenosis
• CT
  • May spot renal cysts and masses – but these are better visualised with USS
  • The best investigation for suspected renal tract pathology
• MRI
  • May be rarely used if CT is contraindicated – e.g. if allergic to IV contrast

Tests that should always be performed upon diagnosis of CKD:

• Renal tract USS
• FBC, CRP, ESR
• Urine ACR
• Fasting lips and glucose
• Urine microscopy for dysmorphic red cells, red cell casts or crystals

Disease Staging

The suffix (p) is used to denote co-existing proteinuria

Progression of CKD

Management

Quick overview

Review annually – check weight, eGFR and urine ACR. Bloods for lipids and T2DM (usually an HbA1c).

• Control hypertension
• Smoking cessation
• Aim for healthy BMI (18.5 – 24.9)
• Avoid nephrotoxic medications
• Lifestyle factors
  • Exercise
  • Diet
  • Alcohol
• If eGFR 30-60 with albuminuria, or 30-45 without albuminuria (moderate disease)
  • All of above
  • Review every 3-6 months
  • Check calcium, phosphate and parathyroid hormone
• If eGFR <30
  • All of above
  • Review every 1-3 months
  • Monitor for oedema
  • Refer to renal physician
  • Discuss advanced care plan, dialysis and renal transplant

The details

• Explain to patients what a CKD is and reassure that the vast majority of patients will not require dialysis
• Most important factors in management are to:
  • Control hypertension
  • Control diabetes
  • Prevent and treat urinary tract obstruction
• Avoid NSAIDs
• Provide influenza and pneumococcal vaccinations
• Advise about the link between CKD and cardiovascular disease
• Repeat urea and creatinine within 5 days of initially abnormal results to ensure there is no rapid progression
  • Repeat again at 90 days to confirm diagnosis of CKD
• Assess urine ACR annually
• Urea and electrolytes annually. More regularly in more severe or rapidly advancing disease
• The three mainstays of preventative health are discussed in further detail below and include:
  • Management of blood pressure
  • Prevention of cardiovascular disease
  • Lifestyle factors
• Consider giving patients an information factsheet, e.g. Australia or UK

Lifestyle factors

• Important to monitor for weight loss and undernutrition
• Weight and perform BMI annually. Undernutrition defined as:
  • Actual body weight is 85% of ideal body weight
  • BMI <20 kg/m2
  • 5% weight loss in 3 months or 10% in 6 months (if not due to oedema)
• Consider supplementation if undernutrition present
  • If weight loss continues, the NG feeding or PEG feeding may be indicated
• Consider protein supplementation
  • In later stages of CKD albumin is lost in the urine in large amounts and can result in weight loss
  • 0.75g/Kg of ideal body weight daily for CKD 4-5
  • 1.2g/Kg ideal body weight if on dialysis
• Supplement vitamin D
• Advise regular moderate exercise
  • 30 minutes daily of moderate intensity exercise (equivalent to a brisk walk) on at least 5 days per week
  • This should include 2 days (60 minutes per week) of strengthening activities
  • Consider referral to an exercise physiologist for a personalised plan – especially if severe co-morbidities
  • A gradual increase in physical activity from a sedentary lifestyle is safe and beneficial for the vast majority of patients
• Advise mediterranean style diet
  • A varied diet that should be rich in vegetables, nuts, fruits, wholegrain, cereals, lean meat, poultry, fish, eggs, beans, legumes and low-fat dairy products
  • Limit salt intake to <6 per day
  • Limit added sugars
  • Limit saturated and trans fats
• Alcohol – advise within safe drinking limits, total cessation probably better

Prevention of cardiovascular disease

• Statins
  • Should be offered as primary and secondary prevention for all patients with CKD
  • If eGFR <30 – consult with renal specialist regarding the dose
• B12 and Folate supplementation
  • Consider in all patients
  • Check serum folate and B12 in all stage 4 and 5 CKD patients every 6 months, and every 3 months if patient is on dialysis
• Aspirin
  • Recommended for secondary prevention only
• Oral anticoagulatns
  • When indicated (e.g. in non-valvular AF), rivaroxaban is generally preferred to warfarin in CKD. Discuss with renal specialist if eGFR <30

Manage blood pressure

• Aim for <130/80 mmHg
• ACE inhibitors are first line
  • Always check U+Es before starting – particularly potassium
  • Repeat 2 weeks after starting medication, and 2 weeks after any dose changes
  • Contra-indicated if potassium is >6 mmol/L (stop treatment immediately)
  • Do not start treatment if potassium is >5 mmol/L
• For dialysis patients
  • Low salt diet (<5g/day)
  • Hypertension usually managed by ultrafiltration

Indications for referral for specialist care

• eGFR <30
• Albumin creatinine ration (ACR) >70mg/mmol, OR
  • ACR >30 mg/mmol WITH haematuria
• Accelerated progression of disease. Defined as:
  • Decrease of eGFR 25% or more + change in category of disease within less than 12 months, OR
  • Decrease in eGFR of >15 within less than 12 months
• Hypertension that is not controlled with at least 4 anti-hypertensive medications
• Known or suspected genetic cause of CKD
• Renal artery stenosis (proven or suspected)
• Renal outflow obstruction – refer to urology rather than renal team

Mineral and Bone disorders

• Disorders of the parathyroid axis (parathyroid hormone, calcium, phosphate and vitamin D) can occur in CKD
  • Typically there is secondary hyperparathyroidism – where PTH is chronically increased – usually in response to high phosphate – which is not properly excreted by the diseased kidney. This rise in PTH causes changes in calcium metabolism
  • CKD is the main cause of parathyroidism
  • Supplementation with vitamin D is frequently required in severe CKD
  • The disruption in this axis, and the subsequent mobilisation of calcium from bone predisposes CKD patients to osteoporosis. Offer treatment for this where appropriate
• Is it not routinely recommended to check levels of PTH, calcium or phosphate unless eGFR <30
  • In patients with eGFR <30, then check PTH, calcium and phosphate at regular intervals – the exact interval will depend on the extent of the abnormality of these levels
  • If abnormalities are present – treat with vitamin D first (cholecalciferol). If this is unsuccessful use a vitamin D analogue (e.g. calcitrol) instead
    • Vitamin D causes increased uptake of calcium from the gut and decreased excretion by the kidney
• In haemodialysis patients – be wary to always check the “adjusted” calcium – and keep in the range of 2.2 – 2.5 mmmol/L – be wary of hypercalcaemia
• Hyperphosphateaemia is also common in CKD
  • Occurs due to decreased filtering of phosphate by the kidneys
  • This causes increases in PTH – causing secondary hyperparathyroidism
  • Secondary hyperparathyroidism causes increased mortality and morbidity, and increased risk of fractures
  • Consider a referral to a dietician to come up with a personalised diet plan which is low in phosphate
  • If protein supplements are required, use ones that are low in phosphate
  • If phosphate still remains high – treat with a phosphate binder –e.g. calcium acetate. This is frequently not tolerated by patients, calcium carbonate is a suitable alternative
    • If hypercalcaemia develops (usually only in CKD stages 4 and 5) then use a non calcium based binder
    • Take phosphate binders with food

Renal replacement Therapy

There are several treatment methods that fall under the category of renal replacement therapy. This includes:

• Peritoneal dialysis – can be performed either in a hospital environment, or at home, after patient training
• Haemodialysis
• Renal transplant

When to start dialysis is a contentious issue. A rough guide would be:

• eGFR <10 ml/minute, OR
• eGFR <15 ml/minute in patient with diabetes

There is no evidence that early dialysis improves outcomes. However, late dialysis often results in marked malnutrition (perhaps due to protein loss).

Refer patients to a renal specialist when eGFR <30 ml/minute to consider their options

Dialysis is also frequently used in AKI. In this circumstance, the on of the main indications is the potassium level (usually >6.5mmol/L for AKI, but 7.0 mmol/L in CKD). In AKI, other considerations include:

• Sodium >155 mmol/L or <120 mmol/L
• Severe acidosis (pH <7.0) – not responsive to bicarbonate
• Severe renal failure – e.g. creatinine >500, urea >30 mmol/L
• Drug toxicity with drugs than can be dialysed

Complications

• Anaemia
• Left ventricular hypertrophy
• Impaired cognitive functioning
• Coagulopathy
• Hypertension, leading to:
  • Cardiovascular disease
  • Heart failure
• Calcium phosphate loading can cause
  • Cardiovascular disease
  • Soft tissue calcification
• Bone changes secondary to hyperparathyroidism
  • Bone pain
  • Fractures
• Uraemic encephelopathy
• Fluid overload
  • Pulmonary oedema
  • Worsens hypertension
• Malnutrition and weight loss
• Low protein
• Glucose intolerance

CKD and T2DM

• Those with both CKD and T2DM are more than twice as likely to have hypoglycaemic episodes
• The lower the eGFR the more likely the patient is to have hypoglycaemia
• Many medications used in the treatment of diabetes require dose reductions or cannot be used in patients with low eGFR – e.g.:
  • Metformin should be reduced when eGFR 30-60 and is contraindicated when eGFR <30
  • SGLT2 inhibitors require dose reduction
  • DPP-4 inhibitors – sitagliptin requires dose reduction, linagliptin does not
  • Sulphonylureas require dose adjustment when eGFR <30
  • GLP1 receptor antagonists – e.g. injectable agents Byetta and Trulicity – contraindicated when eGFR <30
  • Insulin does not require specific dose adjustment but be aware of the increased risks of hypoglycaemia

CKD and Hypertension

• Maintain BP <130/80 for all patients
• Lower BP may have improved outcomes – especially for those at high risk of cardiovascular disease
• ACE-inhibitors and ARB are first line
  • ACE-inhibitor (or ARB) + calcium channel blocker is likely the most effective combination are reducing cardiovascular disease risk
  • ACE-inhibitors cause a reduction in glomerular blood-flow, and there may be a decline in eGFR when ACE-inhibitors are started. If this is <25% reduction, no further action is required. If it is >25% cease the medication and refer to a renal physician
  • Avoid thiazide diuretics if eGFR <45
  • Beta-blockers can also be considered
• Be wary of the risk of hyperkalaemia – especially if diuretics are used in combination with an ACE
  • Cease ACE, ARB and spironolactone in patients with a K+ >6

CKD and medications

• Many drugs require reduced doses once eGFR <60, and some are contraindicated, especially once eGFR <30

CKD and AKI

Preventing AKI is an important part of the management of CKD. In particular, avoiding medications that are known to precipitate AKI or worsen renal function is very important during an acute illness or acute episode of dehydration. Medications that should be a voided can be remembered with the SAD-MANS mnemonic:

• S – Sulphonylurea
• A – Ace-inhibiotrs
• D – Diuretics
• M – Metformin
• A – ARBs
• N – NSAIDs
• S – SGLT2 inhibitors

Managing fluid and electrolytes

• Patients with CKD typically produce normal amounts of urine until the very end stages. Fluid restriction is only required in end stage disease. In fluid restriction, recommended intake is:
  • Urine output PLUS 500mls
• Avoid binge drinking
• Be vigilant to replace losses through sweat – e.g. hot weather
• Dietary restriction of sodium and potassium is sensible but best achieved with good dietary advice (involve dietician)
• Loop diuretics can be helpful to improve sodium balance and hypertension
• Hyperkalaemia
  • If >7 mmol/L – requires dialysis
  • If <7 mmol/L, try to treat the cause. Often dietary; too much:
    • Fruit
    • Chocolate
    • Coffee
  • Also consider GI bleed and ACE inhibitors as causes
• Acidosis
  • This is a common complication in end stage disease and is due to bicarbonate loss
  • Consider oral bicarbonate supplementation
  • It can exacerbate hyperkalaemia, calcium loss from bone, and inhibits protein synthesis – aggravating low protein levels
• Neurological side effects
  • Thought to be a consequence of build of of some toxins
  • Symptoms often alleviated by dialysis
  • Symptoms include:
    • Restless leg syndrome
    • Peripheral neuropathy
    • Sleep disorders
    • Cognitive impairment

References

• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.
• Chronic Kidney Disease – patient.info

Chronic Kidney Disease (CKD) – Health Pathways

Read more about our sources

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