CKD - the basics (for health professionals) - Chronic Kidney Disease Explained

CKD – the basics (for health professionals)

This article is largely written for health professionals. We will now go through the basics of CKD and its management.

Definition

An estimated or measured glomerular filtration rate (GFR) of <60 mL/min – that is present for at least three months with or without evidence of kidney damage; or,
Evidence of kidney damage with or without decreased GFR – that is present for at least three months, as evidenced by: albuminuria (protein in urine), haematuria (blood in urine, after exclusion of urological causes), structural abnormalities (e.g. on renal ultrasound) or pathological abnormalities (e.g. on kidney biopsy).

Note. In other words, there are some milder cases of CKD there is evidence of kidney damage but normal renal function (normal GFR/creatinine; see below).

When considering CKD, it is important to consider the whole of the urinary tract, and the heart. The kidneys receive 20% of cardiac output.

Mild forms of CKD exist in 10% of the population. However, 1 in 100 patients progress towards end-stage renal disease (ESRD).

The inability of the kidneys to carry out their normal function leads to fluid overload (and a brittle fluid state), disturbance in acid-base balance and bone biochemistry, and electrolyte abnormalities (including hyperkalaemia).

Classification of CKD (CKD stage/eGFR classification)

The diagnosis of CKD is based on a classification of its severity, based on eGFR (estimated glomerular filtration rate) – the higher the eGFR, the better. Normal eGFR in humans is 90-120 mls/min. The eGFR is proportional to reciprocal of serum creatinine (normal range 60-120 mcmol/L); i.e. the lower the creatinine, the higher is the GFR, the better.

The CKD classification has 5 grades. See the diagram above.

CKD1+2: risk factors for CKD (eGFR 60-120 mls/min; with evidence of kidney damage) – no symptoms
CKD3: mild CKD (eGFR 30-59 mls/min) – no or very mild symptoms
CKD4: moderate CKD (eGFR 15-29 mls/min) – moderate symptoms
CKD5: severe CKD (kidney failure; eGFR < 15 mls/min) – severe symptoms (require dialysis or a transplant).

– CKD3B is worse than CKD3A.
– CKD4 means the patient may require dialysis or a kidney transplant one day.
– CKD5 means the patient may require dialysis, or a kidney transplant, or supportive care (no dialysis).

Note. CKD is different from Acute Kidney Injury (AKI), which is rapid onset kidney failure with different causes and treatments. This comes on over hours or days. It is not the focus of this article.

GFR, urinary albumin:creatinine ratio (uACR) and prognosis

CKD is further classified based on eGFR and the level of proteinuria. This helps to risk stratify patients, with the worse prognosis based on a lower eGFR, and a higher level of proteinuria (uACR)

Patients are classified as ‘G1-G5’, based on the eGFR, and ‘A1-A3’ based on the uACR as detailed below:

The higher the stage of CKD, the more frequent monitoring patients require. This helps to identify and manage complications, and plan for renal replacement therapy (RRT; ie. dialysis and/or transplantation). The higher the ACR and lower the eGFR, the more at risk a patient is of adverse outcomes, which include CKD progression, acute-on-chronic kidney injury, all-cause mortality, and cardiovascular events.

Causes

CKD is not a diagnosis. It is a syndrome with causes. You should ascertain the underlying pathology (cause) as this guides treatment.

There are 7 groups of causes:

Unknown (often with small kidneys). This is the ‘cause’ in 30% of patients
Diabetes (mainly type 2). This is the cause in 20% of patients, i.e. the second commonest
Renovascular disease. This mainly occurs in older people who are smokers or ex-smokers; and/or people with congestive heart failure as well. It is then called ‘cardiorenal syndrome’
Obstructive nephropathy. This means a blockage in the drainage system of the kidneys – i.e. ureters, bladder, or prostate (in men) – usually due to prostatic disease in a men, or cancer in the pelvis in women. Kidney stones can cause this, but are not a common cause (unless you have one kidney)
Glomerulonephritis / vasculitis. These are ‘autoimmune’ (of which there are 7 types). This means the body’s immune system (normally its defender) attacks the small blood vessels within the kidneys
Tubulointerstitial disease. 3 subgroups: autoimmune, drugs and infection (e.g. reflux nephropathy). The drug causes include non-steroidal anti-inflammatory drugs (NSAIDs; if they are used long-term, especially at high doses), lithium, ciclosporin and tacrolimus
Polycystic kidney disease. This is the only common familial (inherited) cause.

Notes. Simple primary (essential) high blood pressure and simple recurrent urinary tract infections (UTIs) do not cause CKD. You should find another cause in such a CKD patient with simple high BP or UTIs.

The causes of CKD in children and young adults are different.

Ageing and the kidney

Approximately 1 million nephrons are present in each kidney from birth. These nephrons contribute to the kidneys ability to maintain adequate glomerular filtration and allows the kidney to perform its normal functions (e.g. volume regulation, acid-base balance).

As we age there is a progressive loss in renal mass and a number of structural changes occur (e.g. glomerulosclerosis) leading to a decline in renal function. Many doctors think following a peak at the end of the third decade of life, there is an estimated annual decline of 1 mL/min/year in eGFR (though this ‘fact’ is controversial).

Clinical features

Patients are generally asymptomatic with mild-moderate CKD, but start to develop non-specific symptoms at more advanced stages (e.g. CKD4 with eGFR < 30ml/min).

It is always important to look for evidence of an underlying cause of CKD (e.g. large bilateral abdominal masses could be suggestive of PCKD; a bladder suggestive of obstructive nephropathy; or epigastric or femoral bruits suggestive of renovascular disease) .

Symptoms

Frequently asymptomatic in early stages
Anorexia and nausea
Fatigue and weakness
Shortness of breath
Oedema
Muscle cramps
Other: pruritus, pain, poor sleep and concentration, restless legs.

Signs

Pallor (secondary to anaemia)
Hypertension
Fluid overload
Rashes (vasculitis)
Excoriation marks
Peripheral neuropathy.

In severe renal impairment, patients may develop high urea levels that can lead to number of manifestations. These include uraemic encephalopathy (i.e. seizures, confusion, low consciousness), pericarditis (e.g. pericardial effusion and clinical rub on auscultation), and defective platelet function (causes bruising), amongst others.

Investigation

Investigations are used to help diagnose, monitor and assess for complications of CKD.

Urine

Urine dipstick: heavy proteinuria is suggestive of glomerular disease
Urine microscopy – casts
Urinary albumin:creatinine ratio (uACR)

Note. uACR is used instead of a urinary protein:creatinine ratio (uPCR) because of its greater sensitivity at a lower level of proteinuria.

Bloods

FBC
U&E (+ eGFR)
Glucose
Bone biochemistry
Bicarbonate
LFTs
Lipid profile.

Renal screen

Anti-nuclear antibody (ANA) – Systemic Lupus Erythematosus (SLE)
Anti-neutrophil cytoplasmic antibody (ANCA; with PR3 and MPO) – vasculitis
Anti-glomerular basement membrane (anti-GBM) antibody – Goodpasture’s Disease
Anti phospholipase A2 receptor (PLA2R) antibody – primary membranous nephropathy
Complement C3/4 – low in SLE
Double-stranded DNA (DsDNA) – SLE
Serum electrophoresis – paraprotein suggestive of myeloma (and other blood disorders)
Immunoglobulins (IgG, A and M) – e.g. IgA high in IgA nephropathy
Serum free light chains (SFL) – myeloma (and other dysproteinaemias)
Hep B/C, HIV – viral associated GNs (membranous GN with Hep B, mesangiocapillary GN with Hep C, FSGS with HIV).

Imaging

Renal ultrasound (US) – all patients with CKD3B or worse should have an US (and some patients with CKD1-3A)
Nuclear medicine scans, or CT or MR angiography – in a few patients. Renal angiograms are now rarely performed.

A renal ultrasound scan should also be offered to patients with visible or persistent non-visible haematuria or family history of PCKD.

Special

Renal biopsy is required to identify intrinsic (renal) causes of CKD, especially glomerulonephritis and tubulo-interstitial nephritis.

Note. Those with evidence of macrohaematuria in the absence of infection (and no obvious GN) should be investigated initially (and rapidly) by a urologist for urinary tract malignancy.

GFR/creatinine and uACR monitoring

This is highly variable depending on the level of GFR and rate of decline.

CKD1-2. Risk factors for CKD. Creatinine – normal (< 120 mcml/L)

eGFR/creatinine should be measured every 12 months

CKD3A. Mild CKD. Creatinine – normal or <150 mcmol/L

eGFR/creatinine every 6 months

CKD3B. Mild CKD (but worse than CKD3A). Creatinine usually 150-200 mcmol/L

eGFR/creatinine every 4-6 months
Urinary ACR (uACR) – if monitoring the protein level in the urine is important in your disease – every 6 months

CKD4. Moderate CKD. Creatinine usually 200-400 mcmol/L

eGFR/creatinine every 2-4 months
Urinary ACR, if needed, every 4 months

CKD5. Severe CKD (approaching dialysis). Creatinine >400 mcmol/L

eGFR/creatinine every 1-2 months

This is only rough guidance from NICE on the minimum amount of monitoring for patients with CKD. Some patients at high risk of progression or adverse outcomes (e.g. rapidly deteriorating renal function) may need their kidney function checked more frequently.

Note. When on dialysis, and when stable, the frequency of monitoring can go down, to every 6 months.

Management and treatment

The principles of CKD management are to treat the underlying cause, prevent or slow progression (e.g. renoprotective therapy), treat associated complications and plan for RRT.

Renoprotective therapy
Renoprotective therapy is aimed at slowing the progression of CKD, independent of the aetiology. It is centered around tight blood pressure control and reducing proteinuria.

A standard BP target of <140/90 mmHg or below, should be aimed for in patients with CKD. This is broadly in line with the NICE guidelines on hypertension. However, in patients with diabetes, or if the ACR is > 70 mg/mmol then a tighter blood pressure control may be targeted (< 130/80 mmHg).

In adults with CKD, hypertension and an ACR ≤ 30 mg/mmol, the advice on choice of anti-hypertensive should be line with the NICE guidelines on hypertension. In patients with more significant proteinuria, the ideal blood pressure agent is an ACE inhibitor or angiotensin receptor blocker (ARB; both renin-angiotensin system antagonists). These drugs are both antihypertensive and antiproteinuric.

Note. Do not routinely offer a renin-angiotensin system antagonist in CKD if the pre-treatment potassium is > 5 mmol/L.

Sodium–glucose cotransporter 2 inhibitors (SGLT2is)
SGLT2is (e.g. dapagliflozin) are commonly used hypoglycaemic agents for patients with type 2 diabetes mellitus. These medications block SGLT2 receptors expressed on the proximal convoluted tubules of nephrons. In doing so, it prevents reabsorption of filtered glucose (i.e. its antidiabetic effect).

However, inhibition has added benefits on renal haemodynamics including decreasing renal intraglomerular pressure and inhibiting the renin-angiotensin-aldosterone system. This means it can have beneficial effects for patients with chronic kidney disease and heart failure, as well as diabetes.

Dapagliflozin is now recommended in patients with CKD as an add on to patients who take an optimised dose of an ACE/ARB (unless contraindicated) and have:

eGFR >25 and <60 ml/min, AND
Type 2 diabetes mellitus, OR
Urinary ACR ≥ 25 mg/mmol.

It is a complicated area. These two papers may help you:

Other therapies

HMG-CoA reductase inhibitors (statin therapy): prescribed in line with NICE recommendations
Smoking cessation
Antiplatelets for secondary prevention of CVS disease.

Specific treatments

In obstructive nephropathy, a urinary catheter +/- nephrostomies may be required
In unusual cases, suppression of the immune system is necessary using immunosuppression such as prednisolone, cyclophosphamide, ciclosporin/mycophenolate, and rituximab. A nephrologist will decide if these are required.

Complications

A number of important complications develop as a consequence of CKD, which include anaemia, hyperkalaemia, mineral and bone disorders, fluid overload and acidosis.

Anaemia
A normocytic normochromic anaemia is typical of CKD. This anaemia is normally multifactorial. A significant factor in advanced disease is a reduction in the production of erythropoietin (EPO), the hormone that drives erythropoiesis.

It is still important to assess patients for other potential causes of anaemia (e.g. iron-deficiency, folate deficiency), which can subsequently be corrected. The mainstay of tretament for anaemia in CKD is an erythropoietin-stimulating agent (ESA) such as Darbepoetin alfa (e.g. Aranesp), or a hypoxia-inducible factor–prolyl hydroxylase (HIF-PH) inhibitor, like Roxadustat (given as a tablet three times a week).

When the haemoglobin (‘HB’; marker of anaemia) falls below 100 g/L, EPO should be considered. The target haemoglobin is 110-120 g/L in men and women.

In order for EPO therapy to be effective, patients need to have adequate stores of iron that should be regularly checked and replaced. In fact, initiation of EPO is not recommended until iron-deficiency has been managed.

Blood transfusions should be avoided where possible in patients who are being considered for renal transplantation. This is because of the risk of sensitisation (i.e. development of antibodies) to human leucocyte antigens (HLA).

The target haemoglobin concentration in patients with CKD-associated anaemia is 100-120 g/L.

Hyperkalaemia
The ability of the kidneys to maintain adequate acid-base homeostasis and electrolyte balance diminishes with worsening renal function. Many medications, including NSAIDs and potassium-sparing diuretics, may worsen hyperkalaemia. Furthermore, uncontrolled metabolic acidosis may also worsen potassium handling.

Acute rises in potassium should be managed as a medical emergency. This involves stabilisation of the myocardium (with calcium gluconate) and driving potassium into the intracellular compartment (with insulin/dextrose). Chronic elevations in serum potassium can be managed with low potassium diets, potassium-binding resins and correction of acidosis. Dialysis may eventually be required.

Renal bone disease (RBD) or renal osteodystrophy
In CKD, disorders of mineral and bone metabolism reflect a complex spectrum of pathology that results from abnormal calcium and phosphate handling. In health, the kidneys have an important role in the maintenance of calcium homeostasis. They are able to activate vitamin D (calcitriol), a fat-soluble vitamin important for absorption of calcium from the gastrointestinal tract. They are also involved in the reabsorption of calcium and excretion of phosphate.

In disease, reduced kidney function (usually associated with CKD or worse, and a GFR < 30ml/min) leads to hypocalcaemia, hyperphosphataemia and hyperparathyroidism (secondary hyperparathyroidism). These biochemical abnormalities may then lead to bone pathology (e.g. adynamic bone disease, osteomalacia, osteoporosis and osteitis fibrosa cystica). The term ‘renal osteodystrophy’ is used to describe this type of bone pathology seen in CKD.

The treatment of RBD requires management of the underlying biochemical abnormalities:

Hypocalcaemia: phosphate binder (e.g. calcium acetate) and vitamin D (e.g. alfacalcidol)
Hyperphosphataemia: dietary phosphate restriction and calcium acetate
Hyperparathyroidism: calcimimetics (e.g. cinacalcet) or surgery (parathyroidectomy).

Fluid overload
In the presence of significantly reduced GFR, the kidneys are unable to adequately controlled fluid volume. This leads to hypervolaemia and patients may have oedema (ankle, sacral, pulmonary), ascites, raised JVP, gallop rhythm and bilateral pleural effusions.

Note. Heavily nephrotic patients usually have pleural effusions (and sometimes peri-orbital oedema) rather than pulmonary oedema.

Fluid overload can be managed with a combination of fluid restriction, reduced sodium intake and the use of oral diuretics (e.g. furosemide). Dialysis may eventually be required.

Acidosis
Patients with CKD retain hydrogen ions because of abnormalities in their acid-base homeostasis. Acidosis may also exacerbate hyperkalaemia, further compounding the metabolic abnormalities seen in CKD.

Acidosis is characterised by a low pH and low bicarbonate levels. Oral sodium bicarbonate therapy should be considered in patients with an eGFR < 30 ml/min (CKD4 or worse), and bicarbonate level < 20 mmol/L.

Indications for dialysis

If the following complications of CKD occur, and are refractory to medical therapy, dialysis is required:

Absolute indications

Hyperkalaemia
Fluid overload.

Relative indications

Metabolic acidosis
Uraemic complications (e.g. encephalopathy, bleeding, pericarditis).

Renal replacement therapy (RRT)

Haemodialysis, peritoneal dialysis and renal transplant are the 3 forms of RRT that are indicated for ESRD.

Haemodialysis
Haemodialysis involves the removal of waste products and other substances by passing blood through a dialysis machine. Blood comes into contact with a semi-permeable membrane, which contains the dialysate on the other side. Substances may then diffuse between the two fluids (blood and dialysate).

Haemodialysis requires intravenous access in the form of an arteriovenous fistula (or graft) or tunnelled line. Patients usually have haemodialysis for 3-5 hours, 2-3 times a week.

Peritoneal dialysis
Peritoneal dialysis is achieved by using the peritoneal cavity as the primary site of ultrafiltration. A catheter (e.g. Tenckhoff catheter) is inserted into the abdominal cavity, which allows the infusion of the dialysate (usually a glucose solution).

The dialysate then dwells within the abdomen using the peritoneum as a semi-permeable membrane for the transfer of waste products. The dialysate can then be removed after a certain amount of time and the procedure repeated.

Peritoneal dialysis can be achieved by continuous ambulatory peritoneal dialysis (CAPD) where 4 exchanges (of 2 litres of dialysate) are made manually each day; or by automated peritoneal dialysis (APD) where 8-10 litres are exchanged overnight (10-12 hours) by a machine, when the patient sleeps.

Renal transplant
Renal transplant is considered the gold-standard for many patients with ESRD. Transplantation may be from living donors or non-living donors. It is now possible to transplant across the ABO (blood group) and HLA barriers. Non-living donors include donors after cardiac death (DCD) and donors after brain death (DBD).

Renal transplantation requires the use of long-term immunosuppressive therapy to stop the recipient’s immune system from ‘attacking’ the donor tissue.

Despite the overt success of transplantation, it can be associated with a number of complications including graft rejection, complications from immunosuppressive agents (e.g. malignancy, infection) and disease recurrence.

Kidneys from deceased and living donors last about 10 and 15 years respectively. Hence younger patients may require more than one transplant in their lives.

Summary

We have described CKD – the basics (for health professionals). We hope you have found it helpful.

https://www.youtube.com/watch?app=desktop&v=vZBDHh3gzus

Last Reviewed on 5 April 2024