Chronic Kidney Disease (CKD)

Introduction

Chronic kidney disease (CKD) is defined as abnormal kidney function or structure present for greater than three months, with subsequent implications for health.¹

CKD is a common condition estimated to affect about nine to thirteen per cent of the adult population worldwide.²

Aetiology

Causes of CKD

The most common causes of CKD in adults are diabetes and vascular disease.³

Other causes of CKD include:³

• Glomerular disease: such as IgA nephropathy, membranous nephropathy, focal segmental glomerulosclerosis
• Nephrotoxic drugs: aminoglycosides, bisphosphonates, calcineurin inhibitors (such as ciclosporin or tacrolimus), lithium, proton pump inhibitors, mesalazine and NSAIDs
• Obstructive uropathy or reflux nephropathy: structural renal tract disease, neurogenic bladder, benign prostatic hypertrophy, urinary diversion surgery, recurrent urinary tract calculi, or pathology outside the urinary tract such as malignancy or retroperitoneal fibrosis
• Multisystem diseases with renal involvement: systemic lupus erythematosus, vasculitis, myeloma, hepatitis B, hepatitis C, HIV
• Hereditary kidney disease: polycystic kidney disease, Alport syndrome

Pathophysiology⁴

Chronic kidney disease is the end-stage for any cause of severe and/or long-standing kidney injury. Regardless of the cause, once half the nephrons are damaged CKD will progress. 

Damage to the kidneys reduces the number of functioning nephrons, which leads to several adaptations. There is hyperfiltration at the glomeruli, and the increased glomerular permeability contributes to the development of proteinuria.

Another adaptation is the activation of the renin-angiotensin-aldosterone system causing an increase in blood pressure, which furthers the hyperfiltration at the glomerular level. Other adaptations include the release of cytokines and growth factors. 

The increase in capillary pressure within the glomerulus and inflammatory mediators cause chronic inflammation. This reduces the filtration ability of the glomerulus, which manifests as a reduced glomerular filtration rate (eGFR). This can lead to systemic complications, which are discussed later in this article.

Classification of CKD

CKD is classified by eGFR and amount of proteinuria. The prognosis of CKD is colour-coded as shown in Figure 1. Green represents “low risk”, yellow represents “moderate risk”, orange represents “high risk” and red represents “very high risk”. 

Risk factors

Risk factors for chronic kidney disease include:

• Age greater than 50 years
• History of acute kidney injury
• History of childhood kidney disease
• Family history of CKD stage 5
• Diabetes mellitus
• Cardiovascular disease
• Obesity with metabolic syndrome
• Gout
• Solitary functioning kidney
• Smoking
• Black or Hispanic ethnicity
• Male gender

Clinical features

History

CKD is primarily asymptomatic, and symptoms usually only start developing when it is advanced (stages 4-5).³

CKD is usually detected through the presence of hypertension, haematuria and/or proteinuria upon urinalysis, or a reduction in GFR with increased serum creatinine.⁶

In advanced CKD, typical symptoms may include:^3,6

• General symptoms: such as fatigue, nausea and vomiting, cramps, insomnia, restless legs, taste disturbance, bone pain, and pruritus
• Abnormal urine output: such as polyuria, oliguria, or nocturia
• Fluid overload: may present as dyspnoea and orthopnoea
• Sexual dysfunction
• Severe uraemia may also cause hiccups, pericarditis, coma and seizures

Clinical examination

Typical clinical findings in CKD may include:^3,6

• Uraemic fetor: ammonia-like smell of the breath
• Pallor: due to anaemia
• Cachexia
• Cognitive impairment: specifically affecting language, orientation and attention
• Tachypnoea: may be due to fluid overload, anaemia
• Hypertension
• Volume disturbance: volume overload (e.g. peripheral oedema, pulmonary oedema, pleural effusions, ascites) or volume depletion
• Peripheral neuropathy
• Fundoscopy may reveal microvascular damage in patients with diabetes or hypertension

There may be specific clinical findings depending on the underlying cause of CKD:

• Bilateral masses upon palpation of flanks, suggestive of adult polycystic kidney disease. May be accompanied by hepatomegaly due to liver cysts.
• Palpable bladder: may suggest obstructive uropathy, often accompanied by prostatic enlargement in men

Differential diagnoses

Differential diagnoses to consider in the context of suspected CKD include:

• Acute kidney injury: the presence of chronic symptoms of fatigue, weight loss, anorexia, nocturia and pruritus suggest a diagnosis of CKD over AKI
• Acute on chronic kidney disease: where patients with features of CKD experience an acute further deterioration in their renal function, often following a precipitant such as infection or diarrhoea

Investigations

Bedside investigations

Relevant bedside investigations include:³

• Blood pressure: hypertension is common in patients with CKD
• Urinalysis: may reveal haematuria and/or proteinuria, particularly in glomerular disease
• Plasma glucose: to detect undiagnosed diabetes or assess control of diabetes
• ECG: particularly to assess for evidence of left ventricular hypertrophy or ischaemia

Laboratory investigations

Relevant laboratory investigations include:^3,7

• Full blood count: may reveal normochromic normocytic anaemia due to erythropoietin deficiency or functional iron deficiency
• Urea and electrolytes: reveal an elevated serum creatinine and reduced eGFR; electrolyte abnormalities may also be present (e.g. raised potassium, low bicarbonate)
• Serum albumin: hypoalbuminaemia in patients who are nephrotic and/or malnourished
• Urinary albumin (albumin to creatinine ratio): may be increased
• Serum calcium: may be low, normal, or high
• Serum phosphate: often elevated
• Serum PTH: rises as GFR falls (secondary and tertiary hyperparathyroidism)
• Serum alkaline phosphatase: may be raised when in the presence of hyperparathyroidism
• Cholesterol and triglycerides: hyperlipidaemia is common

Other specific laboratory investigations may be required depending on the suspected cause of CKD:

• Serum protein electrophoresis and free light chain measurement: for evidence of a monoclonal gammopathy such as multiple myeloma, primary amyloidosis
• Serology: autoantibodies such as ANCA (anti-neutrophil cytoplasmic antibodies, specifically proteinase 3 or myeloperoxidase) anti-nuclear antibodies (ANA) and serum complement (C3 and C4) when secondary glomerular disease is suspected
• Hepatitis B and C and HIV serology: if suspected as a cause of CKD or if a patient requires dialysis

Imaging

Relevant imaging investigations include:³

• Plain abdominal radiograph: may reveal radio-opaque stones or nephrocalcinosis
• Renal ultrasound: may reveal structural abnormalities (e.g. polycystic kidneys), hydronephrosis, infiltrative disease, loss of cortex, increased echogenicity, and reduction in kidney size (advanced CKD often leads to small, echogenic kidneys)
• CT or MRI scan: may be used to define renal masses and cysts or for further evaluation if obstructive uropathy suspected

Diagnosis

A diagnosis of CKD requires evidence of kidney damage and/or a persistent reduction in renal function.

CKD stages 3 – 5 can be diagnosed based on GFR alone (<60 mL/min/1.73m²).

CKD stages 1 – 2 require additional evidence of renal disease such as:²

• Proteinuria
• Urine sediment abnormalities: particularly red blood cells or casts, or white blood cells
• Electrolyte abnormalities due to tubular dysfunction
• Structural abnormalities
• Histological abnormalities
• History of kidney transplantation

Management

General management

General measures for the management of CKD include:^3,8

• Exercise
• Healthy weight loss
• Smoking cessation
• Good glycaemic control
• Control of blood pressure
• Immunisations: influenza and Pneumococcus
• Avoidance of nephrotoxic medication
• Diet: adequate protein intake, restricted sodium and phosphate intake

Patients should be assessed for cardiovascular risk factors (lipid profile, BMI, exercise, and alcohol and smoking consumption) and offered a statin and antiplatelet drug for the prevention of cardiovascular disease.^3,8

Good blood pressure control is vital in slowing the progression of CKD. In patients with diabetic renal disease or significant proteinuria, an ACE inhibitor or an angiotensin receptor blocker are the first agents of choice, but conversely, they need to be used with care in patients with renovascular disease or those who are at risk of volume depletion or impaired renal perfusion.⁸

An SGLT-2 inhibitor may be offered if the patient is taking the highest dose of ACE inhibitor or angiotensin receptor blocker that they can tolerate.⁹

Dietary phosphate restriction and phosphate binders (e.g. calcium acetate, sevelamer, lanthanum) to control hyperphosphataemia.³

1-alpha-hydroxycholecalciferol is administered if secondary hyperparathyroidism is present.

Monitoring

Monitoring requirements include a full blood count and iron studies (for anaemia), serum calcium, phosphate, and parathyroid hormone level (for renal bone disease).⁸

Risk level, determined by eGFR and albuminuria, guides the frequency of monitoring:⁵

• Low-moderate risk: monitor annually
• High risk: monitor every 6 months
• Very high risk: monitor every 3-4 months

Renal replacement therapy

Renal replacement therapy is an important aspect of the treatment of end-stage CKD. This includes dialysis (either haemodialysis or peritoneal dialysis) and kidney transplantation.

Generally, patients begin dialysis when their GFR reaches approximately 5-10 mL/min/1.73m.^2,5

Some patients, particularly those who are elderly or have significant comorbidities, opt for conservative management (best supportive care) rather than renal replacement therapy.

Haemodialysis

Haemodialysis involves pumping blood from the patient’s body through a dialyser (artificial kidney). Solutes from the blood diffuse into the dialysate and are removed together with fluid. This can be performed in a hospital or at home. Hospital-based regimens are typically for 4 hours three times a week.¹⁰

Good blood flow through the dialysis circuit is required, and patients require either an arterio-venous fistula (which typically takes 6-8 weeks to become usable after formation) or a tunnelled central venous catheter.¹⁰ A fistula is the preferred option due to the higher rate of complications with lines (particularly infection).

Complications of haemodialysis include:¹⁰

• Access-related: infection (including bacteraemia leading to endocarditis, discitis), venous stenosis, access failure
• Haemodynamic instability
• Nausea and vomiting, headache, cramps
• Reactions to dialysis membranes

Peritoneal dialysis

Peritoneal dialysis involves infusing dialysate into the peritoneal cavity through a tunnelled catheter. Solutes and fluid from the peritoneal vessels move across the peritoneal membrane into the dialysate and are removed.¹⁰

This requires a functional peritoneal membrane, so patients may not be suitable if they have had previous intra-abdominal pathology (e.g. previous peritonitis, surgery, adhesions).

The two typical regimens, which may be combined:¹¹

• Continuous ambulatory peritoneal dialysis: manual dialysate exchanges are typically performed four times per day
• Automated dialysis: a machine performs exchanges overnight

Complications of peritoneal dialysis include:¹⁰

• Bacterial or fungal peritonitis
• Catheter problems: infection, blockage, kinking, leaks, displacement (more likely if a patient becomes constipated)
• Weight gain
• Worsening glycaemic control in patients with diabetes
• Failure of peritoneal membrane requiring a switch to haemodialysis
• Encapsulating peritoneal sclerosis

Transplantation

Transplantation provides the best long-term outcome for a patient with CKD and has numerous benefits as it obviates the need for dialysis, can ameliorate anaemia and renal bone disease and improves quality of life and long-term survival.¹⁰

Kidneys may be obtained either from cadaveric donors (heart beating or non-heart-beating) or live donors (genetically related or unrelated).

The patient’s native kidneys are normally left in situ, and the donor kidney is placed in the iliac fossa. Patients receive induction and maintenance immunosuppression to prevent graft rejection.¹⁰

Contraindications to transplantation include active or recent malignancy, active infection, or significant comorbidity (e.g. ischaemic heart disease).¹⁰

Complications

The complications of CKD can be related to the functions of the kidney. The mnemonic ‘A WET BED‘ is a useful way to recall the functions of the kidney and associated complications of CKD.

Table 1. A WET BED: the functions of the kidney and associated complications of CKD

Prognosis¹⁴

CKD is a long-term condition and may progress to end-stage renal disease. It cannot be cured, but many aspects can be managed as outlined above. CKD is a strong risk factor for vascular disease, which is often the cause of death in patients with CKD.

Key points

• CKD is defined as abnormal kidney function or structure present for greater than three months
• The commonest causes in the adult population are diabetes and vascular disease
• CKD is often asymptomatic and is usually picked up through the presence of haematuria or proteinuria upon urinalysis, or a reduced eGFR
• It is usually managed symptomatically, through lifestyle modifications, and management of hypertension and other cardiovascular risk factors
• Complications can include fluid, anaemia, bone-mineral disorder, and increased cardiovascular risk
• In advanced disease, the options include renal replacement therapy (haemodialysis, peritoneal dialysis, renal transplantation) or conservative management

Reviewer

Dr Mahzuz Karim

Consultant nephrologist

Norfolk and Norwich University Hospital

Editor

Dr Chris Jefferies

References

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5. Wilkinson I, Raine T, Wiles K, Goodhart A, Hall C, O’Neill H. Oxford handbook of clinical medicine. 10th ed. Oxford University Press; 2017.
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7. Singh, M. and Krause, M. Chronic Kidney Disease. Investigations. 2021. Available from: [LINK]
8. NICE CKS. Management of chronic kidney disease. 2021 [cited 15 January 2022]. Available from: [LINK]
9. NICE Guideline. Chronic kidney disease: assessment and management. 2021 [cited 22 February 2022]. Available from: [LINK]
10. Rull G, Bonsall A. Renal Replacement Therapy and Transplantation. 2016. Available from: [LINK]
11. National Institute of Diabetes and Digestive and Kidney Diseases. Peritoneal Dialysis. 2022. Available from: [LINK]
12. Bruce Blaus. Kidney Transplant. 2015. License: [CC BY-SA]
13. Singh, M. and Krause, M. Chronic Kidney Disease. Complications. 2021. Available from: [LINK]
14. Singh, M. and Krause, M. Chronic Kidney Disease. Prognosis. 2021. Available from: [LINK]